Clinical trial NCT03015961
Conditions: Postoperative Pain Management
Sponsor: Pacira Pharmaceuticals, Inc
Start date: 2017-02-21; Completion date: 2017-10-30
Enrollment: 38 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Primary Objective: The primary objective of this study is to compare postsurgical pain control following local infiltration analgesia (LIA) with EXPAREL admixed with bupivacaine HCl versus LIA with bupivacaine HCl in adult subjects undergoing open lumbar posterior spinal fusion surgery.

Secondary Objectives: The secondary objectives of this study are to compare additional efficacy, safety, and health economic outcomes following LIA with EXPAREL admixed with bupivacaine HCl versus LIA with bupivacaine HCl in adult subjects undergoing open lumbar posterior spinal fusion surgery.

Detailed description:
This is a Phase 4, multicenter, randomized, double-blind, controlled study in 38 adult subjects undergoing primary, 1-2 level, open lumbar spinal fusion surgery under general anesthesia.

Subjects will be screened within 30 days prior to study drug administration and at least one day prior to surgery. During the screening visit, subjects will be assessed for past or present neurologic, cardiac, and general medical conditions that in the opinion of the Investigator would preclude them from study participation. After the informed consent form (ICF) is signed, a medical history, surgical history, physical examination, 12-lead electrocardiogram (ECG), vital sign measurements, select clinical laboratory evaluations, urine drug screen, alcohol breath test, and urine pregnancy test for women of childbearing potential will be conducted. Study drug, approximately 1-2 mL every 1.0-1.5 cm, will be administered using 20- or 22-gauge needles prior to wound closure.

Administration Instructions/Procedures

Study drug should be injected in the prescribed locations based on the areas of highest nerve density. Study drug will be administered using syringes with 20- or 22-gauge needles prior to wound closure. The Investigator must document the size of the incision. Each infiltration site should be spaced 1.0-1.5 cm apart and should deliver approximately 1-2 mL into both deep and superficial areas (para-spinous fascia, muscle, and subcutaneous layers). Total volume administered will be depended on the number of levels of dissection, as described below. Following infiltration, the tissue should visibly expand with minimal leakage.

Total Volume of Expansion

The Investigator must document the total volume used for each surgery.

1. Level Procedures Group 1: EXPAREL 266 mg in 20 mL + bupivacaine HCl 0.5% in 20 mL + 20 mL normal saline = total volume of 60 mL Group 2: Bupivacaine HCl 0.5% in 20 mL + 40 mL normal saline = total volume of 60 mL
2. Level Procedures Group 1: EXPAREL 266 mg in 20 mL + bupivacaine HCl 0.5% in 20 mL + 50 mL normal saline = total volume of 90 mL Group 2: Bupivacaine HCl 0.5% in 20 mL + 70 mL normal saline = total volume of 90 mL

Drains may be used at the surgeon's discretion. In addition to LIA, all study participants will receive a standardized approach for managing postsurgical pain that includes a scheduled multimodal pain regimen including adjunctive analgesics, non-steroidal anti-inflammatory drugs (NSAIDs). Rescue analgesics will be available as needed.

Postsurgical clinical assessments will include pain intensity scores using a 10-cm visual analog scale (VAS) (see Appendix 1); overall benefit of analgesia score (OBAS) questionnaire (see Appendix 2); total postsurgical opioid consumption; predefined opioid-related AEs; and nurse's satisfaction with overall analgesia (see Appendix 3).

Adverse events will be recorded from the time the ICF is signed through Day 30. If a cardiac AE (e.g., chest pain \[angina, myocardial infarction\], abnormal/irregular heart rate \[bradycardia, tachycardia, extrasystoles\], or shortness of breath), neurological AE (e.g., altered mental status/altered sensorium, dizziness, dysarthria, hyperesthesia, metallic taste, peroral numbness, seizure, tinnitus, tremors, visual disturbance, muscular twitching or rigidity beyond 72 hours postdose, or tingling/paresthesia beyond 72 hours postdose), or serious AE (SAE) occurs during the study a 12-lead ECG, vital signs, and any appropriate clinical laboratory tests should be conducted.

Postsurgical health economic outcome assessments will include hospital length of stay (LOS), use of skilled nursing facility, hospital readmissions, and use of other health services following discharge (phone calls related to postsurgical pain, unscheduled visits related to postsurgical pain, and visits to emergency department) through Day 30.

A follow-up visit will be scheduled for all subjects on postsurgical Day 14. A follow-up phone call will be made on Day 30 to all subjects who received study drug to assess for adverse events (AEs).

Number of Subjects (Planned):

Approximately 194 subjects are planned for enrollment in this study in order to have at least 184 evaluable subjects.

Arms: arm 1: EXPAREL 266 mg + bupivacaine HCl arm 2: Bupivacaine HCl
Interventions: intervention 1: EXPAREL and bupivacaine HCl intervention 2: Bupivacaine HCl
Intervention descriptions: intervention 1: Drug: EXPAREL EXPAREL and bupivacaine HCl

Other Name: bupivacaine liposome injectable suspension Drug: Bupivacaine Single dose of bupivacaine HCl 0.5%

Other Name: bupivacaine HCl intervention 2: Drug: Bupivacaine Single dose of bupivacaine HCl 0.5%

Other Name: bupivacaine HCl

Protocol documents:
Prot_000.pdf: 
 
CLINICAL STUDY PROTOCOL 
AMENDMENT 2 
A Multicenter, Randomized, Double-Blind, Controlled 
Study of EXPAREL for Postsurgical Pain Management in 
Subjects Undergoing Open Lumbar Spinal Fusion Surgery 
 
Protocol No.: 402-C-409 
EudraCT No.: 
IND No.: 
Not applicable   
69,198 
Study Phase: Phase 4 
Study Drug: EXPAREL® (bupivacaine liposome injectable suspension) 
Date: 02 August 2017 (Amendment 2) 
 21 December 2016 (Version 2.0) 
 17 October 2016 (Version 1.1) 
 31 August 2016 (Version 1.0) 
Study Sites: Multicenter study in the US 
Sponsor: Pacira Pharmaceuticals, Inc. 
5 Sylvan Way 
Parsippany, NJ  07054 
Telephone: (973) 254-3560 
 
 
 
 
 
 
Confidentiality Statement 
The information contained in this document is confidential and the property of Pacira Pharmaceuticals, Inc.  
It should not be reproduced, revealed, or sent to third parties other than Institutional Review Boards/Independent 
Ethics Committees and the Investigator’s research support staff participating in the conduct of the study without 
the prior written authorization of Pacira Pharmaceuticals, Inc. 
 
 
 
  


Pacira Pharmaceuticals, Inc. 
                       402-C-409 (Spinal Fusion) 
EXPAREL® 
Clinical Study Protocol Amendment 2 
 
1. 
SIGNATURE PAGE 
 
 
CONFIDENTIAL 
2 
02 August 2017 


Pacira Pharmaceuticals, Inc. 
                       402-C-409 (Spinal Fusion) 
EXPAREL® 
Clinical Study Protocol Amendment 2 
 
2. 
SYNOPSIS 
Name of Sponsor/Company: 
Pacira Pharmaceuticals, Inc. 
5 Sylvan Way 
Parsippany, NJ  07054 
(973) 254-3560 
Individual Study Table Referring to 
Part of the Dossier 
Volume: 
Page: 
 
(For National Authority 
Use Only) 
Name of Finished Product: 
EXPAREL (bupivacaine liposome injectable 
suspension) 
Name of Active Ingredient: 
Bupivacaine, 1.3%, 13.3 mg/mL 
Title of Study: A Multicenter, Randomized, Double-Blind, Controlled Study of EXPAREL for Postsurgical Pain 
Management in Subjects Undergoing Open Lumbar Spinal Fusion Surgery 
Principal Investigator(s): To be determined 
Study Center(s): Multicenter study in the US and EU  
Publications (Reference): None 
Objectives:  
Primary Objective: The primary objective of this study is to compare postsurgical pain control following local 
infiltration analgesia (LIA) with EXPAREL admixed with bupivacaine HCl versus LIA with bupivacaine HCl in 
adult subjects undergoing open lumbar posterior spinal fusion surgery. 
Secondary Objectives: The secondary objectives of this study are to compare additional efficacy, safety, and health 
economic outcomes following LIA with EXPAREL admixed with bupivacaine HCl versus LIA with bupivacaine 
HCl in adult subjects undergoing open lumbar posterior spinal fusion surgery. 
Methodology:  
This is a Phase 4, multicenter, randomized, double-blind, controlled study in approximately 194 adult subjects 
undergoing primary, 1-2 level, open lumbar spinal fusion surgery under general anesthesia. 
Subjects will be screened within 30 days prior to study drug administration and at least one day prior to surgery.   
If a subject can only be screened on the day of surgery, the consent process must have started prior to the day of 
surgery to give ample time for the subject to review the consent. Screening procedures that are standard of care 
(SOC) at the institution may be completed prior to written informed consent, however any screening procedures 
that are not SOC, must be completed after written informed consent, and prior to surgery.   
During the screening visit, subjects will be assessed for past or present neurologic, cardiac, and general medical 
conditions that in the opinion of the Investigator would preclude them from study participation.  After the informed 
consent form (ICF) is signed, a medical history, surgical history, physical examination, 12-lead electrocardiogram 
(ECG), vital sign measurements, select clinical laboratory evaluations, urine drug screen, alcohol breath test, and 
urine pregnancy test for women of childbearing potential will be conducted. 
On Day 1, all eligible subjects will receive the following medications within 4 hours prior to surgery:  
• 
Acetaminophen 975-1000 mg, orally (PO) 
• 
Celecoxib 200 mg, PO 
o 
If a subject has an allergy to celecoxib, naproxen 500 mg PO twice a day or meloxicam 7.5 mg 
PO once a day may be used. 
• 
Gabapentin (eg, Neurontin®) up to 900 mg PO 
• 
Tranexamic Acid (TXA) 1 gm (PO or IV) may be used at the start of surgery at the physician’s discretion. 
• 
Versed 1-2 mg IV for anxiety may be used pre-operatively per physician discretion 
Subjects will be randomized 1:1 to two treatment groups and stratified by surgery type (1-Level or 2-Level). Screw 
type (pedicle or cortical screws) will be recorded in the CRF.  Subjects in Group 1 will receive LIA with 
EXPAREL admixed with bupivacaine HCl and subjects in Group 2 will receive LIA with bupivacaine HCl.  For 
 
 
CONFIDENTIAL 
3 
02 August 2017 
 


Pacira Pharmaceuticals, Inc. 
                       402-C-409 (Spinal Fusion) 
EXPAREL® 
Clinical Study Protocol Amendment 2 
 
Name of Sponsor/Company: 
Pacira Pharmaceuticals, Inc. 
5 Sylvan Way 
Parsippany, NJ  07054 
(973) 254-3560 
Individual Study Table Referring to 
Part of the Dossier 
Volume: 
Page: 
 
(For National Authority 
Use Only) 
Name of Finished Product: 
EXPAREL (bupivacaine liposome injectable 
suspension) 
Name of Active Ingredient: 
Bupivacaine, 1.3%, 13.3 mg/mL 
subjects in Group 1 undergoing 1-Level procedures, EXPAREL 266 mg in 20 mL will be admixed with 
bupivacaine HCl 0.5% in 20 mL and expanded in volume with 20 mL normal saline for a total volume of 60 mL, 
while for subjects undergoing 2-Level procedures EXPAREL 266 mg in 20 mL will be admixed with bupivacaine 
HCl 0.5% in 20 mL and expanded in volume with 50 mL normal saline for a total volume of 90 mL.  Subjects in 
Group 2 undergoing 1-Level procedures will receive LIA with bupivacaine HCl 0.5% in 20 mL expanded in 
volume with 40 mL normal saline for a total volume of 60 mL, while subjects undergoing 2-Level procedures will 
receive LIA with bupivacaine HCl 0.5% in 20 mL expanded in volume with 70 mL normal saline for a total 
volume of 90 mL.   
Trained and qualified Investigators will use their usual surgical technique to perform the surgery.  The following 
medications are permitted during surgery 
• 
Propofol for induction and/or intraoperatively.  
• 
Lidocaine without epinephrine (0.5% or 1%) pre-incision to anaesthetize the incisional area 
o 
Must precede the use of EXPAREL or bupivacaine HCl by at least 20 minutes. 
• 
Fentanyl or short-acting analogues  
• 
Medication for nausea/vomiting prevention per physician’s discretion 
Intraoperative administration of other opioids or any other analgesic, local anesthetics, or anti-inflammatory agents 
will be prohibited in both groups, unless needed to treat an AE. 
Study drug, approximately 1-2 mL every 1.0-1.5 cm, will be administered using 20- or 22-gauge needles prior to 
wound closure.  The tissue should visibly expand with minimal leakage.  Study drug should be injected in the 
prescribed locations based on the areas of highest nerve density to include the muscular (above and below the 
fascia) and subdermal layers. Approximately 2/3 of study drug will be placed subfascial circumferentially above 
and below the paraspinous muscles, the remainder subdermal and subcutaneously.  Drains may be used at the 
surgeon’s discretion.  
If the surgery extends beyond 3 hours and the patient received TXA at the beginning of surgery, an additional 1 gm 
TXA may be dosed at the end of surgery. 
In addition to LIA, all study participants will receive a standardized approach for managing postsurgical pain that 
includes a scheduled multimodal pain regimen including adjunctive analgesics, non-steroidal anti-inflammatory 
drugs (NSAIDs).  Rescue analgesics will be available as needed.  
Postsurgically, all subjects are required to receive the following scheduled medications until hospital discharge: 
• 
Acetaminophen 975-1000 mg PO every 8 hours (q8h).  The total daily dose of acetaminophen is not to 
exceed 3000 mg. Acetaminophen IV can be used if the patient unable to tolerate oral acetaminophen. 
• 
Celecoxib 200 mg PO every 12 hours (q12h) up to 48 hours post surgery. 
o 
If a subject has an allergy to celecoxib, naproxen 500 mg PO twice a day or meloxicam 7.5 mg 
PO once a day may be used. 
• 
Gabapentin up to 900 mg PO q8h  
• 
Cyclobenzaprine (eg, Flexeril®) 10 mg PO  x1 dose (PRN at surgeon discretion) 
Patients can be discharged based on current clinical practice but, at a minimum, should: 
• 
No longer require parenteral pain management 
• 
Be able to tolerate a liquid diet 
• 
Demonstrate safe mobility as determined with occupational therapy/physical therapy input per hospital 
 
 
CONFIDENTIAL 
4 
02 August 2017 
 


Pacira Pharmaceuticals, Inc. 
                       402-C-409 (Spinal Fusion) 
EXPAREL® 
Clinical Study Protocol Amendment 2 
 
Name of Sponsor/Company: 
Pacira Pharmaceuticals, Inc. 
5 Sylvan Way 
Parsippany, NJ  07054 
(973) 254-3560 
Individual Study Table Referring to 
Part of the Dossier 
Volume: 
Page: 
 
(For National Authority 
Use Only) 
Name of Finished Product: 
EXPAREL (bupivacaine liposome injectable 
suspension) 
Name of Active Ingredient: 
Bupivacaine, 1.3%, 13.3 mg/mL 
standards 
Postsurgical Rescue Medication 
Subjects should only receive rescue medication upon request for pain control, as needed.  Postsurgical rescue 
medication will consist of PO immediate-release oxycodone initiating up to 10 mg.  The subject may re-dose, per 
physician judgment, as needed (PRN), if the initial rescue medication fails.  If a subject cannot tolerate PO 
medication or has repeated failure of the rescue medication with oxycodone (PO), IV morphine (2.5-5 mg) or 
hydromorphone (0.5-1 mg) may be administered q4h or PRN.  Patient-controlled analgesia (PCA) is not 
permitted.  No other rescue analgesic agents, including NSAIDs, are permitted until hospital discharge.  After 
discharge, the analgesic regimen may be adjusted for each subject individually as deemed appropriate by the 
physician responsible for the postsurgical care. 
Postsurgical Assessments 
Postsurgical clinical assessments will include pain intensity scores using a 10-cm visual analog scale (VAS) 
(see Appendix 1); overall benefit of analgesia score (OBAS) questionnaire (see Appendix 2); total postsurgical 
opioid consumption; predefined opioid-related AEs; and nurse's satisfaction with overall analgesia (see Appendix 
3).   
Adverse events will be recorded from the time the ICF is signed through Day 30.  If a cardiac AE (eg, chest pain 
[angina, myocardial infarction], abnormal/irregular heart rate [bradycardia, tachycardia, extrasystoles], or shortness 
of breath), neurological AE (eg, altered mental status/altered sensorium, dizziness, dysarthria, hyperesthesia, 
metallic taste, peroral numbness, seizure, tinnitus, tremors, visual disturbance, muscular twitching or rigidity 
beyond 72 hours postdose, or tingling/paresthesia beyond 72 hours postdose), or serious AE (SAE) occurs during 
the study a 12-lead ECG, vital signs, and any appropriate clinical laboratory tests should be conducted. 
Postsurgical health economic outcome assessments will include hospital length of stay (LOS), use of skilled 
nursing facility, hospital readmissions, and use of other health services following discharge (phone calls related to 
postsurgical pain, unscheduled visits related to postsurgical pain, and visits to emergency department) through Day 
30. 
A follow-up visit will be scheduled for all subjects on postsurgical Day 14.  A follow-up phone call will be made 
on Day 30 to all subjects who received study drug to assess for adverse events (AEs). 
Number of Subjects (Planned):  
Approximately 194 subjects are planned for enrollment in this study in order to have at least 184 evaluable 
subjects. 
Eligibility Criteria: 
Inclusion Criteria: 
1. Male or female, at least 18 years of age at screening. 
2. Primary surgical indication is lumbar pain, radiculopathy, disc degeneration, disc herniation, foraminal 
stenosis, or 1-2 level spondylolisthesis or deformity. 
3. Scheduled to undergo primary, 1-2 level, open lumbar spinal fusion surgery under general anesthesia. 
4. American Society of Anesthesiologists (ASA) physical status 1, 2, or 3.  
 
 
CONFIDENTIAL 
5 
02 August 2017 
 


Pacira Pharmaceuticals, Inc. 
                       402-C-409 (Spinal Fusion) 
EXPAREL® 
Clinical Study Protocol Amendment 2 
 
Name of Sponsor/Company: 
Pacira Pharmaceuticals, Inc. 
5 Sylvan Way 
Parsippany, NJ  07054 
(973) 254-3560 
Individual Study Table Referring to 
Part of the Dossier 
Volume: 
Page: 
 
(For National Authority 
Use Only) 
Name of Finished Product: 
EXPAREL (bupivacaine liposome injectable 
suspension) 
Name of Active Ingredient: 
Bupivacaine, 1.3%, 13.3 mg/mL 
5. Female subjects must be surgically sterile; or at least 2 years postmenopausal; or have a monogamous partner 
who is surgically sterile; or practicing double-barrier contraception; or practicing abstinence (must agree to use 
double-barrier contraception in the event of sexual activity); or using an insertable, injectable, or transdermal, 
contraceptive approved by the FDA for greater than 2 months prior to screening.  All women of childbearing 
potential (ie, premenopausal without permanent sterilization) must commit to the use of an acceptable form of 
birth control for the duration of the study and for 30 days after completion of the study. 
6. Able to provide informed consent, adhere to the study visit schedule, and complete all study assessments. 
Exclusion Criteria: 
1. Currently pregnant, nursing, or planning to become pregnant during the study or within 1 month after study 
drug administration. 
2. Serious spinal conditions (to include cauda equina syndrome, infection, tumor, fracture, or severe osteoporosis 
[ie, if taking Bisphosphonate or TNF-α blockers]). 
3. Planned anterior or laterial incisions 
4. Previous spinal surgery at the same level other than microdiscectomy or hemilaminectomy (eg, bi-lateral 
laminectomy, fusion). 
5. Planned concurrent surgical procedure. 
6. Identification of a dural tear during surgery will be an intra-operative exclusion unless it is well repaired (no 
evidence of cerebrospinal fluid [CSF] leak with Valsalva and no plan to restrict activity post-operatively).  
Any injury to the nerve root occurring during surgery will also be considered an intra-operative exclusion. 
7. Concurrent painful physical condition that may require analgesic treatment (such as an NSAID or opioid) in 
the postsurgical period for pain that is not strictly related to the spinal surgery and which may confound the 
postsurgical assessments. 
8. Comorbidity impacting current physical function or Investigator opinion that it may impact postsurgical 
rehabilitation. 
9. Allergy, hypersensitivity, or contraindication to any of the study medications (ie, bupivacaine, oxycodone, 
morphine, hydromorphone, gabapentin, acetaminophen, or cyclobenzaprine) for which an alternative 
medication is not provided in the protocol. 
10. Use of any of the following medications within the times specified before surgery: long-acting opioid 
medication (eg, morphine including MS Contin®, hydromorphone [Dilaudid®], oxycodone [Oxycontin®], 
methadone) daily for more than 3 months duration or within 3 days of surgery. Patients receiving short-acting 
opioids or NSAIDs should be at a steady or plateau dose. Such patients should require or receive no more than 
40 mg morphine (oral) equivalents (eg, approximately 5 mg oxycodone) within 24 hours of surgery. 
11. Initiation of treatment with any of the following medications within 1 month of study drug administration or if 
the medication(s) are being given to control pain: selective serotonin reuptake inhibitors (SSRIs), selective 
norepinephrine reuptake inhibitors (SNRIs), or duloxetine (Cymbalta®).  If a subject is taking one of these 
medications for a reason other than pain control, he or she must be on a stable dose for at least 1 month prior 
to study drug administration.   
12. Current use of systemic glucocorticosteroids within 1 month of enrollment in this study. 
13. Use of dexmedetomidine HCl (Precedex®) within 3 days of study drug administration. 
14. History of coronary or vascular stent placed within the past 3 months (may be extended to 1 year if medically 
indicated per physician discretion).  
 
 
CONFIDENTIAL 
6 
02 August 2017 
 


Pacira Pharmaceuticals, Inc. 
                       402-C-409 (Spinal Fusion) 
EXPAREL® 
Clinical Study Protocol Amendment 2 
 
Name of Sponsor/Company: 
Pacira Pharmaceuticals, Inc. 
5 Sylvan Way 
Parsippany, NJ  07054 
(973) 254-3560 
Individual Study Table Referring to 
Part of the Dossier 
Volume: 
Page: 
 
(For National Authority 
Use Only) 
Name of Finished Product: 
EXPAREL (bupivacaine liposome injectable 
suspension) 
Name of Active Ingredient: 
Bupivacaine, 1.3%, 13.3 mg/mL 
15. Have been treated for a deep vein thrombosis, pulmonary embolism, myocardial infarction, or ischemic stroke 
within the past 6 months (may be extended to 1 year if medically indicated per physician discretion).  
16. Severely impaired renal (eg, serum creatinine clearance ≤ 30) or hepatic function (eg, serum aspartate 
aminotransferase [AST] level >3 times the upper limit of normal [ULN] or serum alanine aminotransferase 
[ALT] level >3 x ULN). 
17. Any neurologic or psychiatric disorder that might impact postsurgical pain or interfere with study assessments. 
18. Malignancy in the last 2 years, per physician discretion. 
19. History of misuse, abuse, or dependence on opioid analgesics, other prescription drugs, illicit drugs, or alcohol 
as defined in DSM-IV.  Dependence or chronic opioid use will be defined as use of more than 30 morphine 
equivalents per day during the prior 90 days. 
20. Failure to pass the alcohol breath test or urine drug screen positive for illicit drugs. 
21. Body weight <50 kg (110 pounds) or a body mass index >44 kg/m2. 
22. Subjects receiving Worker’s compensation for a disability or who are involved in litigation. 
23. Previous participation in an EXPAREL study. 
24. Administration of an investigational drug within 30 days or 5 elimination half-lives of such investigational 
drug, whichever is longer, prior to study drug administration, or planned administration of another 
investigational product or procedure during the subject’s participation in this study. 
Test Product, Dose, Mode of Administration, and Lot Number: 
Name: EXPAREL (bupivacaine liposome injectable suspension) and bupivacaine HCl 0.5% (Group 1) 
Active ingredients: Bupivacaine 
Dosage:  
• 
For subjects undergoing 1-Level procedures: EXPAREL 266 mg in 20 mL admixed with bupivacaine HCl 
0.5% in 20 mL and expanded in volume with 20 mL normal saline for a total volume of 60 mL  
• 
For subjects undergoing 2-Level procedures: EXPAREL 266 mg in 20 mL admixed with bupivacaine HCl 
0.5% in 20 mL and expanded in volume with 50 mL normal saline for a total volume of 90 mL.   
Lot number: To be determined 
Mode of administration: Intraoperative local infiltration 
Reference Product, Dose, Mode of Administration, and Lot Number: 
Name: Bupivacaine HCl 0.5% (Group 2) 
Active ingredient: Bupivacaine 
Dosage:  
• 
For subjects undergoing 1-Level procedures: bupivacaine HCl 0.5% in 20 mL expanded in volume with 
40 mL normal saline for a total volume of 60 mL 
• 
For subjects undergoing 2-Level procedures: bupivacaine HCl 0.5% in 20 mL expanded in volume with 
70 mL normal saline for a total volume of 90 mL.   
Lot number: To be determined.  Commercial product will be provided by Pacira. 
Mode of administration: Intraoperative local infiltration 
 
 
CONFIDENTIAL 
7 
02 August 2017 
 


Pacira Pharmaceuticals, Inc. 
                       402-C-409 (Spinal Fusion) 
EXPAREL® 
Clinical Study Protocol Amendment 2 
 
Name of Sponsor/Company: 
Pacira Pharmaceuticals, Inc. 
5 Sylvan Way 
Parsippany, NJ  07054 
(973) 254-3560 
Individual Study Table Referring to 
Part of the Dossier 
Volume: 
Page: 
 
(For National Authority 
Use Only) 
Name of Finished Product: 
EXPAREL (bupivacaine liposome injectable 
suspension) 
Name of Active Ingredient: 
Bupivacaine, 1.3%, 13.3 mg/mL 
Duration of Subject Participation in Study: 
Participation will begin at the signing of the ICF.  No more than 30 days should pass between signing of the ICF 
and the administration of study drug.  The time from study drug administration through the end of participation is 
30 ± 3 days.  Therefore, subjects may participate in the study for up to 63 days. 
Efficacy Assessments: 
The following efficacy measurements will be assessed at the times specified after the end of surgery: 
• 
Pain intensity scores using the VAS on Day 1, pre-operative; upon arrival at the post-anesthesia care unit 
(PACU); at 4, 6, 8, 10, 12, 24, 28, 32, 36, 48, 52, 56, 60, and 72 hours; immediately prior to each 
administration of rescue pain medication; and just prior to hospital discharge (see Appendix 1).  Note: if 
the subject is sleeping, do not wake him or her for an assessment of pain at 24 or 48 hours after surgery. If 
he or she awakens within the assessment window (ie, 1 hour for the 24-hour assessment and 2 hours for 
the 48-hour assessment), a pain score may be collected then. 
†: If discharge occurs prior to any of the scheduled VAS assessments collected at 4 to 72 hours 
postsurgery or scheduled OBAS assessments collected at 24 to 72 hours, the study coordinator must stress 
to the subject the importance of completing the scheduled VAS and OBAS Assessments.  These 
assessments should be recorded by the subject in the patient log provided upon discharge. 
• 
Amount of all opioid rescue analgesics taken through postsurgical Day 30. 
• 
Predefined treatment-emergent opioid-related AEs. 
• 
The OBAS questionnaire at 24, 48, and 72 hours (see Appendix 2).  Note: if discharge occurs before 72 
hours, the study coordinator must stress to the patient the importance of completing the scheduled OBAS 
questionnaire up to 72 hours.  Completion of the questionnaire should be recorded by the patient in the 
patient log provided upon discharge. 
• 
Nurse’s satisfaction with overall analgesia will be assessed at 24, 48, and 72 hours or upon hospital 
discharge (see Appendix 3). 
• 
The Pain Interference Scale (short form 6b) pre-op and Day 14 (see Appendix 4)  
Efficacy Endpoints: 
The efficacy endpoints listed below will be assessed based on the efficacy measurements conducted at the times 
specified after the end of surgery. 
Primary Efficacy Endpoint: 
The primary efficacy endpoint is the area under the curve (AUC) of the VAS pain intensity scores from 0-72 
hours. 
Secondary Endpoints: 
• 
Total opioid consumption (in IV morphine equivalents) from 0–48 hours 
• 
Proportion of subjects who are pain free (defined as a VAS pain intensity score of ≤1.5 and no prior 
rescue medication) at each assessed timepoint.  
• 
The VAS pain intensity scores at each assessed timepoint.  
• 
The AUC of the VAS pain intensity scores through 24, 36, 48, 60, and 72 hours. 
• 
The AUC of the VAS pain intensity scores from 24–48 and 48–72 hours. 
• 
The sum of the pain intensity scores (SPIS) through 24, 48, and 72 hours. 
 
 
CONFIDENTIAL 
8 
02 August 2017 
 


Pacira Pharmaceuticals, Inc. 
                       402-C-409 (Spinal Fusion) 
EXPAREL® 
Clinical Study Protocol Amendment 2 
 
Name of Sponsor/Company: 
Pacira Pharmaceuticals, Inc. 
5 Sylvan Way 
Parsippany, NJ  07054 
(973) 254-3560 
Individual Study Table Referring to 
Part of the Dossier 
Volume: 
Page: 
 
(For National Authority 
Use Only) 
Name of Finished Product: 
EXPAREL (bupivacaine liposome injectable 
suspension) 
Name of Active Ingredient: 
Bupivacaine, 1.3%, 13.3 mg/mL 
• 
SPIS from 24–48 and 48–72 hours. 
• 
Total inpatient postsurgical opioid consumption (in mg) through 24 and 72 hours or hospital discharge.  
• 
Total postsurgical opioid consumption (in mg) from hospital discharge through Day 30. 
• 
Percentage of opioid-free subjects through 24, 48, and 72 hours or hospital discharge.  
• 
Time to first opioid rescue through 72 hours or hospital discharge. 
• 
Incidence of the following opioid-related AEs until the discharge order is written: respiratory depression, 
hypoventilation, hypoxia, dry mouth, nausea, vomiting, constipation, altered mental status, pruritus, 
urinary retention, and postoperative ileus. 
• 
The OBAS total score at 24, 48, and 72 hours 
• 
Nurse's satisfaction with overall analgesia at 24, 48, and 72 hours or upon hospital discharge. 
Health Economic Outcomes Assessments: 
The health economic outcomes will include: 
• 
Hospital length of stay (LOS). 
• 
Hospital readmissions. 
• 
Use of skilled nursing facility. 
• 
Use of other health services following hospital discharge (phone calls related to pain, unscheduled visits 
related to pain, and visits to the emergency department). 
Health Economic Outcomes Endpoints: 
• 
Hospital LOS, defined as the time from completion of the wound closure until the hospital discharge order 
is written or through postsurgical Day 30, whichever is sooner. 
• 
Percentage of subjects meeting the protocol-specified minimum criteria for discharge (ie, no requirement 
for parenteral pain management, able to tolerate a liquid diet, able to demonstrate safe mobility, not 
requirement for active wound management) and discharged by time (eg, a “responder analysis”) 
• 
Incidence of hospital readmission through Day 30.  
• 
Incidence of skilled nursing facility use. 
• 
Total time spent in skilled nursing facility. 
• 
Number of phone calls related to postsurgical pain. 
• 
Number of unscheduled visits related to postsurgical pain. 
• 
Number of visits to the emergency department. 
Safety Assessment:  
• 
Adverse events from the time the ICF is signed through postsurgical Day 30. 
Safety Endpoint: 
• 
Incidence of treatment-emergent AEs (TEAEs) and SAEs through postsurgical Day 30. 
 
 
CONFIDENTIAL 
9 
02 August 2017 
 


Pacira Pharmaceuticals, Inc. 
                       402-C-409 (Spinal Fusion) 
EXPAREL® 
Clinical Study Protocol Amendment 2 
 
Name of Sponsor/Company: 
Pacira Pharmaceuticals, Inc. 
5 Sylvan Way 
Parsippany, NJ  07054 
(973) 254-3560 
Individual Study Table Referring to 
Part of the Dossier 
Volume: 
Page: 
 
(For National Authority 
Use Only) 
Name of Finished Product: 
EXPAREL (bupivacaine liposome injectable 
suspension) 
Name of Active Ingredient: 
Bupivacaine, 1.3%, 13.3 mg/mL 
Statistical Methods:  
A comprehensive statistical analysis plan will be developed for this study.  Demographic and baseline 
characteristics will be summarized descriptively by treatment group.  Efficacy data will be summarized by 
treatment group.  Superiority of treatment with EXPAREL admixed with bupivacaine HCl (Group 1) versus 
treatment with bupivacaine HCl (Group 2) will be determined using an analysis of variance (ANOVA) with 
treatment as the main effect on the AUC of the VAS pain intensity scores through 48 hours.  If superiority of 
pain control is demonstrated, then the total opioid use (in morphine equivalent doses) through 48 hours in Group 1 
will be compared to that of Group 2 using an ANOVA.  This hierarchical testing procedure will protect the type 1 
error rate.  Secondary efficacy endpoints will be analyzed using ANOVA, chi-square tests, and log-rank tests, as 
appropriate.  Safety endpoints will be summarized descriptively by treatment group. 
 
 
 
CONFIDENTIAL 
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02 August 2017 
 


Pacira Pharmaceuticals, Inc. 
 
402-C-409 (Spinal Fusion) 
EXPAREL® 
Clinical Study Protocol Amendment 2 
 
Table 1. 
Time and Events Schedule of Study Procedures 
 
 
Screen 
Visit 
D1 
Preop 
0 
min OR PACU 
Arrival 4h 6h 8h 10h 12h 24h 28h 32h 36h 48h 52h 56h 60h 72h D14 
Visit 
D30 
Call 
Time 
Window 
Within 
30 days 
 
 
 
 
±15 
min 
±30 
min 
±30 
min ±1h ±1h ±1h ±2h ±2h ±2h ±2h ±2h ±2h ±2h ±4h ±3d ±3d 
Obtain signed ICF 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assess/confirm eligibility 
X 
Xa 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record medical and surgical history 
X 
Xa 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record demographics and baseline characteristics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Conduct pregnancy test for WOCBP 
X 
Xa 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Conduct urine drug screen 
X 
Xa 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol breath test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Perform physical examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Measure vital signs (temperature, heart rate, respiratory rate and 
blood pressure) 
X 
Xa 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical labs (direct bilirubin and either GGT and LDH or ALT and 
AST) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Perform 12-lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record VAS pain intensity score1,2,3,4 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Randomize subject, prepare study drug 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer scheduled presurgical medications5 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer study drug according to randomization schedule; record 
start and stop times 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record intraoperative opioids administered and doses 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record surgery start and stop times 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record times and doses of all opioid rescue medication administered 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer scheduled postsurgical analgesics1,6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete OBAS questionnaire4 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Nurse’s satisfaction with postsurgical pain control4 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Pain Interference Scale 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Record date and time of actual discharge 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Document any hospital readmissions 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Document use of skilled nursing facility 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Document any unscheduled phone calls or office visits related to 
pain after discharge 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Document any unscheduled visits to the ER after discharge 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Record prior and concomitant medications7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record AEs (beginning at the time ICF is signed)8 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
CONFIDENTIAL 
11 
02 August 2017 
 


Pacira Pharmaceuticals, Inc. 
 
402-C-409 (Spinal Fusion) 
EXPAREL® 
Clinical Study Protocol Amendment 2 
 
Abbreviations: AE = adverse event; ALT = alanine transaminase; AST = aspartate transaminase; d = day; D = day; ECG = electrocardiogram; ER = emergency room; 
GGT=Gamma-glutamyl transpeptidase; h = hours; ICF = informed consent form; LDH = lactate dehydrogenase; min = minutes; OBAS = overall benefit of analgesia score; 
OR = operating room; PACU = post-anesthesia care unit; Preop = preoperative; q12h = every 12 hours; VAS = visual analog scale; WOCBP = women of childbearing potential. 
a:   If the Screening Visit is conducted within 10 days of the date of surgery, the following Day-1 pre-op assessments are not required: assess/confirm eligibility; record medical 
and surgical history; conduct pregnancy test for WOCBP; conduct urine drug screen; and measure vital signs (temperature, heart rate, respiratory rate and blood pressure) 
 
* 
Postsurgical assessments will be conducted at the timepoints specified after the end of surgery.  All assessments conducted after baseline (ie, study drug administration) will 
be timed from the end of surgery, defined as the time of last suture/staple.  At timepoints when multiple assessments coincide, the VAS pain intensity assessment will be 
conducted first. 
 
1 
Timepoints shown through 72 hours. Note: if discharge occurs before 72 hours, the study coordinator must stress to the patient the importance of completing the scheduled 
pain intensity assessments up to 72 hours.  These assessments should be recorded by the patient in the patient log provided upon discharge.    
2 
The preoperative pain intensity assessment should be conducted prior to administration of any premedication. 
3 
Also record VAS pain intensity scores immediately prior to each administration of rescue pain medication, and just prior to hospital discharge.   
4 
And just prior to hospital discharge.  Note: if discharge occurs before 72 hours, the study coordinator must stress to the patient the importance of completing the scheduled 
OBAS questionnaire up to 72 hours.  Completion of the questionnaire should be recorded by the patient in the patient log provided upon discharge. 
5 
Administer presurgical analgesics (ie, acetaminophen 975-1000 mg orally (PO), celecoxib 200 mg PO [or naproxen 500 mg PO twice a day or meloxicam 7.5 mg PO once a 
day in case of allergy], and gabapentin up to 900 mg PO). 
6 
Administer scheduled post-surgical analgesics (ie, acetaminophen 975-1000 mg PO every 8 hours (q8h) [maximum of 3000 mg per day; acetaminophen IV can be used if the 
patient is unable to tolerate oral acetaminophen], celecoxib 200 mg PO every 12 hours up to 48 hours (q12h; or naproxen 500 mg PO twice a day or meloxicam 7.5 mg PO 
once a day in case of allergy), cyclobenzaprine 10 mgq8h, and gabapentin up to 900 mg PO q8h). 
7 
Instruct subject to discontinue prohibited medications.  Record date and time of all medications starting at least 30 days prior to study drug administration until hospital 
discharge.  Record medications administered for treatment of an AE through Day 30.    
8 
If a cardiac AE (eg, chest pain [angina, myocardial infarction], abnormal/irregular heart rate [bradycardia, tachycardia, extrasystoles], or shortness of breath), neurological AE 
(eg, altered mental status/altered sensorium, dizziness, dysarthria, hyperesthesia, metallic taste, peroral numbness, seizure, tinnitus, tremors, visual disturbance, muscular 
twitching or rigidity beyond 72 hours postdose, or tingling/paresthesia beyond 72 hours postdose), or serious AE (SAE) occurs during the study, a 12-lead ECG, vital signs, 
PK draw, and any appropriate clinical laboratory tests should be conducted as close as possible to when the event occurs.
 
 
  
CONFIDENTIAL 
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02 August 2017 
 


Pacira Pharmaceuticals, Inc. 
 
402-C-409 (Spinal Fusion) 
EXPAREL® 
 
Clinical Study Protocol Amendment 2 
3. 
TABLE OF CONTENTS 
1. 
SIGNATURE PAGE ....................................................................................................2 
2. 
SYNOPSIS ...................................................................................................................3 
3. 
TABLE OF CONTENTS ...........................................................................................13 
4. 
LIST OF ACRONYMS/ABBREVIATIONS AND DEFINITIONS OF 
TERMS .......................................................................................................................17 
5. 
ETHICS ......................................................................................................................19 
5.1. 
Institutional Review Board/Independent ethics committee ........................................19 
5.2. 
Ethical Conduct of the Study ......................................................................................19 
5.3. 
Subject Information, Consent, and Assent .................................................................19 
6. 
INVESTIGATORS AND STUDY ADMINISTRATION STRUCTURE .................19 
7. 
INTRODUCTION ......................................................................................................20 
7.1. 
Indication ....................................................................................................................20 
7.2. 
Current Therapies/Treatments ....................................................................................20 
7.3. 
EXPAREL (Bupivacaine Liposome Injectable Suspension) ......................................21 
7.4. 
Summary of Human Experience with EXPAREL ......................................................21 
7.4.1. 
Wound Infiltration New Drug Application (NDA) ....................................................21 
7.4.1.1. 
Nerve Block Supplemental NDA ...............................................................................22 
7.5. 
Postmarketing Exposure .............................................................................................23 
8. 
OBJECTIVES .............................................................................................................24 
8.1. 
Primary Objective .......................................................................................................24 
8.2. 
Secondary Objectives .................................................................................................24 
9. 
OVERALL STUDY DESIGN AND PLAN ...............................................................24 
9.1. 
Overall Study Design and Plan ...................................................................................24 
9.1.1. 
Study Design ...............................................................................................................24 
9.1.2. 
Duration of the Study and Subject Participation ........................................................27 
9.1.3. 
Study Stopping Rules .................................................................................................27 
9.2. 
Discussion of Study Design ........................................................................................27 
10. 
STUDY POPULATION .............................................................................................27 
10.1. 
Inclusion Criteria ........................................................................................................27 
10.2. 
Exclusion Criteria .......................................................................................................28 
 
 
 
CONFIDENTIAL 
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02 August 2017 
 


Pacira Pharmaceuticals, Inc. 
 
402-C-409 (Spinal Fusion) 
EXPAREL® 
 
Clinical Study Protocol Amendment 2 
10.3. 
Removal of Subjects From Therapy or Assessment ...................................................30 
10.3.1. 
Withdrawal Secondary to Adverse Events .................................................................30 
10.3.2. 
Voluntary or Study Investigator Withdrawal .............................................................30 
11. 
TREATMENTS ..........................................................................................................30 
11.1. 
Treatments to be Administered ...................................................................................30 
11.1.1. 
Administration Instructions/Procedures .....................................................................31 
11.1.2. 
Study Drug Administration Considerations................................................................31 
11.2. 
Identity of Investigational Product(s) .........................................................................32 
11.2.1. 
Description of EXPAREL ..........................................................................................32 
11.2.2. 
Description of Reference Product ...............................................................................32 
11.2.3. 
Description of Diluents ...............................................................................................32 
11.3. 
Method of Assigning Subjects to Treatment ..............................................................32 
11.3.1. 
Randomization Scheme ..............................................................................................32 
11.3.2. 
Randomization Procedures .........................................................................................33 
11.3.3. 
Replacement of Subjects .............................................................................................33 
11.4. 
Selection of Doses in the Study ..................................................................................33 
11.5. 
Blinding ......................................................................................................................33 
11.5.1. 
Blinding Procedures ....................................................................................................33 
11.5.2. 
Unblinding Procedures ...............................................................................................34 
11.6. 
Prior and Concomitant Therapy and Medications ......................................................34 
11.6.1. 
Before Study Drug Administration .............................................................................34 
11.6.2. 
During Surgery ...........................................................................................................35 
11.6.3. 
After Surgery ..............................................................................................................36 
11.7. 
Treatment Compliance ................................................................................................36 
11.8. 
Accountability of Study Drug .....................................................................................36 
12. 
STUDY ENDPOINTS AND MEASUREMENTS ....................................................37 
12.1. 
Efficacy Measurements ..............................................................................................37 
12.2. 
Efficacy Endpoints ......................................................................................................37 
12.3. 
Health Economic Outcomes Assessments ..................................................................38 
12.4. 
Health Economic Outcomes Endpoints ......................................................................39 
12.5. 
Safety Assessments .....................................................................................................39 
12.6. 
Safety Endpoints .........................................................................................................39 
 
 
 
CONFIDENTIAL 
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02 August 2017 
 


Pacira Pharmaceuticals, Inc. 
 
402-C-409 (Spinal Fusion) 
EXPAREL® 
 
Clinical Study Protocol Amendment 2 
12.7. 
Appropriateness of Measures .....................................................................................39 
13. 
STUDY PROCEDURES ............................................................................................39 
13.1. 
Instructions for Conducting Procedures and Measures ..............................................39 
13.1.1. 
Pain Intensity Assessment ..........................................................................................40 
13.1.2. 
Clinical Laboratory Tests ...........................................................................................40 
13.1.3. 
Vital Signs ..................................................................................................................40 
13.1.4. 
Physical Examination .................................................................................................40 
13.1.5. 
Adverse Events of Special Interest .............................................................................40 
13.2. 
Screening Procedures ..................................................................................................41 
13.3. 
Baseline Procedures (Day 1 Prior to Surgery) ............................................................42 
13.4. 
Intraoperative Procedures ...........................................................................................42 
13.5. 
Postoperative Assessments Through Hospital Discharge ...........................................43 
13.6. 
Day 14 Visit ................................................................................................................43 
13.7. 
Day 30 Phone Call ......................................................................................................44 
14. 
ADVERSE EVENT REPORTING ............................................................................44 
14.1. 
Adverse Events ...........................................................................................................44 
14.1.1. 
Definitions ..................................................................................................................44 
14.1.2. 
Recording Adverse Events .........................................................................................45 
14.1.3. 
Severity of Adverse Events ........................................................................................46 
14.1.4. 
Relationship of Adverse Events to Study Drug ..........................................................46 
14.1.5. 
Outcome of Adverse Events .......................................................................................47 
14.1.6. 
Action Taken with Subject due to an Adverse Event .................................................47 
14.2. 
Serious Adverse Events ..............................................................................................47 
14.2.1. 
Definition of a Serious Adverse Event .......................................................................47 
14.2.2. 
Reporting Serious Adverse Events .............................................................................48 
15. 
STATISTICAL METHODS .......................................................................................49 
15.1. 
Study Hypothesis ........................................................................................................49 
15.2. 
Study Endpoints ..........................................................................................................49 
15.3. 
Determination of Sample Size ....................................................................................49 
15.4. 
Analysis Populations ..................................................................................................49 
15.5. 
Handling Subject Dropouts and Discontinuations ......................................................50 
15.6. 
Statistical Analyses .....................................................................................................50 
 
 
 
CONFIDENTIAL 
15 
02 August 2017 
 


Pacira Pharmaceuticals, Inc. 
 
402-C-409 (Spinal Fusion) 
EXPAREL® 
 
Clinical Study Protocol Amendment 2 
15.6.1. 
Efficacy Analyses .......................................................................................................50 
15.6.1.1. 
Primary Efficacy Analyses .........................................................................................50 
15.6.2. 
Secondary Efficacy Measures .....................................................................................51 
15.6.3. 
Safety Analyses ..........................................................................................................51 
15.6.3.1. 
Adverse Events ...........................................................................................................51 
15.7. 
Significance Testing ...................................................................................................51 
16. 
REFERENCES ...........................................................................................................52 
17. 
INVESTIGATOR AGREEMENT .............................................................................54 
18. 
APPENDICES ............................................................................................................55 
Appendix 1: Subject’s Reported Pain Intensity ..........................................................................56 
Appendix 2: Overall Benefit of Analgesia Score Questionnaire (OBAS) ..................................57 
Appendix 3: Nurse’s Satisfaction with Postsurgical Pain Control (Likert Scale).......................58 
Appendix 4: Pain Interference Scale ...........................................................................................59 
 
LIST OF TABLES 
Table 1. 
Time and Events Schedule of Study Procedures ........................................................11 
 
 
 
 
CONFIDENTIAL 
16 
02 August 2017 
 


Pacira Pharmaceuticals, Inc. 
 
402-C-409 (Spinal Fusion) 
EXPAREL® 
 
Clinical Study Protocol Amendment 2 
4. 
LIST OF ACRONYMS/ABBREVIATIONS AND DEFINITIONS 
OF TERMS 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine transaminase 
ASA 
American Society of Anesthesiology 
AST 
Aspartate transaminase 
AUC 
Area under the plasma concentration-versus-time curve 
BMI 
Body mass index 
CFR 
Code of Federal Regulations 
Cmax  
The maximum observed bupivacaine plasma concentration obtained 
directly from the experimental data without interpolation 
CRF 
Case Report Form 
CSF 
Cerebrospinal Fluid 
ECG 
Electrocardiogram 
ER 
Emergency room 
EU 
European Union 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transpeptidase 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
IRB 
Institutional Review Board  
IRT 
Interactive Response Technology 
IV 
Intravenous 
JCAHO 
Joint Commission on Accreditation of Healthcare Organizations 
LDH 
Lactate dehydrogenase 
LIA 
Local infiltration analgesia  
LOS 
Length of stay 
MPADSS 
Modified Post-Anesthesia Discharge Scoring System 
NDA 
New Drug Application 
NRS 
Numeric rating scale 
 
 
 
CONFIDENTIAL 
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02 August 2017 
 


Pacira Pharmaceuticals, Inc. 
 
402-C-409 (Spinal Fusion) 
EXPAREL® 
 
Clinical Study Protocol Amendment 2 
NRS-R 
Neurobehavioral rating scale-revised 
NSAID 
Non-steroidal anti-inflammatory drug 
OBAS 
Overall Benefit of Analgesia Score 
PACU 
Post-anesthesia care unit 
PCA 
Patient-controlled analgesia 
PK 
Pharmacokinetic 
PMR 
Postmarketing Requirement 
PLIF 
Posterior lumbar interbody fusion 
PO 
Oral 
PRN 
As needed 
PTAE 
Pretreatment adverse event 
SAE  
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
sNDA 
Supplemental New Drug Application 
SNRI 
Serotonin and norepinephrine reuptake inhibitor 
SPIS 
Sum of the pain intensity scores 
SSRI 
Selective serotonin reuptake inhibitor 
t1/2 
The apparent terminal elimination half-life calculated as 0.693/λz 
TEAE 
Treatment-emergent adverse event 
TKA 
Total Knee Arthroplasty 
TLIF 
Transdoraminal lumbar interbody fusion 
TXA 
Tranexemic acid 
US 
United States (of America) 
VAS 
Visual analog scale 
WHO 
World Health Organization 
 
 
 
CONFIDENTIAL 
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02 August 2017 
 


Pacira Pharmaceuticals, Inc. 
 
402-C-409 (Spinal Fusion) 
EXPAREL® 
 
Clinical Study Protocol Amendment 2 
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 Conference on Harmonisation (ICH) Good Clinical Practices (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, Consent, and Assent 
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- or IEC-approved 
Informed Consent Form (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 enroll.  The 
subject and the study staff with whom he or she discusses the ICF will sign and date the ICF.  A 
copy of the fully signed ICF will be given to the subject. 
The Investigator will explain to the subject that they are completely free to decline entering the 
study and to withdraw from the study at any time, for any reason, without risking his or her 
medical care.  Similarly, the Investigator and/or Pacira Pharmaceuticals, Inc. (Pacira) 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 
2013).   
6. 
INVESTIGATORS AND STUDY ADMINISTRATION 
STRUCTURE 
Information regarding the Investigators, sites, laboratories, and other service providers is 
available upon request to the IRB/IECs and regulatory agencies. 
 
 
 
CONFIDENTIAL 
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02 August 2017 
 


Pacira Pharmaceuticals, Inc. 
 
402-C-409 (Spinal Fusion) 
EXPAREL® 
 
Clinical Study Protocol Amendment 2 
7. 
INTRODUCTION 
7.1. 
Indication 
EXPAREL® was developed to provide a prolonged period of decreased pain and decreased 
opioid use with a single dose administration without the use of indwelling catheters.  It is 
indicated for use as an analgesic injected into the surgical site for postsurgical pain relief. 
Effective postsurgical pain control is a critical element in patient recovery following surgery, 
as the majority of patients may experience significant pain, particularly in the first few days.  
Improved postsurgical pain management contributes to better healing, faster patient mobilization, 
shortened hospital stays, and reduced healthcare costs (American Society of Anesthesiologists 
Task Force on Pain Management 1995). 
7.2. 
Current Therapies/Treatments 
Current modalities of postsurgical analgesic treatment include wound infiltration and nerve block 
with local anesthetic agents, usually combined with the systemic administration of analgesics 
(multimodal therapy).  Multimodal therapy usually includes opioid medications, non-steroidal 
anti-inflammatory drugs (NSAIDs), and/or acetaminophen provided through a variety of routes 
including intravenous (IV), transdermal patch, and oral (PO) administration.  Opioids are widely 
used and considered some of the most powerful analgesics; however, they also have considerable 
drawbacks including time and resources required for monitoring opioid-related side effects.  
A reduction in the use of postoperative opioids is desirable to decrease the incidence and severity 
of opioid-induced adverse effects, such as respiratory depression, nausea, vomiting, constipation, 
somnolence, pruritus, and urinary retention.   
With over 70 million surgeries performed annually in the US, postoperative pain is a ubiquitous 
condition among our population.  While it is a predictable component of the postoperative 
process, such pain is often poorly managed, resulting in clinical and physiological changes that 
increase morbidity and mortality (inability to ambulate early, etc.), diminish quality of life, 
and extend length of stay, thereby increasing hospital expenditures (Oderda 2007) and reducing 
patient satisfaction.  Effective relief of acute pain with minimal opioid complications, on the 
other hand, may improve clinical outcomes, avoid complications (eg, delay in regaining bowel 
function or an inability to tolerate liquid and solid oral intake, etc.), and conserve healthcare 
resources.  As such, the Joint Commission on Accreditation of Healthcare Organizations 
(JCAHO) requires that all healthcare facilities practice adequate pain management and monitor 
opioid-related adverse events (AEs) (Apfelbaum 2003). 
Opioid analgesics have long been established to be the most effective agents used for the 
management of moderate to severe postoperative pain, and are currently considered the mainstay 
of treatment.  However, AEs related to opioid administration (eg, nausea, vomiting, ileus, 
confusion) represent one important reason that there is a need to develop opioid-sparing 
strategies.  Indeed, fear of gastrointestinal side effects such as nausea and vomiting, as well as 
respiratory depression, present major limitations for the widespread use of opioid analgesics 
(Chernin 2001 and Viscusi 2009).  Furthermore, management of opioid-related events often 
 
 
 
CONFIDENTIAL 
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Pacira Pharmaceuticals, Inc. 
 
402-C-409 (Spinal Fusion) 
EXPAREL® 
 
Clinical Study Protocol Amendment 2 
requires medical attention (eg, opioid antagonists, antiemetic agents) and increased 
pharmacy/nursing time, which may raise healthcare expenses (Carroll 1994).   
7.3. 
EXPAREL (Bupivacaine Liposome Injectable Suspension) 
Bupivacaine is one of the longer-acting local anesthetics, but even so it has a limited duration 
of action after local administration, usually reported as less than 8 hours.  EXPAREL (Pacira 
Pharmaceuticals, Inc., Parsippany, NJ) is a bupivacaine liposome injectable suspension.  
It consists of microscopic spherical, multivesicular liposomes (DepoFoam® drug delivery 
system), organized in a honeycomb-like structure comprising numerous non-concentric internal 
aqueous chambers containing a bupivacaine base at a concentration of 13.3 mg/mL.  Each 
chamber is separated from adjacent chambers by lipid membranes.  The lipids (phospholipids, 
cholesterol, and triglycerides) are naturally occurring or close analogs of endogenous lipids.  
Bupivacaine is slowly released from the DepoFoam particles by a complex mechanism involving 
reorganization of the barrier lipid membranes and subsequent diffusion of the drug over an 
extended period of time.  A small amount of extra-liposomal bupivacaine (ie, not bound within 
the DepoFoam particles) enables EXPAREL to have a similar onset of action to standard 
bupivacaine HCl.  Because of this, EXPAREL has been noted in wound infiltration studies to 
have a bimodal curve (Apseloff 2013), with an initial peak at approximately 0-2 hours and a 
second peak at approximately 24-48 hours (Hu 2013).  
EXPAREL was approved by the US FDA in 2011 for administration into the surgical site to 
produce postsurgical analgesia.  The active ingredient (bupivacaine) and inactive ingredient 
(DepoFoam) of EXPAREL are each contained, though separately, in FDA-approved products: 
• Bupivacaine HCl solution, a well-characterized anesthetic/analgesic, with more than 
35 years of its use in the US. 
• DepoFoam, a liposomal extended-release formulation contained in the marketed product 
DepoCyt® (1999).  The form of DepoFoam used in each of the products – DepoCyt and 
EXPAREL – has a slightly different mixture of lipid components.   
7.4. 
Summary of Human Experience with EXPAREL 
7.4.1. 
Wound Infiltration New Drug Application (NDA)  
During the original clinical development program (wound infiltration), Pacira conducted 
21 clinical studies and 1observational follow-up study to investigate EXPAREL (formerly 
known as SKY0402™).  Across these studies, a total of 1307 adult human subjects received 
EXPAREL at doses ranging from 9-665 mg and by various routes: local administration into the 
surgical wound, subcutaneous, perineural, and epidural.  The investigational drug product has 
been well tolerated and the reported AEs occurred at a similar rate as the corresponding 
bupivacaine HCl controls in the active comparator studies.   
In doses up to 665 mg of EXPAREL, no signal of any of the central nervous system or 
cardiovascular system AEs observed with high doses of bupivacaine HCl solution have been 
observed.  Two thorough QTc studies have been conducted; EXPAREL did not cause significant 
QTc prolongation even at the highest dose evaluated.   
 
 
 
CONFIDENTIAL 
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Pacira Pharmaceuticals, Inc. 
 
402-C-409 (Spinal Fusion) 
EXPAREL® 
 
Clinical Study Protocol Amendment 2 
Across all studies, the types of treatment-emergent adverse events (TEAEs) reported and the 
incidence rates generally were similar between the EXPAREL All Doses group (all doses 
combined) and the bupivacaine HCl group.  The incidence rate for each of the three most 
common TEAEs (nausea, constipation, and vomiting) was lower in the EXPAREL All Doses 
group than in the bupivacaine HCl group.   
EXPAREL was demonstrated to produce statistically significant and clinically meaningful 
analgesia in two pivotal placebo-controlled Phase 3 studies (SKY0402-C-317 and SKY0402-
C-316) involving both orthopedic and soft tissue procedures over 36 and 72 hours, respectively.  
In addition to meeting their primary endpoints (area under the curve [AUC] of the numeric rating 
scale [NRS] at rest [NRS-R] pain intensity scores through 72 hours [Study SKY0402-C-316] and 
through 24 hours [Study SKY0402-C-317]), key secondary endpoints also were met, 
demonstrating prolonged analgesia and reduction of opioid use by various measures (percentage 
of subjects who received no supplementary opioid medication; total amount of postoperative 
consumption of opioid medication; and time to first use of opioid medication).  The robust nature 
of the efficacy results in both pivotal studies SKY0402-C-316 and SKY0402-C-317 was 
demonstrated across subgroups of subjects with various prognostic features and across 
demographic subgroups.   
An analysis was performed to compare the incidence of opioid-related AEs between the 
EXPAREL and bupivacaine HCl groups in all bupivacaine-controlled, parallel-group wound 
infiltration studies (SIMPLE TKA 311, SKY0402-C-208, SIMPLE Hemorrhoidectomy 312, 
SKY0402-C-209, SKY0402-C-207, SKY0402-C-201, and SIMPLE Breast Augmentation 315).  
There was a statistically significantly lower incidence of opioid-related AEs in the EXPAREL 
≤266 mg group compared to the bupivacaine HCl group through 72 hours postdose.  This was 
consistent with the statistically significantly lower total postoperative consumption of opioids 
in the EXPAREL ≤266 mg group through 72 hours postdose.  Fewer subjects in the EXPAREL 
≤266 mg group had at least one opioid-related AE compared to the bupivacaine HCl group 
(25.6% versus 45.6%; p<0.0001).  The total opioid medication administered (adjusted geometric 
mean) through 72 hours postdose was statistically significantly lower in the EXPAREL ≤266 mg 
group (7.94 mg) compared to the bupivacaine HCl group (15.84 mg); p<0.0001.  The EXPAREL 
>266 mg group did not show a statistically significant advantage favoring EXPAREL; the mean 
(standard deviation [SD]) of the average number of opioid-related AEs per subject was 
0.58 (0.522), and the total opioid medication administered (adjusted geometric mean) through 
72 hours postdose was 22.82 mg in the EXPAREL >266 mg group. 
Please see the EXPAREL Full Prescribing Information for safety information regarding the use 
of EXPAREL for the treatment of postsurgical pain in the setting of wound infiltration. 
7.4.1.1. 
Nerve Block Supplemental NDA 
A total of 335 adult human subjects received EXPAREL as a nerve block in 6 clinical studies 
(SKY0402-002, SKY0402-C-111, SKY0402-C-203, SKY0402-C-211, 402-C-322, and 402-C-
323) involving three different surgical models (femoral nerve block, intercostal nerve block, and 
ankle nerve block).  Doses administered ranged from 2 mg to 310 mg.  The data from three of 
these studies (SKY0402-002, SKY0402-C-203, and SKY0402-C-211) were included in the 
 
 
 
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Pacira Pharmaceuticals, Inc. 
 
402-C-409 (Spinal Fusion) 
EXPAREL® 
 
Clinical Study Protocol Amendment 2 
wound infiltration NDA as well as the nerve block supplemental NDA (sNDA).  Additional 
nerve block studies are ongoing. 
Phase 3 Nerve Block Studies 
Study 402-C-322 was a Phase 3, multicenter, randomized, double-blind, parallel-group, placebo-
controlled study to investigate the efficacy and safety of intercostal nerve block using EXPAREL 
compared with placebo in subjects undergoing posterolateral thoracotomy. 
While there was no statistically significant difference in the mean AUC of the NRS-R pain 
intensity scores through 72 hours between subjects in the EXPAREL group and in the placebo 
group, a treatment effect was evident through 12 to 24 hours based upon a post hoc analysis.  
Intercostal nerve block with EXPAREL was well tolerated these subjects with similar numbers 
of TEAEs between the treatment groups, most of which were mild or moderate in severity.  
Twelve subjects (12.8%) in the EXPAREL group and 9 subjects (9.9%) in the placebo group 
experienced one or more treatment-emergent serious AEs (SAEs), none of which were 
considered by the Investigator to be related to the study drug.  Two of these subjects in the 
EXPAREL group (none were considered related to the study drug) and four of these subjects in 
the placebo group died.  
Study 402-C-323 was a Phase 2/3, multicenter, randomized, double-blind, parallel-group, 
placebo-controlled, dose-ranging study in subjects undergoing primary unilateral total knee 
arthroscopy (TKA) under general or spinal anesthesia.  Part 1 evaluated three dose levels of 
EXPAREL versus placebo with respect to the magnitude and duration of the analgesic effect 
achieved following single-dose injection femoral nerve block with EXPAREL, and subsequently 
selected a single therapeutic dose of EXPAREL from the three dose levels to be tested in Part 2. 
Femoral nerve block with EXPAREL at 67 mg, 133 mg, and 266 mg was well tolerated in 
subjects undergoing TKA.  There were no discernible safety differences across the treatment 
groups.  There was a dose response in EXPAREL-treated subjects.  A dose of 266 mg was 
selected for Part 2. 
The primary objective of Part 2 was to compare the magnitude and duration of the analgesic 
effect of single-injection femoral nerve block of the selected single dose level of EXPAREL with 
placebo (preservative-free normal saline for injection).  The difference in the AUC of the NRS-R 
pain intensity scores through 72 hours between the EXPAREL group and the placebo group was 
statistically significant.  Additionally, the difference in the total postsurgical opioid consumption 
(mg) through 72 hours between the EXPAREL 266 mg group and the placebo group was 
statistically significant indicating lower opioid consumption in the EXPAREL group.  
The incidences of TEAEs and treatment-emergent SAEs were similar between the EXPAREL 
266 mg group and the placebo group.  There were no deaths or withdrawals due to an AE during 
the study. 
Please refer to the Investigator’s Brochure for additional information regarding the completed 
studies.   
7.5. 
Postmarketing Exposure 
As of June 2016, more than 2 million adult patients have received EXPAREL in the 
postmarketing setting. 
 
 
 
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Pacira Pharmaceuticals, Inc. 
 
402-C-409 (Spinal Fusion) 
EXPAREL® 
 
Clinical Study Protocol Amendment 2 
8. 
OBJECTIVES 
8.1. 
Primary Objective 
 
The primary objective of this study is to compare postsurgical pain control following local 
infiltration analgesia (LIA) with EXPAREL admixed with bupivacaine HCl versus LIA with 
bupivacaine HCl in adult subjects undergoing open lumbar posterior spinal fusion surgery. 
8.2. 
Secondary Objectives 
 
The secondary objectives of this study are to compare additional efficacy, safety, and health 
economic outcomes following LIA with EXPAREL admixed with bupivacaine HCl versus LIA 
with bupivacaine HCl in adult subjects undergoing open lumbar posterior spinal fusion surgery 
9. 
OVERALL STUDY DESIGN AND PLAN 
9.1. 
Overall Study Design and Plan 
9.1.1. 
Study Design 
This is a Phase 4, multicenter, randomized, double-blind, controlled study in approximately 194 
adult subjects undergoing primary, 1-2 level, open lumbar spinal fusion surgery under general 
anesthesia. 
Subjects will be screened within 30 days prior to study drug administration.   
If a subject can only be screened on the day of surgery, the consent process must have started 
prior to the day of surgery to give ample time for the subject to review the consent. Screening 
procedures that are standard of care (SOC) at the institution may be completed prior to written 
informed consent, however any screening procedures that are not SOC, must be completed after 
written informed consent, and prior to surgery. 
During the screening visit, subjects will be assessed for past or present neurologic, cardiac, and 
general medical conditions that in the opinion of the Investigator would preclude them from 
study participation.  After the ICF is signed, a medical history, surgical history, physical 
examination, 12-lead electrocardiogram (ECG), vital sign measurements, urine drug screen, 
alcohol breath test, and urine pregnancy test for women of childbearing potential will be 
conducted. 
On Day 1, all eligible subjects will receive the following medications within 4 hours prior to 
surgery:  
• Acetaminophen 975-1000 mg, orally (PO) 
• Celecoxib 200 mg, PO 
o If a subject has an allergy to celecoxib, naproxen 500 mg PO twice a day or 
meloxicam 7.5 mg PO once a day may be used. 
 
 
 
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402-C-409 (Spinal Fusion) 
EXPAREL® 
 
Clinical Study Protocol Amendment 2 
• Gabapentin (eg, Neurontin) up to 900 mg, PO 
• TXA 1 gm (PO or IV) may be used at the start of surgery at the physician’s discretion 
• Versed 1-2 mg IV for anxiety may be used pre-operatively per physician discretion 
Subjects will be randomized 1:1 to two treatment groups and stratified by surgery type (1-Level 
or 2-Level).  Screw type (pedicle or cortical screws) will be recorded in the CRF.  Subjects in 
Group 1 will receive LIA with EXPAREL admixed with bupivacaine HCl and subjects in Group 
2 will receive LIA with bupivacaine HCl.  For subjects in Group 1 undergoing 1-Level 
procedures, EXPAREL 266 mg in 20 mL will be admixed with bupivacaine HCl 0.5% in 20 mL 
and expanded in volume with 20 mL normal saline for a total volume of 60 mL, while for 
subjects undergoing 2-Level procedures EXPAREL 266 mg in 20 mL will be admixed with 
bupivacaine HCl 0.5% in 20 mL and expanded in volume with 50 mL normal saline for a total 
volume of 90 mL.  Subjects in Group 2 undergoing 1-Level procedures will receive LIA with 
bupivacaine HCl 0.5% in 20 mL expanded in volume with 40 mL normal saline for a total 
volume of 60 mL, while subjects undergoing 2-Level procedures will receive LIA with 
bupivacaine HCl 0.5% in 20 mL expanded in volume with 70 mL normal saline for a total 
volume of 90 mL.  Trained and qualified Investigators will use their usual surgical technique to 
perform the surgery.  The following medications are permitted during surgery: 
• Propofol for induction and/or intraoperatively.  
• Lidocaine without epinephrine (0.5% or 1%) pre-incision to anaesthetize the 
incisional area 
o Must precede the use of EXPAREL or bupivacaine HCl by at least 20 
minutes. 
• Fentanyl or short-acting analogues  
• Any medication for nausea/vomiting prevention can be given at the physician’s 
discretion. 
Intraoperative administration of other opioids or any other analgesic, local anesthetics, or anti-
inflammatory agents will be prohibited in both groups, unless needed to treat an AE. 
Study drug, approximately 1-2 mL every 1.0-1.5 cm, will be administered using 20- or 22-gauge 
needles prior to wound closure.  The tissue should visibly expand with minimal leakage.  Study 
drug should be injected in the prescribed locations based on the areas of highest nerve density to 
include the muscular (above and below the fascia) and subdermal layers. Approximately 2/3 of 
study drug will be placed subfascial circumferentially above and below the paraspinous muscles, 
the remainder subdermal and subcutaneously.  Drains may be used at the surgeon’s discretion.  
If the surgery extends beyond 3 hours and the patient received TXA at the beginning of surgery, 
an additional 1 gm TXA may be dosed at the end of surgery. 
In addition to LIA, all study participants will receive a standardized approach for managing 
postsurgical pain that includes a scheduled multimodal pain regimen including adjunctive 
analgesics, NSAIDs.  Result analgesics will be available as needed.  
 
 
 
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Pacira Pharmaceuticals, Inc. 
 
402-C-409 (Spinal Fusion) 
EXPAREL® 
 
Clinical Study Protocol Amendment 2 
Postsurgically, all subjects are required to receive the following scheduled medications until 
hospital discharge: 
• Acetaminophen 975-1000 mg PO every 8 hours (q8h).  The total daily dose of 
acetaminophen is not to exceed 3000 mg. Acetaminophen IV can be used if the 
patient is unable to tolerate oral acetaminophen 
• Celecoxib 200 mg PO every 12 hours (q12h) up to 48 hours post surgery. 
o If a subject has an allergy to celecoxib, naproxen 500 mg PO twice a day or 
meloxicam 7.5 mg PO once a day may be used. 
• Gabapentin (eg, Neurontin) up to 900 mg PO q8h  
• Cyclobenzaprine (eg, Flexeril) 10 mg PO  x1 dose (PRN at surgeon discretion) 
A prewritten order sheet with the scheduled medications will be given to the nurses for the 
subjects in this study. 
Postsurgical Rescue Medication 
Subjects should only receive rescue medication upon request for pain control, as needed.  
Postsurgical rescue medication will consist of PO immediate-release oxycodone initiating up to 
10 mg.  The subject may re-dose, per physician judgment, as needed (PRN), if the initial rescue 
medication fails.  If a subject cannot tolerate PO medication or has repeated failure of the rescue 
medication with oxycodone (PO), IV morphine (2.5-5 mg) or hydromorphone (0.5-1 mg) may be 
administered q4h or PRN.  Patient-controlled analgesia (PCA) is not permitted.  No other 
rescue analgesic agents, including NSAIDs, are permitted until hospital discharge.  After 
discharge, the analgesic regimen may be adjusted for each subject individually as deemed 
appropriate by the physician responsible for the postsurgical care. 
Postsurgical Assessments 
Postsurgical clinical assessments will include pain intensity scores using a 10-cm VAS 
(see Appendix 1); OBAS questionnaire (see Appendix 2); total postsurgical opioid consumption; 
predefined opioid-related AEs; and nurse’s satisfaction with overall analgesia (see Appendix 3).   
Adverse events will be recorded from the time the ICF is signed through Day 30.  If a cardiac AE 
(eg, chest pain [angina, myocardial infarction], abnormal/irregular heart rate [bradycardia, 
tachycardia, extrasystoles], or shortness of breath), neurological AE (eg, altered mental 
status/altered sensorium, dizziness, dysarthria, hyperesthesia, metallic taste, peroral numbness, 
seizure, tinnitus, tremors, visual disturbance, muscular twitching or rigidity beyond 72 hours 
postdose, or tingling/paresthesia beyond 72 hours postdose), or SAE occurs during the study, a 
12-lead ECG, vital signs, and any appropriate clinical laboratory tests should be conducted. 
Postsurgical health economic outcome assessments will include hospital length of stay (LOS), 
use of skilled nursing facility, hospital readmissions, and use of other health services following 
discharge (phone calls related to postsurgical pain, unscheduled visits related to postsurgical 
pain, and visits to emergency department) through Day 30. 
A follow-up visit will be scheduled for all subjects on postsurgical Day 14.  A follow-up phone 
call will be made on Day 30 to all subjects who received study drug to assess for AEs. 
 
 
 
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Pacira Pharmaceuticals, Inc. 
 
402-C-409 (Spinal Fusion) 
EXPAREL® 
 
Clinical Study Protocol Amendment 2 
9.1.2. 
Duration of the Study and Subject Participation 
Participation will begin at the signing of the ICF.  No more than 30 days should pass between 
signing of the ICF and the administration of EXPAREL.  The time from study drug 
administration through the end of participation is 30 ± 3 days.  Therefore, subjects may 
participate in the study for up to 63 days. 
9.1.3. 
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 (ie, 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 suggest a potential threat to the safety of the study 
participants. If such action is taken, a thorough review of all available data will be conducted and 
may include unblinded data review by an Independent Safety Monitoring Committee. 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. 
. 
9.2. 
Discussion of Study Design 
EXPAREL is approved for infiltration into a surgical site.  This Phase 4 study is designed to 
compare postsurgical pain control and total opioid consumption following LIA with EXPAREL 
admixed with bupivacaine HCl versus LIA with bupivacaine HCl in adult subjects undergoing 
open posterior lumbar spinal fusion surgery. 
All subjects will receive an opioid analgesic(s) to control breakthrough postsurgical pain, as 
needed. 
If a cardiac or neurological AE of special interest or SAE occurs during the study,  a 12-lead 
ECG, vital signs, and any appropriate clinical laboratory tests must be conducted as close as 
possible to when the event occurs.   
10. 
STUDY POPULATION 
Subjects must meet all eligibility criteria to be enrolled in this study. 
10.1. 
Inclusion Criteria 
Subjects eligible for study entry must meet all of the following criteria: 
1. Male or female, at least 18 years of age at screening. 
 
 
 
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402-C-409 (Spinal Fusion) 
EXPAREL® 
 
Clinical Study Protocol Amendment 2 
2. Primary surgical indication is lumbar pain, radiculopathy, disc degeneration, disc 
herniation, foraminal stenosis, or 1-2 level spondylolisthesis or deformity. 
3. Scheduled to undergo primary, 1-2 level, open spine fusion under general anesthesia. 
4. American Society of Anesthesiologists (ASA) physical status 1, 2, or 3.  
5. Female subjects must be surgically sterile; or at least 2 years postmenopausal; or have a 
monogamous partner who is surgically sterile; or practicing double-barrier contraception; 
or practicing abstinence (must agree to use double-barrier contraception in the event of 
sexual activity); or using an insertable, injectable, or transdermal, contraceptive approved 
by the FDA for greater than 2 months prior to screening.  All women of childbearing 
potential (ie, premenopausal without permanent sterilization) must commit to the use of an 
acceptable form of birth control for the duration of the study and for 30 days after 
completion of the study. 
6. Able to provide informed consent, adhere to the study visit schedule, and complete all 
study assessments. 
10.2. 
Exclusion Criteria 
A subject will not be eligible for the study if he or she meets any of the following criteria:  
1. Currently pregnant, nursing, or planning to become pregnant during the study or within 1 
month after study drug administration. 
2. Serious spinal conditions (to include cauda equina syndrome, infection, tumor, fracture, or 
severe osteoporosis [ie, if taking bisphosphonate or TNF-α blockers]). 
3. Planned anterior or lateral incisions 
4. Previous spinal surgery at the same level other than microdiscectomy or hemilaminectomy 
(eg, bi-lateral laminectomy, fusion). 
5. Planned concurrent surgical procedure. 
6. Identification of a dural tear during surgery will be an intra-operative exclusion unless it is 
well repaired (no evidence of CSF leak with Valsalva and no plan to restrict activity post-
operatively).  Any injury to the nerve root occurring during surgery will also be considered 
an intra-operative exclusion. 
7. Concurrent painful physical condition that may require analgesic treatment (such as an 
NSAID or opioid) in the postsurgical period for pain that is not strictly related to the spinal 
surgery and which may confound the postsurgical assessments. 
8. Comorbidity impacting current physical function or Investigator opinion that it may impact 
postsurgical rehabilitation. 
9. Allergy, hypersensitivity, or contraindication to any of the study medications (ie, 
bupivacaine, oxycodone, morphine, hydromorphone, gabapentin, acetaminophen, or 
cyclobenzaprine) for which an alternative medication is not provided in the protocol.   
 
 
 
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402-C-409 (Spinal Fusion) 
EXPAREL® 
 
Clinical Study Protocol Amendment 2 
10. Use of any of the following medications within the times specified before surgery: long-
acting opioid medication (eg, morphine including MS Contin®, hydromorphone 
[Dilaudid®], oxycodone [Oxycontin®], methadone) daily for more than 3 months duration 
or within 3 days of surgery.  Patients receiving short-acting opioids or NSAIDs should be 
at a steady or plateau dose. Such patients should require or receive no more than 40 mg 
morphine (oral) equivalents (eg, approximately 5 mg oxycodone) within 24 hours of 
surgery. 
11. Initiation of treatment with any of the following medications within 1 month of study drug 
administration or if the medication(s) are being given to control pain: selective serotonin 
reuptake inhibitors (SSRIs), selective norepinephrine reuptake inhibitors (SNRIs), or 
duloxetine (Cymbalta).  If a subject is taking one of these medications for a reason other 
than pain control, he or she must be on a stable dose for at least 1 month prior to study drug 
administration.   
12. Current use of systemic glucocorticosteroids within 1 month of enrollment in this study. 
13. Use of dexmedetomidine HCl (Precedex) within 3 days of study drug administration. 
14. History of coronary or vascular stent placed within the past 3 months (may be extended to 
1 year if medically indicated per physician discretion).  
15. Have been treated for a deep vein thrombosis, pulmonary embolism, myocardial infarction, 
or ischemic stroke within the past 6 months (may be extended to 1 year if medically 
indicated per physician discretion). 
16. Severely impaired renal (eg, serum creatinine clearance ≤ 30) or hepatic function (eg, 
serum AST level >3 x ULN or serum ALT level >3 x ULN). 
17. Any neurologic or psychiatric disorder that might impact postsurgical pain or interfere with 
study assessments. 
18. Malignancy in the last 2 years, per physician discretion. 
19. History of misuse, abuse, or dependence on opioid analgesics, other prescription drugs, 
illicit drugs, or alcohol as defined in DSM-IV.  Dependence or chronic opioid use will be 
defined as use of more than 30 morphine equivalents per day during the prior 90 days. 
20. Failure to pass the alcohol breath test or urine drug screen positive for illicit drugs. 
21. Body weight <50 kg (110 pounds) or a body mass index >44 kg/m2. 
22. Subjects receiving Worker’s compensation for a disability or who are involved in litigation. 
23. Previous participation in an EXPAREL study. 
24. 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. 
 
 
 
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402-C-409 (Spinal Fusion) 
EXPAREL® 
 
Clinical Study Protocol Amendment 2 
10.3. 
Removal of Subjects From Therapy or Assessment 
Every reasonable effort should be made to maintain subject compliance and participation in the 
study.  Subjects who withdraw from the study after receiving study drug should undergo safety 
assessments through the end of the study (Day 30).   
If a subject who withdraws from the study has an ongoing AE, every effort must be made to 
follow such events until satisfactory resolution is obtained, or further follow-up is otherwise no 
longer warranted.  
10.3.1. 
Withdrawal Secondary to Adverse Events 
If a subject experiences an AE that renders him or her incapable of continuing with the 
remaining study assessments, then he or she will be discontinued from further participation in the 
study.  A final evaluation visit should be performed so that the subject’s study participation can 
be terminated in a safe and orderly manner. 
Otherwise, the subject will be instructed to notify the study personnel of any abnormalities 
during the intervals between study visits and to come to the study site if medical evaluation is 
needed and the urgency of the situation permits.  Any subject exhibiting undesirable side effects 
will receive appropriate treatment at the discretion of the Investigator.   
This study involves a single administration 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 will be obtained by the 
Investigator. 
10.3.2. 
Voluntary or Study Investigator Withdrawal 
Subjects are free to discontinue participation in the study at any time, without prejudice to future 
treatment.  Nevertheless, subjects will be encouraged to complete at least the study safety 
assessments.  In addition, a subject may be discontinued from the study if he or she refuses to 
comply with study procedures.  Reasons for discontinuation from the study will be recorded. 
If a subject is discontinued by the Investigator or voluntarily withdraws from the study after 
receiving study drug, the subject will be asked to complete a final evaluation so that he or she 
can be withdrawn in a safe and orderly manner.  In the final evaluation, vital signs (temperature, 
resting heart rate, respiratory rate, and blood pressure) and any changes in the subject's health 
status will be recorded.   
After termination from the study, the subject may be followed for safety including monitoring of 
AEs through Day 30.   
11. 
TREATMENTS 
11.1. 
Treatments to be Administered 
Study Drug (Group 1) 
 
 
 
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402-C-409 (Spinal Fusion) 
EXPAREL® 
 
Clinical Study Protocol Amendment 2 
Subjects randomized to EXPAREL will receive LIA with EXPAREL admixed with bupivacaine 
HCl.  For subjects undergoing 1-Level procedures, EXPAREL 266 mg in 20 mL will be admixed 
with bupivacaine HCl 0.5% in 20 mL and expanded in volume with 20 mL normal saline for a 
total volume of 60 mL, while for subjects undergoing 2-Level procedures EXPAREL 266 mg in 
20 mL will be admixed with bupivacaine HCl 0.5% in 20 mL and expanded in volume with 
50 mL normal saline for a total volume of 90 mL.   
Active Comparator (Group 2) 
Subjects randomized to bupivacaine will receive LIA with bupivacaine HCl.   Subjects 
undergoing 1-Level procedures will receive LIA with bupivacaine HCl 0.5% in 20 mL expanded 
in volume with 40 mL normal saline for a total volume of 60 mL, while subjects undergoing 
2-Level procedures will receive LIA with bupivacaine HCl 0.5% in 20 mL expanded in volume 
with 70 mL normal saline for a total volume of 90 mL. 
Postsurgical Pain Management 
The use of postsurgical pain medication in cases of insufficient analgesia is permitted per the 
institution’s standard of care.  The Investigator must record all pain management medications 
provided to the subjects through Day 30.    
11.1.1. 
Administration Instructions/Procedures 
Study drug should be injected in the prescribed locations based on the areas of highest nerve 
density.  Study drug will be administered using syringes with 20- or 22-gauge needles prior to 
wound closure.  The Investigator must document the size of the incision.  Each infiltration site 
should be spaced 1.0-1.5 cm apart and should deliver approximately 1-2 mL into both deep and 
superficial areas (para-spinous fascia, muscle, and subcutaneous layers).  Total volume 
administered will be depended on the number of levels of dissection, as described below.  
Following infiltration, the tissue should visibly expand with minimal leakage.   
Total Volume of Expansion  
The Investigator must document the total volume used for each surgery. 
1-Level Procedures 
Group 1:  EXPAREL 266 mg in 20 mL + bupivacaine HCl 0.5% in 20 mL + 20 mL normal 
saline = total volume of 60 mL 
Group 2:  Bupivacaine HCl 0.5% in 20 mL + 40 mL normal saline = total volume of 60 mL 
2-Level Procedures 
Group 1:  EXPAREL 266 mg in 20 mL + bupivacaine HCl 0.5% in 20 mL + 50 mL normal 
saline = total volume of 90 mL 
Group 2:  Bupivacaine HCl 0.5% in 20 mL + 70 mL normal saline = total volume of 90 mL 
11.1.2. 
Study Drug Administration Considerations 
As there is a potential risk of severe adverse effects associated with the administration of 
bupivacaine, the study site must be equipped to treat subjects with evidence of cardiac toxicity.   
 
 
 
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402-C-409 (Spinal Fusion) 
EXPAREL® 
 
Clinical Study Protocol Amendment 2 
EXPAREL may not be administered to a subject if the vial has been open for more than 4 hours.  
In order to prevent the study drug from settling, gently inverting and re-inverting the syringe 
several times prior to administration is recommended.  No agents are to be admixed with 
EXPAREL other than bupivacaine HCL 0.5% in 20 mL.  
11.2. 
Identity of Investigational Product(s) 
11.2.1. 
Description of EXPAREL 
EXPAREL is formulated as a sterile, non-pyrogenic, white to off-white, preservative-free, 
homogeneous suspension of bupivacaine encapsulated into multivesicular lipid-based particles 
(the DepoFoam drug delivery system).  Bupivacaine is present at a nominal concentration of 
13.3 mg/mL.  EXPAREL will be provided in 20 mL, 1.3% (13.3 mg/mL) single-use, clear glass 
vials.  EXPAREL vials should be stored refrigerated between 2°C to 8°C (36°F to 46°F). 
11.2.2. 
Description of Reference Product 
Bupivacaine HCl is a long-acting local anesthetic, used for surgical anesthesia and acute pain 
management.  It is an alternative to NSAIDs and opioids.  A multimodal approach of pain 
management with the use of a long-acting local anesthetic can reduce the total consumption of 
NSAIDs and opioids during the critical first 12 hours post-surgery.   
11.2.3. 
Description of Diluents 
Normal saline (0.9% sodium chloride solution) for injection will be used for the dilution (volume 
expansion) of study drug.   
11.3. 
Method of Assigning Subjects to Treatment 
11.3.1. 
Randomization Scheme 
Subjects will be randomized 1:1 to two treatment groups and stratified by surgery level (1-Level 
or 2-level).  Screw type (pedicle or cortical screws) will be recorded in the CRF.  Subjects in 
Group 1 will receive LIA with EXPAREL admixed with bupivacaine HCl and subjects in Group 
2 will receive LIA with bupivacaine HCl.  For subjects in Group 1 undergoing 1-Level 
procedures, EXPAREL 266 mg in 20 mL will be admixed with bupivacaine HCl 0.5% in 20 mL 
and expanded in volume with 20 mL normal saline for a total volume of 60 mL, while for 
subjects undergoing 2-Level procedures EXPAREL 266 mg in 20 mL will be admixed with 
bupivacaine HCl 0.5% in 20 mL and expanded in volume with 50 mL normal saline for a total 
volume of 90 mL.  Subjects in Group 2 undergoing 1-Level procedures will receive LIA with 
bupivacaine HCl 0.5% in 20 mL expanded in volume with 40 mL normal saline for a total 
volume of 60 mL, while subjects undergoing 2-Level procedures will receive LIA with 
bupivacaine HCl 0.5% in 20 mL expanded in volume with 70 mL normal saline for a total 
volume of 90 mL.  The volume of study drug to be used will be the same for both screw types. 
The stratification is to ensure equal representation of the treatment groups within each level of 
stratification.  The sample size within a stratification is not fixed.  It is not expected that there 
will be sufficient subjects test within all strata. 
 
 
 
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Pacira Pharmaceuticals, Inc. 
 
402-C-409 (Spinal Fusion) 
EXPAREL® 
 
Clinical Study Protocol Amendment 2 
The randomization code will be generated by a centralized randomization system, which will 
also be used to communicate subject randomizations to study sites.  All randomized subjects will 
have both a unique subject identifier and a unique random code identifier.  No subject or random 
code identifiers are to be reused once assigned. 
11.3.2. 
Randomization Procedures 
Once a subject is identified as being qualified for the study per the eligibility criteria (see 
Section 10.1 and Section 10.2), and is at the study site for surgery, the authorized site staff or 
designee will obtain a randomization assignment.  The subject will be considered randomized 
into the study once the study treatment assignment is received. 
11.3.3. 
Replacement of Subjects 
Subjects who are withdrawn from the study before receiving study drug may be replaced.  
Once assigned, subject numbers will not be reused; subjects enrolled to replace those who 
withdraw will be assigned a unique subject number. 
11.4. 
Selection of Doses in the Study 
During the clinical development of EXPAREL, single doses ranging from 2 mg to 665 mg have 
been safely administered via various routes.  Pharmacokinetic studies have shown that because 
EXPAREL releases bupivacaine gradually as the lipid structure breaks down, administration of 
EXPAREL 266 mg results in a maximum plasma concentration (Cmax) equivalent to that seen 
with standard bupivacaine HCl 100 mg.  EXPAREL 266 mg, the FDA-approved and marketed 
dose, was selected for this study. 
11.5. 
Blinding  
11.5.1. 
Blinding Procedures 
Subjects will be randomized using central interactive response technology (IRT) and treatment 
assignment will be known to the Investigator performing the surgery.  However, the subject will 
be blinded to their treatment assignment, as will be any study personnel performing study 
evaluations.  Routine medical review of the treated subject data will be conducted by the Pacira 
Medical Monitoring Team on a bi-weekly basis, or as needed, throughout the conduct of this 
study (as described in Section 9.1.3), which will evaluate all reported AEs for severity, 
seriousness, and relationship to the study drug. 
To maintain the double-blind study design, only the unblinded study personnel who are NOT 
involved with protocol-specific, postsurgical assessments may prepare and administer the study 
drug.  Staff members conducting study-specific, postsurgical assessments and the subjects will 
remain blinded to the assigned treatment throughout the study.  
At each site, only the designated unblinded pharmacist will receive the unblinded randomization 
assignments and be responsible for preparing study drug. 
 
 
 
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EXPAREL® 
 
Clinical Study Protocol Amendment 2 
11.5.2. 
Unblinding Procedures 
Subject treatment assignments should not be unblinded during the study by blinded study 
personnel.  The Investigator will have the ability to unblind a subject through the randomization 
system if he or she feels that subject safety warrants such unblinding.  However, the Investigator 
should discuss the safety issues with the Medical Monitor before attempting such unblinding, 
if possible.  Any unblinding will be documented through immediate notification of the Pacira 
study team and the Investigator within the IRT system used for randomization.  The reason for 
unblinding will be documented.  Any accidental unblinding events (ie, through mishaps in the 
operating room or miscommunication among study staff) must be reported to Pacira 
immediately.  
Any unblinding performed through the randomization system will be recorded as a transaction 
and the appropriate study personnel will be notified that such a transaction occurred. 
Any incidence(s) of unblinding will be noted in the clinical study report with a full discussion of 
the events leading to the decision to unblind. 
11.6. 
Prior and Concomitant Therapy and Medications  
Any medications for the condition for which the procedure is being performed administered 
within 30 days prior to study drug administration will be recorded on the case report form (CRF), 
as well all medications through Day 30 after study drug administration or until the subject is 
withdrawn from the study, whichever is sooner.  Additionally, any medications administered in 
association with an AE will be recorded through Day 30.   
11.6.1. 
Before Study Drug Administration  
Permitted Prior Medications and Therapy 
Prophylactic antibiotics are permitted, according to the surgeon’s preference.   
Gabapentin (Neurontin) or pregabalin (Lyrica) is permitted pre-operatively if the duration has 
been less than 6 weeks. 
On the day of surgery (Day 1), all eligible subjects will receive the following medications: 
• Acetaminophen 975-1000 mg PO 
• Celecoxib 200 mg, PO 
o If a subject has an allergy to celecoxib, naproxen 500 mg PO twice a day or 
meloxicam 7.5 mg PO once a day may be used 
• Gabapentin up to 900 mg, PO 
• TXA 1 gm (PO or IV) may be used at the start of surgery at the physician’s discretion  
• Versed 1-2 mg IV for anxiety may be used pre-operatively per physician discretion 
Restricted Prior Medications and Therapy 
Before screening 
 
 
 
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EXPAREL® 
 
Clinical Study Protocol Amendment 2 
• Bupivacaine and any other local anesthetic are not permitted within 7 days of 
screening 
Within 3 days pre-op 
• Long-acting opioid medication (eg, morphine including MS Contin, hydromorphone 
[Dilaudid], oxycodone [Oxycontin], methadone) daily for more than 3 months 
duration or within 3 days pre-op  
• Patients receiving short-acting opioids or NSAIDs should be at a steady or plateau 
dose. Such patients should require or receive no more than 20 mg morphine 
equivalents (eg, 4 Percocet) within 24 hours of surgery. 
• Dexmedetomidine HCl (Precedex) 
Within 1 month pre-op 
• Selective serotonin reuptake inhibitors (SSRIs), selective norepinephrine reuptake 
inhibitors (SNRIs), or Duloxetine (Cymbalta).   
o Note: If a subject is taking one of these medications for a reason other than 
pain control, he or she must be on a stable dose for at least 1 month prior to 
study drug administration.   
• Dermal or systemic glucocorticosteroids (eg, Decadron) are prohibited within 1 
month of enrollment in this study. 
• Use 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 is not permitted. 
11.6.2. 
During Surgery 
Permitted 
• Propofol for induction and/or intraoperatively.  
• Lidocaine without epinephrine (0.5% or 1%) pre-incision to anaesthetize the 
incisional area 
o Must precede the use of EXPAREL or bupivacaine HCl by at least 20 
minutes. 
• Fentanyl or short-acting analogues  
• Any medication for nausea/vomiting prevention can be given at the physician’s 
discretion. 
Restricted 
• No drugs are to be admixed with study drug other that bupivacaine HCl (eg, 
epinephrine, dexamethasone, clonidine). 
 
 
 
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EXPAREL® 
 
Clinical Study Protocol Amendment 2 
• Local anesthetics other than lidocaine (as described above) will not be permitted to be 
locally administered during surgery because they are known to interact with 
EXPAREL resulting in the displacement of bupivacaine and elevated plasma levels. 
• The use of long-acting opioids (eg, morphine, hydromorphone HCl), acetaminophen/ 
paracetamol, ketorolac, or other NSAIDs will not be permitted intraoperatively except 
for emergency use to treat an AE.   
• Decadron is not permitted for nausea/vomiting prevention 
11.6.3. 
After Surgery  
Permitted 
• Acetaminophen 975-1000 mg PO q8h.  The total daily dose of acetaminophen is not 
to exceed 3000 mg. Acetaminophen IV can be used if the patient is unable to tolerate 
oral acetaminophen 
• Celecoxib 200 mg PO q12h up to 48 hours post-surgery 
o If a subject has an allergy to celecoxib, naproxen 500 mg PO twice a day or 
meloxicam 7.5 mg PO once a day may be used. 
• Gabapentin (eg, Neurontin) up to 900 mg PO q8h  
• Cyclobenzaprine (eg, Flexeril) 10 mg PO x1 dose (PRN at surgeon discretion) 
Restricted 
• No other analgesics, including fentanyl, are permitted up to 72 hours after study drug 
administration or discharge from the hospital. 
• PCA is not permitted.   
• Anesthetics in the “caine” family, which may interfere with the bupivacaine PK 
profile, are prohibited through Day 14. 
For study purposes, it is important to standardize pain management modalities through hospital 
discharge.  Therefore, the study staff must adhere closely to the treatment options and 
requirements noted in the protocol.  After hospital discharge, the analgesic regimen may be 
adjusted for each subject individually as deemed appropriate by the physician responsible for the 
postsurgical care. 
11.7. 
Treatment Compliance 
Not applicable because the study drug (EXPAREL or bupivacaine HCl) will be administered 
preoperatively by the study staff. 
11.8. 
Accountability of Study Drug 
Any shipment of EXPAREL for the study will contain an investigational drug transmittal and 
receipt form to assist the Investigator or designee (eg, pharmacist) in maintaining current and 
accurate inventory records.  At a minimum, the pharmacist or designee will maintain accurate 
 
 
 
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EXPAREL® 
 
Clinical Study Protocol Amendment 2 
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.  Drug allocations 
will also be logged in the IRT which will maintain records.  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 an unblinded 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 unblinded study monitor and appropriate regulatory 
authorities at any time.  A copy of the inventory records, drug accountability information, and 
notice of return or destruction will be returned to Pacira at the end of the study.  Only authorized 
personnel identified by the Investigator will have the ability to access and administer the drug. 
12. 
STUDY ENDPOINTS AND MEASUREMENTS 
12.1. 
Efficacy Measurements 
The following efficacy measurements will be conducted:   
• 
Pain intensity scores using the VAS on Day 1, pre-operative; upon arrival at the post-
anesthesia care unit (PACU); at 4, 6, 8, 10, 12, 24, 28, 32, 36, 48, 52, 56, 60, and 72 
hours; immediately prior to each administration of rescue pain medication; and just prior 
to hospital discharge (see Appendix 1).  Note: if the subject is sleeping, do not wake him 
or her for an assessment of pain at 24 or 48 hours after surgery. If he or she awakens 
within the assessment window (ie, 1 hour for the 24-hour assessment and 2 hours for the 
48-hour assessment), a pain score may be collected then. 
†: If discharge occurs prior to any of the scheduled VAS assessments collected at 4 to 72 
hours postsurgery or scheduled OBAS assessments collected at 24 to 72 hours, the study 
coordinator must stress to the subject the importance of completing the scheduled VAS 
and OBAS assessments.  These assessments should be recorded by the subject in the 
patient log provided upon discharge. 
• 
Amount of all opioid rescue analgesics taken through Day 30. 
• 
Predefined treatment-emergent opioid-related AEs. 
• 
The OBAS questionnaire at 24, 48, and 72 hours (see Appendix 2).  Note: if discharge 
occurs before 72 hours, the study coordinator must stress to the patient the importance of 
completing the scheduled OBAS questionnaire up to 72 hours.  Completion of the 
questionnaire should be recorded by the patient in the patient log provided upon 
discharge. 
• 
Nurse’s satisfaction with overall analgesia will be assessed at 24, 48, and 72 hours or 
upon hospital discharge (see Appendix 3). 
12.2. 
Efficacy Endpoints 
The efficacy endpoints listed below will be assessed based on the efficacy measurements 
conducted at the times specified after the end of surgery. 
Primary Efficacy Endpoint: 
 
 
 
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EXPAREL® 
 
Clinical Study Protocol Amendment 2 
The co-primary efficacy endpoints are the AUC of the VAS pain intensity scores from 12−48 
hours and the total opioid consumption (in IV morphine equivalents) from 0–48 hours. 
Secondary Endpoints: 
• Proportion of subjects who are pain free (defined as a VAS pain intensity score of 
≤1.5 and no prior rescue medication) at each assessed timepoint.  
• The VAS pain intensity scores at each assessed timepoint.  
• The AUC of the VAS pain intensity scores through 24, 36, 48, 60, and 72 hours. 
• The AUC of the VAS pain intensity scores from 24–48 and 48–72 hours. 
• The sum of the pain intensity scores (SPIS) through 24, 48, and 72 hours. 
• SPIS from 24–48 and 48–72 hours. 
• Total inpatient postsurgical opioid consumption (in mg) through 24 and 72 hours or 
hospital discharge.  
• Total postsurgical opioid consumption (in mg) from hospital discharge through 
Day 30. 
• Percentage of opioid-free subjects through 24, 48, and 72 hours or hospital discharge.  
• Time to first opioid rescue through 72 hours or hospital discharge. 
• Incidence of the following opioid-related AEs until the discharge order is written: 
respiratory depression, hypoventilation, hypoxia, dry mouth, nausea, vomiting, 
constipation, altered mental status, pruritus, urinary retention, and postoperative ileus. 
• The OBAS total score at 24, 48, and 72 hours. Note: if discharge occurs before 72 
hours, the study coordinator must stress to the patient the importance of completing 
the scheduled OBAS questionnaire up to 72 hours.  Completion of the questionnaire 
should be recorded by the patient in the patient log provided upon discharge. 
• Pain interference pre-operative and at Day 14. 
• Nurse's satisfaction with overall analgesia at 24, 48, and 72 hours or upon hospital 
discharge. 
12.3. 
Health Economic Outcomes Assessments 
The health economic outcomes will include: 
• Hospital LOS. 
• Hospital readmissions. 
• Use of skilled nursing facility. 
• Use of other health services following hospital discharge (phone calls related to pain, 
unscheduled visits related to pain, and visits to the emergency department). 
 
 
 
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12.4. 
Health Economic Outcomes Endpoints 
• Hospital LOS, defined as the time from completion of the wound closure until the 
hospital discharge order is written or through Day 30, whichever is sooner. 
• Percentage of subjects meeting the protocol-specified minimum criteria for discharge 
(ie, no requirement for parenteral pain management, able to tolerate a liquid diet, able 
to demonstrate safe mobility, not requirement for active wound management) and 
discharged by time (eg, a “responder analysis”). 
• Incidence of hospital readmission through Day 30.  
• Incidence of skilled nursing facility use. 
• Total time spent in skilled nursing facility. 
• Number of phone calls related to postsurgical pain. 
• Number of unscheduled visits related to postsurgical pain. 
• Number of visits to the emergency department. 
12.5. 
Safety Assessments 
The following safety measurements will be conducted at the timepoints specified after the end of 
study drug administration: 
• Adverse events from the time the ICF is signed through Day 30. 
12.6. 
Safety Endpoints 
The following safety endpoints will be assessed based on the safety measurements conducted at 
the specified timepoints: 
• Incidence of TEAEs and SAEs through Day 30. 
12.7. 
Appropriateness of Measures 
Endpoints selected for this study are based on validated methodologies and other well 
established clinical measurements used in other peer-reviewed studies in both the peer reviewed 
literature and at regulatory authorities.  
13. 
STUDY PROCEDURES 
A time and events schedule for study procedures is provided in Table 1. 
13.1. 
Instructions for Conducting Procedures and Measures 
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.  All assessments conducted after baseline (ie, study drug 
administration) will be timed from the end of surgery, defined as the time of the last 
suture/staple.  Postsurgical is defined as after the end of surgery.   
 
 
 
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Clinical Study Protocol Amendment 2 
Subjects can be discharged based on current clinical practice but, at a minimum, should: 
• No longer require parenteral pain management 
• Be able to tolerate a liquid diet 
• Demonstrate safe mobility as determined with occupational therapy/physical therapy 
input per hospital standards 
13.1.1. 
Pain Intensity Assessment 
Pain intensity will be assessed using a 10-cm VAS (Carlsson 1983, McCormack 1988, and 
Scott 1976) at baseline (on Day 1 prior to surgery and prior to any premedication); upon arrival 
at the PACU; at 4, 6, 8, 10, 12, 24, 28, 32, 36, 48, 52, 56, 60, and 72 hours; and immediately 
prior to each administration of postoperative rescue opioid pain management medication through 
72 hours or hospital discharge (see Appendix 1).   
13.1.2. 
Clinical Laboratory Tests 
The following select clinical laboratory tests will be conducted at screening:  
1.  Direct bilirubin 
2.  Gamma-glutamyl transpeptidase (GGT) and lactate dehydrogenase (LDH)  
OR  
Alanine transaminase (ALT) and aspartate transaminase (AST).   
Clinical laboratory tests, as appropriate, may also be conducted if a subject experiences an AE of 
special interest (ie, cardiac AE or neurological AE) or an SAE (see Section 13.1.5).  
13.1.3. 
Vital Signs 
The scheduled vital signs (temperature, resting heart rate, respiratory rate, and blood pressure) 
will be measured at screening; baseline (on Day 1 prior to surgery; Note: the Day-1 pre-op 
assessment is not required if the Screening Visit occurred within 10 days of the surgery) and if a 
subject experiences an AESI (ie, cardiac AE or neurological AE) or an SAE (see Section 13.1.5).   
13.1.4. 
Physical Examination 
A full physical examination will be conducted at screening, including a 12-lead ECG and urine 
pregnancy test.  Superficial abnormalities that may interfere with participation in the study will 
be noted.  A targeted physical examination will be conducted on Day 14 and will include 
examination of the surgical site.   
13.1.5. 
Adverse Events of Special Interest 
If a cardiac or neurological AESI or SAE occurs during the study a 12-lead ECG, vital signs, PK 
draw, and any appropriate clinical laboratory tests must be conducted.     
Cardiac AEs of special interest include:  
• Chest pain (angina, myocardial infarction)  
• Abnormal/irregular heart rate (bradycardia, tachycardia, extrasystoles) 
 
 
 
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• Shortness of breath requiring intervention.   
Neurologic AEs of special interest include:  
• Altered mental status/altered sensorium 
• Rigidity 
• Dysarthria 
• Seizure 
• Tremors 
• Metallic taste 
• Tinnitus 
• Perioral numbness 
• Visual disturbance 
• Severe or worsening dizziness 
Additionally, the following events are of special interest if they persist or occur beyond 72-hours 
postdose:  
• Dizziness 
• Hyperesthesia 
• Muscular twitching 
• Tingling/paresthesia 
13.2. 
Screening Procedures 
• Explain study purpose and procedures. 
• Obtain written informed consent/assent before performing any study-related 
procedures. 
• Assess eligibility including urine drug screen and alcohol breath test. 
• Record relevant medical/surgical history, demographics, and baseline characteristics. 
• Conduct urine pregnancy test for women of childbearing potential. 
• Perform physical examination. 
• Conduct the following clinical laboratory tests:  
1.  Direct bilirubin 
2.  Gamma-glutamyl transpeptidase (GGT) and lactate dehydrogenase (LDH)  
OR  
Alanine transaminase (ALT) and aspartate transaminase (AST).   
 
 
 
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• Measure vital signs (temperature, resting heart rate, respiratory rate, and blood 
pressure).  
• Conduct 12-lead ECG after subject has rested in a supine position. 
• Record concomitant medications. 
• Record AEs starting at the signing of the ICF. 
All subjects who are screened for enrollment, but do not meet eligibility criteria, or who decline 
to participate will be documented on a screening log with the reason for non-participation. 
13.3. 
Baseline Procedures (Day 1 Prior to Surgery) 
• Confirm eligibility including urine drug test (Note: this assessment is not required if 
the Screening Visit occurred within 10 days of the surgery). 
• Update relevant medical and surgical history (Note: this assessment is not required if 
the Screening Visit occurred within 10 days of the surgery). 
• Conduct urine pregnancy test for women of childbearing potential (Note: this 
assessment is not required if the Screening Visit occurred within 10 days of the 
surgery).  A negative pregnancy test result must be available before surgery. 
• Record baseline VAS pain intensity score prior to any premedication (see Appendix 
1). 
• Measure vital signs (temperature, resting heart rate, respiratory rate, and blood 
pressure) (Note: this assessment is not required if the Screening Visit occurred within 
10 days of the surgery). 
• Include Pain Interference questionnaire. 
• Record changes to concomitant medications since screening. 
• Record AEs and any treatment(s) for the events. 
• Administer required pre-operative medications 
13.4. 
Intraoperative Procedures 
• Confirm eligibility. 
• Administer study drug per randomization. 
• Record start and stop times of study drug administration. 
• Record dosage of study drug administered and total volume. 
• Record surgery start and stop times.  
• Record concomitant medications. 
• Record AEs and any treatment(s) for the events. 
 
 
 
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• Refer to Section 13.1.5 for additional procedures in the event a cardiac or 
neurological AESI or SAE occurs. 
13.5. 
Postoperative Assessments Through Hospital Discharge 
• Record VAS pain intensity score upon arrival at the PACU; at 4, 6, 8, 10, 12, 24, 28, 
32, 36, 48, 52, 56, 60, and 72 hours; and immediately prior to each administration of 
postoperative rescue medication (see Appendix 1). Note: if the subject is sleeping, do 
not wake him or her for an assessment of pain at 24 or 48 hours after surgery. If he or 
she awakens within the assessment window (ie, 1 hour for the 24-hour assessment 
and 2 hours for the 48-hour assessment), a pain score may be collected then. 
†: If discharge occurs prior to any of the scheduled VAS assessments collected at 4 to 
72 hours postsurgery or scheduled OBAS assessments collected at 24 to 72 hours, the 
study coordinator must stress to the subject the importance of completing the 
scheduled VAS and OBAS Assessments.  These assessments should be recorded by 
the subject in the patient log provided upon discharge. 
• Include OBAS questionnaire (24, 48 and 72 hours). Note: if discharge occurs before 
72 hours, the study coordinator must stress to the patient the importance of 
completing the scheduled OBAS questionnaire up to 72 hours.  Completion of the 
questionnaire should be recorded by the patient in the patient log provided upon 
discharge  
• Obtain nursing likert scale (24, 48 and 72 hours ) or until hospital discharge 
• Administer postoperative rescue medication upon request, as needed (see Section 
11.1).  
• Administer scheduled post-op meds 
• Record other concomitant medications. 
• Record AEs and any treatment(s) for the events. 
• Refer to Section 13.1.5 for additional procedures in the event a cardiac or 
neurological AESI or SAE occurs. 
• Record date and time of discharge. 
• Provide patient with patient log for recording of daily opioid pain management 
medication use and remind patient that the completed patient log should be brought to 
the Day-14 Visit 
13.6. 
Day 14 Visit 
• Perform targeted physical examination of the surgical site. 
• Include Pain Interference questionnaire. 
 
 
 
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• Record date and amount of all opioid pain management medication used up to Day 
14. Note: upon discharge, the patient will record daily opioid pain management 
medication use in the provided patient log. 
• Document any unscheduled phone calls, unscheduled office visits, or emergency 
room (ER) visits related to pain after discharge. 
• Record concomitant medications. 
• Record AEs and any treatment(s) for the events. 
• Refer to Section 13.1.5 for additional procedures in the event a cardiac or 
neurological AE of special interest or SAE occurs. 
13.7. 
Day 30 Phone Call 
• Document any unscheduled phone calls, unscheduled office visits, or ER visits 
related to pain since the Day 14 visit. 
• Record AEs and any treatment(s) for the events.  
• Record times and doses of all analgesic medication administered since the 
postsurgical Day 14 visit. 
• Record concomitant medications. 
14. 
ADVERSE EVENT REPORTING  
Consistent with the current regulatory guidance provided by the US FDA CFR Part 312 and the 
ICH GCP, AE and SAE are defined in Section 14.1.1 and Section 14.2.1, respectively.   
The concepts of AEs and SAEs represent regulatory instruments used to evaluate and monitor 
the safety of clinical study subjects.  Therefore, these terms only apply in light of their regulatory 
definition.  The term serious, in a regulatory sense, does not necessarily mean severe.  The SAE 
concept is used primarily to identify, during the conduct of the study, those SAEs that may 
require expedited reporting to regulatory authorities. 
14.1. 
Adverse Events 
14.1.1. 
Definitions  
Definition of Adverse Event (AE): Any untoward medical occurrence associated with the use of 
a drug in humans, whether or not considered drug related.  An AE (also referred to as an adverse 
experience) can be any unfavorable and unintended sign (eg, 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 (eg, 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 
 
 
 
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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 (eg, migraine) is considered an AE.   
An AE that occurs after the ICF is signed and before the start of the study drug administration is 
identified as a pretreatment AE (PTAE).  An AE that occurs after the administration of the study 
treatment through 30 days is considered a TEAE.   
Definition of Adverse Reaction: Any AE caused by a drug.  Adverse reactions are a subset of all 
suspected adverse reactions for which there is reason to conclude that the drug caused the event. 
Definition of Suspected Adverse Reaction: Any AE for which there is a reasonable possibility 
that the drug caused the AE.  For the purposes of Investigational New Drug (IND) safety 
reporting, "reasonable possibility" means there is evidence to suggest a causal relationship 
between the drug and the AE. A suspected adverse reaction implies a lesser degree of certainty 
about causality than adverse reaction, which means any AE caused by a drug.  Suspected adverse 
reactions are a subset of all AEs for which there is a reasonable possibility that the drug caused 
the event. 
14.1.2. 
Recording Adverse Events 
It is the responsibility of the Investigator to document all AEs (ie, PTAEs and TEAEs) with an 
onset after the subject signs the ICF.  For the purpose of this study, all AEs that occur through 
Day 30 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; ie, lined through and 
initialed).  Whenever possible, abnormal laboratory results should be reported as their clinical 
corollary (eg, low potassium should be recorded as hypokalemia). 
A continuous AE with varying grades of severity should be recorded as one AE.  The highest 
grade of severity experienced by that subject during the course of the continuous AE should 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 (ie, 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 (eg, new high 
blood pressure medication), does not necessarily indicate an AE. 
Information recorded on the AE CRF will include the AE term, the date and time of onset, 
severity, seriousness, relationship to study drug, action taken with subject due to an AE, and the 
outcome of the AE, including the date and time of resolution, if applicable.   
 
 
 
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14.1.3. 
Severity of Adverse Events 
In general, the severity of an AE should be categorized using the following guidelines:  
Mild: 
An AE that is easily tolerated by the subject, causing minimal 
discomfort and not interfering with everyday activities. 
Moderate: 
An AE that is discomforting and interferes with normal everyday 
activities. 
Severe: 
An AE that prevents normal everyday activities. 
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. 
14.1.4. 
Relationship of Adverse Events to Study Drug 
The Investigator will assess the relationship of the AE to study drug after careful medical 
consideration on a case-by-case basis.  General guidelines 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 (eg, 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); or 
Definite:  
The pharmacological properties of the study drug(s) or of the substance 
class, and the course of the AE after dechallenge and, if applicable, after 
rechallenge, and/or specific test indicate involvement of the study 
drug(s) in the occurrence/worsening of the AE, and no indication of 
other causes exists. 
 
 
 
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402-C-409 (Spinal Fusion) 
EXPAREL® 
 
Clinical Study Protocol Amendment 2 
14.1.5. 
Outcome of Adverse Events 
The Investigator will assess the outcome of the AE after careful medical consideration, on a 
case-by-case basis.  General guidelines are provided below: 
Recovered/Resolved: 
The event resolved and the subject recovered from the AE. 
Recovered/Resolved 
with Sequelae: 
The initial event resolved, but has a continuing abnormal condition 
as a result of the AE. 
Not Recovered/ 
Not Resolved: 
At the time of last assessment, the event was ongoing, with an 
undetermined outcome.  Note: ongoing AEs are not to be considered 
resolved as a result of death. 
Recovering/Resolving: 
At the time of last assessment, the event was decreasing in 
frequency, severity, etc., and a resolution was expected. 
Fatal: 
The AE directly caused death. 
Unknown: 
There was an inability to access the subject or the subject’s records 
to determine the outcome (eg, subject withdrew consent or was 
lost to follow-up). 
14.1.6. 
Action Taken with Subject due to an Adverse Event 
The Investigator will provide any actions taken regarding the subject (eg, treatment, diagnostic 
tests, laboratory tests, or therapy) for each reported AE. 
• None. 
• Medication. 
• Non-pharmaceutical therapy.  (The specific therapy used must be recorded in the 
CRF.) 
• Discontinued from study. 
• Other.  (The specific action taken must be recorded in the CRF.) 
14.2. 
Serious Adverse Events 
14.2.1. 
Definition of a Serious Adverse Event 
Definition of an SAE: An AE or suspected adverse reaction is considered “serious” if, in the 
view of either the Investigator or Sponsor, it results in any of the following outcomes: 
• Death1. 
• A life-threatening adverse event2.  
• Inpatient hospitalization or prolongation of existing hospitalization3. 
 
 
 
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402-C-409 (Spinal Fusion) 
EXPAREL® 
 
Clinical Study Protocol Amendment 2 
• A persistent or significant incapacity4. 
• Congenital anomaly/birth defect. 
• Medically significant5. 
1Death: Any event resulting in a subject’s death must be reported as an SAE.  However, death, 
in and of itself, is not an AE; it is an outcome.  The cause of death is the AE.  Therefore, the 
Investigator should make every effort to obtain and document the cause of death for all subjects 
who die during the study.  If, despite all efforts, the cause of death remains unknown, the AE 
should be documented as an “unspecified fatal event.” 
2Life-threatening: An AE is considered life-threatening if, in the view of either the Investigator 
or Sponsor, its occurrence places the subject at immediate risk of death.  It does not include an 
AE that had it occurred in a more severe form might have caused death. 
3Hospitalization: It should be noted that hospitalization, in and of itself, does not represent an 
SAE.  It is the AE leading to the subject’s hospitalization that becomes “serious” when it 
requires inpatient care.  Consequently, an SAE should not be reported in case of preplanned 
hospitalizations for a pre-existing condition that did not worsen during the study.  However, 
any medical condition that delays a subject’s discharge from the hospital (ie, prolonged 
hospitalization) or requires the subject to be readmitted should be reported as an SAE. 
4Persistent or significant incapacity: A substantial disruption of a person’s ability to conduct 
normal life functions. 
5Medically Significant: Important medical events that may not result in death, be life-
threatening, or require hospitalization, may be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.  Examples of such medically 
significant events include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, 
or the development of drug dependency or drug abuse. 
14.2.2. 
Reporting Serious Adverse Events 
Any SAE or death that occurs at any time after the subject signs the ICF through Day 30, 
whether or not related to EXPAREL, must be reported by the Investigator or designee to Pacira 
Drug Safety within 24 hours of discovery by either email (drugsafety@pacira.com) or fax 
(973-201-0649).  In addition, the Investigator or designee is encouraged to contact the Medical 
Monitor to discuss the case, as needed.   
Investigators should not wait to receive additional information to fully document the event 
before notifying Pacira Drug Safety or designee of the SAE.  The fax or email report should be 
followed by a full written summary using the SAE Form detailing relevant aspects of the SAE 
in question.  Where applicable, information from relevant hospital records and autopsy reports 
should be obtained and all subject-identifying information redacted prior to forwarding to Pacira.  
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. 
 
 
 
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402-C-409 (Spinal Fusion) 
EXPAREL® 
 
Clinical Study Protocol Amendment 2 
If the Investigator is made aware of any SAEs after Day 30, these should also be reported to 
Pacira Drug Safety or designee provided the SAE is considered related to EXPAREL.  The site 
would then provide a completed SAE form within 1 business day and the event would be 
followed until resolution, or until adequate stabilization is met.  
15. 
STATISTICAL METHODS 
A comprehensive statistical analysis plan (SAP) will be developed for this study.   
15.1. 
Study Hypothesis 
The primary null hypothesis is: 
H0: AUC(0-72)VAS,EXPAREL = AUC(0-72)VAS,Placebo 
The primary alternative hypothesis is:  
HA: AUC(0-72)VAS,EXPAREL ≠ AUC(0-72)VAS,Placebo 
15.2. 
Study Endpoints 
 
The endpoints to be assessed in this study are listed in Section 12.2 (Efficacy Endpoints), 
Section 12.4 (Health Economic Outcomes Endpoints), and Section 12.6 (Safety Endpoints). 
15.3. 
Determination of Sample Size  
The sample size was calculated based on VAS pain and total opioid results reported in Hughes et 
al (2016) and length of stay reported in the paper by Zheng et al (2002).  Based on the reported 
efficacy for VAS pain intensity scores and assuming a 2-sided 0.05 alpha and a common SD of 
70, a sample size of 50 subjects per treatment group should have at least 80% power to detect a 
40-unit treatment difference.  For total opioid consumption assuming a 2-sided 0.05 alpha and 
common standard deviation of the log-dose of 0.6 and 80% power a sample size of 64 subjects 
per treatment group is needed to detect a 30% difference in total opioid consumption through 48 
hours.  For length of stay assuming a 2-sided 0.05 alpha and common standard deviation of 2.4 
and 80% power a sample size of 92 subjects per treatment group is needed to detect a 1 day 
difference in length of stay.   Allowing for a 5% drop-outs rate a sample size of 97 subjects per 
treatment group should be enrolled to ensure 92 subjects provide length of stay data. A total 
study sample size of 184 evaluable subjects will provide 80% power to detect a 1-day difference 
in length of stay; 92% power to detect a 30% difference in total opioid consumption; and 97% 
power to detect a 40 point difference in VAS-AUC(0-72). 
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 subjects in the safety analysis set who undergo the 
planned surgery.  All analyses based on the efficacy analysis set will be by randomized treatment 
regardless of treatment actually received. 
 
 
 
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402-C-409 (Spinal Fusion) 
EXPAREL® 
 
Clinical Study Protocol Amendment 2 
The per-protocol efficacy analysis set will include all subjects in the efficacy analysis set and do 
not have any major protocol violations.   
15.5. 
Handling Subject Dropouts and Discontinuations 
Subjects who discontinue after dosing will not be replaced. 
For the calculation of the AUC of VAS pain intensity scores through any of the time periods, the 
following methods will be used for imputing missing data:  
Missing scores before the first non-missing score will be replaced by the median score at the 
missing timepoint from other subjects in the same treatment group. Missing scores after the last 
non-missing score will be replaced by the last non-missing score (last observation carried 
forward). Missing scores between two non-missing scores will use linear interpolation to replace 
the missing score.  
Additional methods for dealing with missing data will be described in the SAP. 
15.6. 
Statistical Analyses 
Continuously valued data will be summarized using descriptive statistics (n [number of subjects 
contributing data], mean, SD, median, minimum, and maximum).  Discretely valued data will be 
tabulated (n and percent) by category.  The denominator for all percentages will be the number 
of subjects who underwent the planned surgery. 
15.6.1. 
Efficacy Analyses 
All efficacy analyses will be based on randomized treatment, regardless of actual treatment 
received. 
15.6.1.1. Primary Efficacy Analyses 
The primary efficacy measure in this study is the AUC of the VAS pain intensity scores through 
72 hours.  
For the AUC of the VAS pain intensity scores through 72 hours, each EXPAREL dose will be 
compared to placebo using analysis of variance (ANOVA) with treatment and site as main 
effects. Each EXPAREL dose will be compared to placebo at the 0.025 level of significance to 
control the overall level of significance to not exceed 0.05. Based on the model, the difference 
between the treatment groups will be estimated along with the 2-sided 97.5% confidence 
intervals (CIs).  
Handling of Subjects Requiring Rescue Medication  
For AUC of the VAS pain intensity scores, prior to analysis the windowed Worst-Observation-
Carried-Forward (wWOCF) imputation method will be applied. For subjects who take rescue 
pain medication, their pain intensity scores recorded within the window of controlled type of 
rescue medication will be replaced by the ‘worst’ observation. All pain scores within that 
window will be replaced by the ‘worst’ observation. The worst observation will be the highest 
score in the time interval from the end of surgery up to the time prior to taking their first rescue 
pain medication. Note that pain intensity scores in the window that are higher than the worst 
 
 
 
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EXPAREL® 
 
Clinical Study Protocol Amendment 2 
value prior to rescue pain medication will not be overwritten. If no pain intensity score is 
available prior to the first rescue pain medication, the worst observation from all available 
measurements will be used instead. 
15.6.2. 
Secondary Efficacy Measures 
See significance testing in Section 15.7 for an explanation of the statistical approach for 
secondary efficacy measures. 
Total postsurgical opioid consumption through 24, 48 and 72 hours will be converted to 
morphine equivalents and analyzed using the same ANOVA model as the primary endpoint. 
Percentage of opioid-free subjects through 24, 48 and 72 hours will be analyzed using a 
Cochran-Mantel-Haenszel (CMH) test stratified by site.  
Time to first opioid rescue through 72 hours will be analyzed by the Kaplan-Meier method.  The 
treatment difference in time to first opioid will be tested using the Gehan-Wilcoxon test. 
The VAS AUC(12-24), AUC(12-72), AUC(24-48) and AUC(48-72) will be analyzed in the same manner 
as the primary efficacy endpoint [AUC(0-72)]. 
The OBAS total score and nurse’s satisfaction with overall analgesia at 24, 48 and 72 hours will 
be analyzed using an ANOVA. 
Hospital LOS will be analyzed using an ANOVA. 
The incidence of hospital readmission and skilled nursing facility use will be analyzed using a 
CMH test stratified by site. 
15.6.3. 
Safety Analyses 
15.6.3.1. Adverse Events 
Adverse event verbatim terms will be mapped to preferred terms and related system organ class 
using the Medical Dictionary for Regulatory Activities (MedDRA). Events that start prior to the 
start of study drug administration will be identified in listings only. Incidence rates of TEAEs 
and the proportion of subject prematurely withdrawn from the study due to a TEAE will be 
shown for each treatment group. Incidence rates will also be displayed for each treatment group 
for study drug-related TEAEs and by severity. Incidence rates of SAEs will also be shown each 
treatment group. All incidence rates will be categorized and displayed by system organ class and 
preferred term. 
15.7. 
Significance Testing 
The primary efficacy endpoint will be tested at the 0.05 alpha level. 
If the primary efficacy endpoint is statistically significant the secondary endpoints will be tested 
at the 0.05 alpha level in a family-wise sequential hierarchical testing procedure.  The exact 
procedure will be detailed in the SAP. 
 
 
 
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EXPAREL® 
 
Clinical Study Protocol Amendment 2 
16. 
REFERENCES 
American Society of Anesthesiologists Task Force on Pain Management.  Practice guidelines 
for acute pain management in the postoperative setting: A report by the American Society 
for Anesthesiologist Task Force on Pain Management Acute Pain Section.  Anesthesiology. 
1995;82:1071-1081. 
Apfelbaum JL, Chen C, Mehta SS, et al.  Postoperative pain experience: Results from a national 
survey suggests postoperative pain continues to be undermanaged.  Anesth Analg.  
2003;97:535-540. 
Apseloff G, Onel E, Patou G.  Time to onset of analgesia following local infiltration of liposome 
bupivacaine in healthy volunteers: a randomized, single-blind, sequential cohort, crossover 
study.  Int J Clin Pharmacol Ther.  2013;51:367-373. 
Carlsson AM.  Assessment of Chronic Pain.  I.  Aspects of the Reliability and Validity of the 
Visual Analogue Scale.  Pain.  1983;16:87-101. 
Carroll NV, Miederhoff PA, Cox FM, et al.  Costs incurred by outpatient surgical centers in 
managing postoperative nausea and vomiting.  J Clin Anesth.  1994;6:364-369. 
Chernin T.  Painkillers and pill popping.  Drug Topics.  2001;15:31.  Accessed 04 January 2011.  
Available at: http://drugtopics.modernmedicine.com/drugtopics/PainManagement/ 
ArticleStandard/article/detail/118858. 
Chung F.  Discharge criteria – A new trend.  Can J Anesth. 1995;42:1056-1058. 
Chung F, Chan VW, Ong D.  A post-anesthetic discharge scoring system for home readiness 
after ambulatory surgery.  J Clin Anesth.  1995;7(6):500-506. 
Joshi GP, Cushner FD, Barrington JW, et al.  Best Infiltration Practices: Local Analgesia 
Infiltration Techniques – Hip & Knee Arthroplasty.  2014.  Available online through 
GuidelineCentral.com  http://eguideline.guidelinecentral.com/i/319830-hip-and-knee-
arthroplasty-orthopedic-surgery   
Guild GN, Galindo RP, Marino J, et al.   Periarticular regional analgesia in total knee 
arthroplasty: A review of the neuroanatomy and injection technique.  Orthop Clin N Am.  
2015;46(1):1–8. 
Hu D, Onel E, Singla N, et al.  Pharmacokinetic profile of liposome bupivacaine injection 
following a single administration at the surgical site.  Clin Drug Investig.  2013;33:109-115. 
Hughes J, Chaput CD, Maldonado YM, Rahm MD.  Efﬁcacy of liposomal bupivacaine for 
postoperative pain after spine surgery - retrospective control.  NASS 31st Annual Meeting 
Proceedings.  The Spine Journal 16 (2016) S251–S337  
Joshi GP, Cushner FD, Barrington JW, et al.  Techniques for periarticular infiltration with 
liposomal bupivacaine for the management of pain after hip and knee arthroplasty: A consensus 
recommendation.  J Surg Orthop Adv.  2015;24(1):27-35. 
 
 
 
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402-C-409 (Spinal Fusion) 
EXPAREL® 
 
Clinical Study Protocol Amendment 2 
Lehmann N, Joshi GP, Dirkmann D, et al.  Development and longitudinal validation of the 
overall benefit of analgesia score: a simple multi-dimensional quality assessment instrument.  
Br J Anasth.  2010;105(4):511-518.  Epub 2010 Aug 6. 
McCormack HM, DJ Horne, Sheather S.  Clinical applications of visual analogue scales: 
A critical review.  Psychol Med.  1988;18(4):1007-1019. 
Oderda GM, Said Q, Evans RS, et al.  Opioid-related adverse drug events in surgical 
hospitalizations: Impact on cost and length of stay.  Ann Pharmacother.  2007;41(3):400-406. 
Scott J, Huskinsson EC.  Graphic representation of pain.  Pain.  1976;2(2):175-184. 
Viscusi ER.  New and emerging treatment options for acute postoperative pain in the inpatient 
setting: Barriers to effective pain management.  Medscape Pharmacists.  15 December 2009.  
Accessed 04 January 2011.  Available at: http://www.medscape.org/viewarticle/713472_2. 
Zheng F, Cammisa FP, Sandue HA, Girardi FP, and Khan SN.  Factors predicting hospital stay, 
operative time, blood loss, and transfusion in patients undergoing revision posterior lumbar spine 
decompression, fusion, and segmental instrumentation.  SPINE (2002) Volume 27, Number 8, pp 
818–824. 
 
 
 
 
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EXPAREL® 
 
Clinical Study Protocol Amendment 2 
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. 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 
Pharmaceuticals, Inc. 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 (eg, 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 Pharmaceuticals, Inc. 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 Pharmaceuticals, Inc. and/or 
the investigational product(s) will be disclosed to the regulatory authorities by Pacira 
Pharmaceuticals, Inc. 
____________________________________ 
_____________________________ 
Signature of Investigator 
 
 
 
 
 
 
 
 
 
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402-C-409 (Spinal Fusion) 
EXPAREL® 
 
Clinical Study Protocol Amendment 2 
18. 
APPENDICES 
 
 
 
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EXPAREL® 
 
Clinical Study Protocol Amendment 2 
Appendix 1: Subject’s Reported Pain Intensity 
Subjects will be evaluated for pain using a 10-cm VAS at baseline (on Day 0 prior surgery and 
prior to any premedication); upon arrival at the PACU; at, 4, 6, 8, 10, 12, 24,28, 32, 36, 48, 52, 
60,and 72; and immediately prior to each administration of rescue medication; and just prior to 
hospital discharge.  Note: if discharge occurs before 72 hours, the study coordinator must stress 
to the patient the importance of completing the scheduled pain intensity assessments up to 72 
hours.  These assessments should be recorded by the patient in the patient log provided upon 
discharge.    
Subjects will be asked, "How much pain are you experiencing right now?  Please place a vertical 
mark on the line below to indicate the level of pain you are experience right now.  
 
 
 
(For reference only; not for clinical use.) 
 
 
 
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EXPAREL® 
 
Clinical Study Protocol Amendment 2 
Appendix 2: 
Overall Benefit of Analgesia Score Questionnaire (OBAS) 
The OBAS questionnaire will be completed at 24, 48, and 72 hours after surgery (Lehmann 
2010).  Note: if discharge occurs before 72 hours, the study coordinator must stress to the patient 
the importance of completing the scheduled OBAS questionnaire up to 72 hours.  Completion of 
the questionnaire should be recorded by the patient in the patient log provided upon discharge. 
1.   Please rate your current pain at rest on a scale between  
0=minimal pain and 4=maximum imaginable pain 
2.   Please grade any distress and bother from vomiting in the past 24 h  
(0=not at all to 4=very much) 
3.   Please grade any distress and bother from itching in the past 24 h  
(0=not at all to 4=very much) 
4.   Please grade any distress and bother from sweating in the past 24 h  
(0=not at all to 4=very much) 
5.   Please grade any distress and bother from freezing in the past 24 h  
(0=not at all to 4=very much) 
6.   Please grade any distress and bother from dizziness in the past 24 h  
(0=not at all to 4=very much) 
7.   How satisfied are you with your pain treatment during the past 24 h  
(0=not at all to 4=very much) 
 
 
 
 
 
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EXPAREL® 
 
Clinical Study Protocol Amendment 2 
 
Appendix 3: 
Nurse’s Satisfaction with Postsurgical Pain Control (Likert Scale) 
The nurse’s satisfaction with postsurgical pain control will be assessed at 24, 48, and 72 hours 
after surgery or upon hospital discharge. 
 
Please circle the number below that best describes your overall satisfaction with the pain 
medication your patient received after surgery.  (Circle one number only.) 
 
1. Extremely dissatisfied 
2. Dissatisfied 
3. Neither satisfied nor dissatisfied 
4. Satisfied  
5. Extremely satisfied 
 
 
 
 
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EXPAREL® 
 
Clinical Study Protocol Amendment 2 
Appendix 4: 
Pain Interference Scale 
 
 
 
 
 
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SAP_001.pdf: 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
A Multicenter, Randomized, Double-Blind, Controlled Study of 
EXPAREL for Postsurgical Pain Management in Subjects Undergoing 
Open Lumbar Spinal Fusion Surgery 
 
 
 
Protocol No.: 
402-C-409 
IND No.: 69,198 
Study Phase: 
4 
Study Drug: 
EXPAREL (bupivacaine liposome injectable 
suspension) 
Date/Version: 2 August 2017 (Amendment 2) 
Prepared by: Napoleon Oleka, PhD  
Pharma Data Associates, LLC 
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. 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Digitally signed by Vincent Yu 
DN: cn=Vincent Yu, o=Pacira, ou=Biometrics, 
email=vincent.yu@pacira.com,  c=US 
Date: 2018.03.16 15:38:25 -04'00' 
 
 
 
 
 
 
 
 
 
 
 
 
Digitally signed by Richard Scranton 
DN: cn=Richard Scranton, o=Pacira 
Pharmaceuticals Inc., ou=Chief Scientific Officer, 
email=Richard.Scranton@pacira.com,  c=US 
Date: 2018.03.16 07:51:31 -04'00' 
3/16/2018 
 
 
 
Digitally signed by Michael Rozycki 
DN: cn=Michael Rozycki, o=Regulatory 
Affairs, ou=Clinical Regulatory, 
email=michael.rozycki@pacira.com, c=US 
Date: 2018.03.15 11:37:47 -04'00' 
Vincent Yu 
Richard Scranton 
Michael Rozycki 


CONFIDENTIAL 
Page 3 of 44 
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Pacira Pharmaceuticals, Inc. 
402-C-409 
EXPAREL® 
Statistical Analysis Plan 
 
2. 
TABLE OF CONTENTS 
1. 
SIGNATURE PAGE 
2 
2. 
TABLE OF CONTENTS 
3 
3. 
LIST OF ACRONYMS/ABBREVIATIONS 
4 
4. 
INTRODUCTION 
5 
5. 
STUDY OBJECTIVES 
5 
5.1. 
Primary Objective 
5 
5.2. 
Secondary Objectives 
5 
6. 
STUDY OVERVIEW 
5 
7. 
DEFINITIONS 
6 
8. 
ANALYSIS SET 
6 
9. 
STATISTICAL METHODS 
6 
9.1. 
General Principles 
6 
9.1.1. 
Handling Missing Values 
6 
9.1.1.1. 
Study Drug Administration Date or Time 
6 
9.1.1.2. 
Adverse Event or Concomitant Medications Dates or Times 
7 
9.2. 
Subject Disposition 
7 
9.3. 
Demographics and Baseline Characteristics 
7 
9.3.1. 
Demographics 
7 
9.3.2. 
Baseline Characteristics 
7 
9.4. 
Prior and Concomitant Medications 
8 
9.5. 
Study Drug Exposure 
8 
9.6. 
Efficacy Analysis 
8 
9.7. 
Health Economic Outcomes 
8 
9.8. 
Safety Analyses 
9 
9.8.1. 
Adverse Events 
9 
9.8.2. 
Vital Signs 
9 
9.8.3. 
Electrocardiograms 
9 
9.8.4. 
Physical examination 
9 
9.8.5. 
Clinical Laboratory 
9 
9.8.6. 
Other Analysis (urine drug screen, pregnancy test, alcohol breath test) 
9 
9.9. 
Pharmacokinetic Analysis 
9 
10. 
SAMPLE SIZE CALCULATIONS 
10 
11. 
TIME AND EVENTS SCHEDULE OF STUDY PROCEDURES 
11 
12. 
TABLE OF CONTENTS FOR LISTING MOCK-UPS 
13 


CONFIDENTIAL 
Page 4 of 44 
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Pacira Pharmaceuticals, Inc. 
EXPAREL® 
402-C-409 
Statistical Analysis Plan 
 
 
 
3. 
LIST OF ACRONYMS/ABBREVIATIONS 
 
Abbreviation 
Description 
AE 
Adverse event 
ATC 
Anatomical therapeutic class 
AUC 
Area under the curve 
BMI 
Body mass index 
CRF 
Case report form 
CSR 
Clinical study report 
d 
days 
ECG 
Electrocardiogram 
EMA 
European Medicines Agency 
ER 
Emergency room 
FDA 
Food and Drug Administration 
FSH 
Follical stimulating hormone 
GCP 
Good Clinical Practice 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IV 
Intravenous 
LIA 
Local infiltration analgesia 
LOS 
Length of stay 
MedDRA 
Medical dictionary for regulatory affairs 
min, m 
minutes 
MPADSS 
Modified Post-Anesthesia Discharge Scoring System 
n 
Number of subjects 
OBAS 
Overall Benefit of Analgesia Score 
OR 
Operating room 
PACU 
Post-anesthesia care unit 
PK 
Pharmacokinetic(s) 
PT 
Preferred Term 
NRS 
NRS-R 
Numeric rating scale 
Numeric rating scale at rest 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SE 
Standard error 
SOC 
System Organ Class 
TEAE 
Treatment-emergent adverse event 
VAS 
Visual analog scale 
WHO-DD 
World Health Organization – Drug Dictionary 
WOCB 
Women of child-bearing potential 
yrs 
years 


CONFIDENTIAL 
Page 5 of 44 
5 March 2018 
Pacira Pharmaceuticals, Inc. 
EXPAREL® 
402-C-409 
Statistical Analysis Plan 
 
 
 
INTRODUCTION 
 
This is a Phase 4, Multicenter, Randomized, Double-Blind, Controlled Study of EXPAREL for 
Postsurgical Pain Management in Subjects Undergoing Open Lumbar Spinal Fusion Surgery. 
Approximately 194 adult subjects undergoing primary, 1-2 level, open lumbar spinal fusion 
surgery under general anesthesia are planned for enrollment, in order to have at least 184 
evaluable subjects. 
This study was prematurely terminated by the sponsor. At the time of termination, the study has 
enrolled and treated 38 subjects. 
The purpose of this SAP is to outline how the collected data will be summarized and presented 
for the abbreviated study report. 
This SAP is developed based on 
• 
Protocol 402-C-409 Amendment 2 issued on 2 August 2017. 
• 
CRF version 1.0 issued on 30 September 2016. 
The reader of this SAP is encouraged to also read the clinical protocol and other identified 
documents for details on the planned conduct of this study.  Operational aspects related to 
collection and timing of planned clinical assessments are not repeated in this SAP unless relevant 
to the planned analyses. 
 
 
4. 
STUDY OBJECTIVES 
4.1. 
Primary Objective 
The primary objective of this study is to compare postsurgical pain control following local 
infiltration analgesia (LIA) with EXPAREL admixed with bupivacaine HCl versus LIA with 
bupivacaine HCl in adult subjects undergoing open lumbar posterior spinal fusion surgery. 
 
4.2. 
Secondary Objectives 
The secondary objectives of this study are to compare additional efficacy, safety, and health 
economic outcomes following LIA with EXPAREL admixed with bupivacaine HCl versus LIA 
with bupivacaine HCl in adult subjects undergoing open lumbar posterior spinal fusion surgery. 
 
 
5. 
STUDY OVERVIEW 
Subjects were screened within 30 days prior to study drug administration and at least one day 
prior to surgery. During the screening visit, subjects were assessed for past or present neurologic, 
cardiac, and general medical conditions that in the opinion of the Investigator would preclude 
them from study participation. After the informed consent form (ICF) was signed, a medical 
history, surgical history, physical examination, 12-lead electrocardiogram (ECG), vital sign 
measurements, clinical laboratory evaluations, urine drug screen, alcohol breath test, and urine 
pregnancy test for women of childbearing potential were collected (see Time and Events 
Schedule of Study Procedures in Section 12). 


CONFIDENTIAL 
Page 6 of 44 
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Pacira Pharmaceuticals, Inc. 
EXPAREL® 
402-C-409 
Statistical Analysis Plan 
 
 
 
Subjects were randomized 1:1 to two treatment groups and stratified by surgery level (1-Level or 
2-Level). Subjects in Group 1 received LIA with EXPAREL admixed with bupiviaine HCl and 
subjects in Group 2 received LIA with bupivacaine HCl. 
 
 
6. 
DEFINITIONS 
Study Day 
Study Day is calculated as the date of event minus the date of study drug administration plus 
one (1), if the date of event is on or after the date of study drug administration. Study Day equals 
the date of event minus the date of study drug administration if the date of event is before the 
date of study drug administration.  Study days before the date of study drug administration will 
have negative values while those on or after the date of study drug administration are positive. 
Treatment-emergent Adverse Events 
Treatment-emergent adverse events (TEAEs) are AEs that occur after the administration of the 
study treatment through 30 days. 
Time 0 (zero) 
Time 0 is defined as the date and time of the start of study drug administration. 
Study Baseline 
Study Baseline is defined as the last available measurement or assessment prior to the start of 
study drug administration. 
 
 
7. 
ANALYSIS SET 
All Subjects: all the listings presented in this SAP will be based on all randomized subjects, 
unless specified otherwise. 
 
 
8. 
STATISTICAL METHODS 
8.1. 
General Principles 
Only listings of subject data collected during the study will be provided. All listings will be 
sorted by treatment group, site ID, subject ID, and, if applicable, collection date and time. 
 
8.1.1. Handling Missing Values 
Data will be included in the listing as is. No imputed values will be included in the listings. 
However, in order to provide the drug safety profile, the missing or partial date/time will be 
imputed only for the determination of treatment emergency or prior/concomitant status. 
8.1.1.1. 
Study Drug Administration Date or Time 
It is expected that all necessary information on study drug administration (start and stop date and 
time) will be complete.  Any such information that is missing and cannot be obtained through 


CONFIDENTIAL 
Page 7 of 44 
5 March 2018 
Pacira Pharmaceuticals, Inc. 
EXPAREL® 
402-C-409 
Statistical Analysis Plan 
 
 
 
query resolution may be imputed, on a case-by-case basis, in a conservative manner that 
minimizes bias. 
 
8.1.1.2. 
Adverse Event or Concomitant Medications Dates or Times 
For AEs or concomitant medications with missing or partially missing start/stop date/time, the 
following imputation rules will be applied when determining AE treatment-emergent status or 
medication prior/concomitant status: 
 
For partial start date/time: 
• If the year is unknown, then the date will be assigned as the date and time of first dose of 
study treatment. 
• If the month is unknown, then: 
i) 
If the year matches the year of study drug administration, then the month and day 
will be imputed to be the date and time of the first dose of study treatment. 
ii) 
Otherwise, ‘January’ will be assigned. 
• If the day is unknown, then: 
i) 
If the month and year match the month and year of the dose of the study drug 
administration date, then the day will be imputed to be the day of study drug 
administration date. 
ii) 
Otherwise, ‘01’ will be assigned. 
• If the time is unknown, then: 
i) 
If the date (day, month, and year) matches the date of administration of study drug, 
then the time will be imputed to be the time of dose of study drug date. 
ii) 
Otherwise, ‘00:00’ will be assigned. 
 
8.2. 
Subject Disposition 
A listing of subject disposition will be provided, which will include information on study 
completion status among others. 
 
8.3. 
Demographics and Baseline Characteristics 
 
8.3.1. Demographics 
Listing of demographic data will include: 
• Age (years) 
• Sex 
• Ethnicity 
• Primary Race 
Age is presented as collected. 
 
8.3.2. Baseline Characteristics 
Listing of baseline characteristic data will include: 
• Height (cm) 


CONFIDENTIAL 
Page 8 of 44 
5 March 2018 
Pacira Pharmaceuticals, Inc. 
EXPAREL® 
402-C-409 
Statistical Analysis Plan 
 
 
 
• Weight (kg) 
• Body Mass Index (BMI) (kg/m2) 
The formula for BMI is 𝑤𝑤/(ℎ2), where w is weight in kilograms and h is height in meters. Weight 
in pounds will be converted to kilograms using the conversion factor of 2.2046 pounds to 
1 kilogram.  Height in inches will be converted to centimeters using the conversion factor of 2.54 
centimeters to 1 inch.  Height in centimeters will be converted to meters using the conversion 
factor of 100 centimeters to 1 meter. 
 
8.4. 
Prior and Concomitant Medications 
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHO-DD Sept. 2016 Enhanced) and will be classified according to the anatomical 
therapeutic chemical (ATC) classification system term (Level 4) and preferred name. 
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). 
Listing of prior and concomitant medications will include subject identification, treatment group, 
ATC class term and preferred name among others. 
 
8.5. 
Study Drug Exposure 
A listing of study drug exposure, which includes volume of injection administered, will be 
provided. 
 
8.6. 
Efficacy Analysis 
Listing of the following efficacy assessments will be provided: 
-Pain intensity scores using the VAS 
-Pain Interference Scale (short form 6b) 
-Opioid rescue analgesics consumption 
-Treatment-emergent opioid-related AEs 
-OBAS questionnaire at 24, 48, and 72 hours or upon hospital discharge 
-Nurse's satisfaction with overall analgesia 
-Modified Postanesthesia Discharge Scoring System (MPADSS) criteria for discharge 
readiness 
 
8.7. 
Health Economic Outcomes 
Listing of the following health economic outcomes assessments done during the study will be 
provided: hospital length of stay (LOS), hospital readmissions, use of skilled nursing facility, and 
use of other health services following hospital discharge. 


CONFIDENTIAL 
Page 9 of 44 
5 March 2018 
Pacira Pharmaceuticals, Inc. 
EXPAREL® 
402-C-409 
Statistical Analysis Plan 
 
 
 
8.8. 
Safety Analyses 
 
8.8.1. Adverse Events 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA 
version 19.1 or later). 
A treatment emergent adverse event (TEAE) is any adverse event with the onset date and time on 
or after the start date and time of study drug administration through postsurgical Day 30. Cardiac 
AEs of special interest include chest pain (angina, myocardial infarction), abnormal/irregular 
heart rate (bradycardia, tachycardia, extrasystoles), and shortness of breath requiring 
intervention. Neurologic AEs of special interest include altered mental status/altered sensorium, 
rigidity, dysarthria, seizure, tremors, metallic taste, tinnitus, perioral numbness, visual 
disturbance, and severe or worsening dizziness. In addition, the following events are of special 
interest if they persist or occur beyond 72-hours postdose: dizziness, hyperesthesia, muscular 
twitching, and tingling/paresthesia. 
If an AE has a partial onset date and time the imputed start and stop dates and times will be used 
to determine treatment-emergence (e.g., an AE with stop date and time before the start date and 
time of study treatment is not treatment-emergent). 
A listing of all AEs will be provided, with a flag indicating TEAEs. 
 
8.8.2. Vital Signs 
Vital signs are resting heart rate (bpm), respiratory rate (beats per minute), oral body temperature 
(oC), systolic blood pressure (mmHg), and diastolic blood pressure (mmHg). 
Listing of all vital signs collected at screening/Day 1 (pre-op) will be provided. 
 
8.8.3. Electrocardiograms 
Data listings for ECG parameters collected at screening will be provided. The investigator’s 
overall interpretation will be included. 
 
8.8.4. Physical examination 
Listing of physical examination data collected at screening will be provided. 
 
8.8.5. Clinical Laboratory 
Listing of all clinical laboratory (hematology, chemistry, and urinalysis) tests collected at 
screening will be provided. 
 
8.8.6. Other Analysis (urine drug screen, pregnancy test, alcohol breath test) 
A data listing of these will be provided. 
 
8.9. 
Pharmacokinetic Analysis 
Drug concentrations are collected to assist the interpretation of adverse events. A data listing will 
be provided. 


CONFIDENTIAL 
Page 10 of 44 
5 March 2018 
Pacira Pharmaceuticals, Inc. 
EXPAREL® 
402-C-409 
Statistical Analysis Plan 
 
 
 
9. 
SAMPLE SIZE CALCULATIONS 
The sample size was calculated based on VAS pain and total opioid results reported in Hughes et 
al (2016) and length of stay reported in the paper by Zheng et al (2002). Based on the reported 
efficacy for VAS pain intensity scores and assuming a 2-sided 0.05 alpha and a common SD of 
70, a sample size of 50 subjects per treatment group should have at least 80% power to detect a 
40-unit treatment difference. For total opioid consumption assuming a 2-sided 0.05 alpha and 
common standard deviation of the log-dose of 0.6 and 80% power a sample size of 64 subjects 
per treatment group is needed to detect a 30% difference in total opioid consumption through 48 
hours. For length of stay assuming a 2-sided 0.05 alpha and common standard deviation of 2.4 
and 80% power a sample size of 92 subjects per treatment group is needed to detect a 1 day 
difference in length of stay. Allowing for a 5% drop-outs rate a sample size of 97 subjects per 
treatment group should be enrolled to ensure 92 subjects provide length of stay data. A total 
study sample size of 184 evaluable subjects will provide 80% power to detect a 1-day difference 
in length of stay; 92% power to detect a 30% difference in total opioid consumption; and 97% 
power to detect a 40 point difference in VAS-AUC(0-72). 


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Statistical Analysis Plan 
CONFIDENTIAL 
Page 11 of 44 
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10. 
TIME AND EVENTS SCHEDULE OF STUDY PROCEDURES 
 
 


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Statistical Analysis Plan 
CONFIDENTIAL 
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Abbreviations: AE = adverse event; ALT = alanine transaminase; AST = aspartate transaminase; d = day; D = day; ECG = electrocardiogram; ER = emergency room; 
GGT=Gamma-glutamyl transpeptidase; h = hours; ICF = informed consent form; LDH = lactate dehydrogenase; min = minutes; OBAS = overall benefit of analgesia score; OR = 
operating room; PACU = post-anesthesia care unit; Preop = preoperative; q12h = every 12 hours; VAS = visual analog scale; WOCBP = women of childbearing potential. 
 
a:   If the Screening Visit is conducted within 10 days of the date of surgery, the following Day-1 pre-op assessments are not required: assess/confirm eligibility; record medical 
and surgical history; conduct pregnancy test for WOCBP; conduct urine drug screen; and measure vital signs (temperature, heart rate, respiratory rate and blood pressure) 
 
*   Postsurgical assessments will be conducted at the timepoints specified after the end of surgery. All assessments conducted after baseline (ie, study drug administration) will be 
timed from the end of surgery, defined as the time of last suture/staple. At timepoints when multiple assessments coincide, the VAS pain intensity assessment will be 
conducted first. 
 
1      Timepoints shown through 72 hours. Note: if discharge occurs before 72 hours, the study coordinator must stress to the patient the importance of completing the scheduled pain 
intensity assessments up to 72 hours. These assessments should be recorded by the patient in the patient log provided upon discharge. 
2      The preoperative pain intensity assessment should be conducted prior to administration of any premedication. 
3      Also record VAS pain intensity scores immediately prior to each administration of rescue pain medication, and just prior to hospital discharge. 
4      And just prior to hospital discharge. Note: if discharge occurs before 72 hours, the study coordinator must stress to the patient the importance of completing the scheduled 
OBAS questionnaire up to 72 hours. Completion of the questionnaire should be recorded by the patient in the patient log provided upon discharge. 
5      Administer presurgical analgesics (ie, acetaminophen 975-1000 mg orally (PO), celecoxib 200 mg PO [or naproxen 500 mg PO twice a day or meloxicam 7.5 mg PO once a 
day in case of allergy], and gabapentin up to 900 mg PO). 
6      Administer scheduled post-surgical analgesics (ie, acetaminophen 975-1000 mg PO every 8 hours (q8h) [maximum of 3000 mg per day; acetaminophen IV can be used if the 
patient is unable to tolerate oral acetaminophen], celecoxib 200 mg PO every 12 hours up to 48 hours (q12h; or naproxen 500 mg PO twice a day or meloxicam 7.5 mg PO 
once a day in case of allergy), cyclobenzaprine 10 mgq8h, and gabapentin up to 900 mg PO q8h). 
7 
Instruct subject to discontinue prohibited medications. Record date and time of all medications starting at least 30 days prior to study drug administration until hospital 
discharge. Record medications administered for treatment of an AE through Day 30. 
8      If a cardiac AE (eg, chest pain [angina, myocardial infarction], abnormal/irregular heart rate [bradycardia, tachycardia, extrasystoles], or shortness of breath), neurological AE 
(eg, altered mental status/altered sensorium, dizziness, dysarthria, hyperesthesia, metallic taste, peroral numbness, seizure, tinnitus, tremors, visual disturbance, muscular 
twitching or rigidity beyond 72 hours postdose, or tingling/paresthesia beyond 72 hours postdose), or serious AE (SAE) occurs during the study, a 12-lead ECG, vital signs, PK 
draw, and any appropriate clinical laboratory tests should be conducted as close as possible to when the event occurs. 


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11. 
TABLE OF CONTENTS FOR LISTING MOCK-UPS 
LISTING 16.1-7: RANDOMIZATION – ALL SUBJECTS 
15 
LISTING 16.2-1: SUBJECT DISPOSITION 
16 
LISTING 16.2-2: DEMOGRAPHICS – ALL SUBJECTS 
17 
LISTING 16.2-3: BASELINE CHARACTERISTICS – ALL SUBJECTS 
18 
LISTING 16.2-4: PROTOCOL DEVIATION – ALL SUBJECTS 
19 
LISTING 16.2-5: INCLUSION/EXCLUSION CRITERIA – ALL SUBJECTS 
20 
LISTING 16.2-6: MEDICAL HISTORY – ALL SUBJECTS 
21 
LISTING 16.2-7: STUDY DRUG EXPOSURE – ALL SUBJECTS 
22 
LISTING 16.2-8: VISITS – ALL SUBJECTS 
23 
LISTING 16.2-9.1: ADMISSION AND DISCHARGE – ALL SUBJECTS 
24 
LISTING 16.2-9.2: SURGERY – ALL SUBJECTS 
25 
LISTING 16.2-10: PAIN INTENSITY - VISUAL ANALOG SCALE – ALL SUBJECTS 
26 
LISTING 16.2-11: PAIN INTERFERENCE 
27 
LISTING 16.2-12: DISCHARGE READINESS – ALL SUBJECTS 
28 
LISTING 16.2-13: NURSE SATISFACTION – ALL SUBJECTS 
29 
LISTING 16.2-14: OBAS QUESTIONNAIRE – ALL SUBJECTS 
30 
LISTING 16.2-15: LAST PHONE CALL – ALL SUBJECTS 
31 
LISTING 16.2-16.1: ALL ADVERSE EVENTS 
32 
LISTING 16.2-16.2: ALL SERIOUS ADVERSE EVENTS – ALL SUBJECTS 
32 
LISTING 16.2-16.3: TREATMENT-EMERGENT SERIOUS ADVERSE EVENTS – ALL SUBJECTS 
33 
LISTING 16.2-16.4: TREATMENT-EMERGENT SERIOUS ADVERSE EVENTS LEADING TO STUDY DISCONTINUATION – ALL SUBJECTS 
33 
LISTING 16.2-16.5: TREATMENT-EMERGENT OPIOID-RELATED ADVERSE EVENTS – ALL SUBJECTS 
33 
LISTING 16.2-16.6.1: CARDIAC TREATMENT-EMERGENT ADVERSE EVENTS OF SPECIAL INTEREST – ALL SUBJECTS 
33 
LISTING 16.2-16.6.2: NEUROLOGIC TREATMENT-EMERGENT ADVERSE EVENTS OF SPECIAL INTEREST – ALL SUBJECTS 
33 
LISTING 16.2-17: PHARMACOKINETICS – ALL SUBJECTS 
34 
LISTING 16.2-18: VITAL SIGNS ASSESSMENT – ALL SUBJECTS 
35 
LISTING 16.2-19.1: CONCOMITANT MEDICATIONS – ALL SUBJECTS 
36 


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LISTING 16.2-19.2: PRIOR MEDICATIONS – ALL SUBJECTS 
36 
LISTING 16.2-19.3: INTRAOPERATIVE OPIOIDS – ALL SUBJECTS 
37 
LISTING 16.2-19.4: RESCUE MEDICATION – ALL SUBJECTS 
37 
LISTING 16.2-20: ELECTROCARDIOGRAM FINDINGS – INVESTIGATOR ASSESSMENT – ALL SUBJECTS 
38 
LISTING 16.2-21: PHYSICAL EXAMINATION 
39 
LISTING 16.2-22: URINE DRUG SCREEN – ALL SUBJECTS 
40 
LISTING 16.2-23: PREGNANCY TEST FOR WOMEN OF CHILD BEARING POTENTIAL 
41 
LISTING 16.2-24: CLINICAL LABORATORY TESTS-HEMATOLOGY – ALL SUBJECTS 
42 
LISTING 16.2-25: CLINICAL LABORATORY TESTS-CHEMISTRY – ALL SUBJECTS 
42 
LISTING 16.2-26: CLINICAL LABORATORY TESTS-URINALYSIS – ALL SUBJECTS 
42 
LISTING 16.2-27: UNIQUE ADVERSE EVENTS TERMS AND ASSOCIATED CODED TERMS 
43 
LISTING 16.2-28: UNIQUE MEDICATION TERMS AND ASSOCIATED CODED TERMS 
44 


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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-409 
Listing 16.1-7: Randomization – All Subjects 
Randomization 
Site 
Surgery 
Screw 
Subject 
Number 
Date/ Day[1] 
Time 
Number 
Treatment 
type 
type 
XXX-YYYY 
XXX 
yyyy-mm-dd/ xxx 
hh:mm 
XXXXX 
XXXXXX 
2-Level 
pedicle 
 
 
 
 
 
 
 
 
 
[1]Day = Visit date – first dose date +1 if Visit is on/after first dose; Otherwise Day=Visit date – first dose date. 
Source: list SAS datasets used to create table 
M:\402C409\production\programs\tlf\L16_1-7.sas 
DateTime 
 
Note to programmer: Analysis set will by ‘Y’ if subject in set, blank otherwise. 


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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-409 
Listing 16.2-1: Subject Disposition – All Subjects 
Treatment: 
Subject 
Informed 
Consent 
Date/ Day[1] 
Randomization 
Date/ Day[1] 
First 
Dose 
Date/ Day[1] 
Last 
Visit 
Date/ Day[1] 
End of 
Study 
Status 
Primary Reason for 
Early Termination 
XXX-YYYY 
yyyy-mm-dd/ xxx 
yyyy-mm-dd/ xxx 
yyyy-mm-dd/ xxx 
yyyy-mm-dd/ xxx 
Completed 
Study Terminated By Sponsor 
 
 
 
 
 
 
 
 
 
 
 
[1]Day = Visit date – first dose date +1 if Visit is on/after first dose; Otherwise Day=Visit date – first dose date. 
 
Source: list SAS datasets used to create table 
M:\402C409\production\programs\tlf\L16_2-1.sas 
DateTime 
 
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, concatenate into “Primary Reason” as “Other, Specify: ….”. 


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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-409 
Listing 16.2-2: Demographics – All Subjects 
Treatment: 
Subject 
Subject 
Initials 
Birth Date 
Age 
(yrs) 
Sex 
Child Bearing 
Potential? 
Primary Race 
Ethnicity 
ASA 
Class 
Country 
XXX-YYYY 
AMZ 
yyyy-mm-dd 
XX 
XXXXXX 
XXXXXXXXXXXXXXXXXX 
XXXXXXXXX 
XXXXXXX 
 
 
 
 
 
 
 
 
 
 
 
Source: list SAS datasets used to create table 
M:\402C409\production\programs\tlf\L16_2-2.sas 
DateTime 
 
Note to programmer: If Primary Race is ‘other’ then Primary Race should be ‘Other: other-specify-text’. 


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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-409 
Listing 16.2-3: Baseline Characteristics – All Subjects 
Treatment: 
Subject 
Date 
Height (cm) 
Weight (kg) 
Body Mass Index 
(kg/m2) 
XXX-YYYY 
yyyy-mm-ddThh:mm 
XXX.X 
XXX.X 
XX.X 
 
 
 
 
 
 
 
 
 
 
 
Source: list SAS datasets used to create table 
M:\402C409\production\programs\tlf\L16_2-3.sas 
DateTime 


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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-409 
Listing 16.2-4: Protocol Deviation – All Subjects 
Treatment: 
Subject 
Date of 
Deviation / 
Day[1] 
Time of 
Deviation 
Deviation Type 
Deviation 
Description 
Action Taken 
If Other, specify 
XXX-YYYY 
yyyy-mm-dd/ xxx 
Thh:mm 
Study Drug Error 
xxxxxxxxxxxxxxx 
Staff Retraining 
 
 
 
 
 
 
 
 
 
 
 
[1]Day = Visit date – first dose date +1 if Visit is on/after first dose; Otherwise Day=Visit date – first dose date. 
 
Source: list SAS datasets used to create table 
M:\402C409\production\programs\tlf\L16_2-4.sas 
DateTime 


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Pacira Pharmaceuticals 
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Protocol: 402-C-409 
Listing 16.2-5: Inclusion/Exclusion Criteria – All Subjects 
Treatment: 
Subject 
Met all 
eligibility 
criteria? 
Category 
Criterion ID 
Failed 
Protocol Version 
Enrolled under 
XXX-YYYY 
No 
Exclusion 
Original 
 
 
 
 
 
 
 
 
 
 
 
Source: list SAS datasets used to create table 
M:\402C409\production\programs\tlf\L16_2-5.sas 
DateTime 


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Protocol: 402-C-409 
Listing 16.2-6: Medical History – All Subjects 
Treatment:  
 
Subject 
ID 
V: Verbatim Term 
S: System Organ Class[1] 
P: Preferred Term[1] 
Start 
Date 
Stop 
Date 
xxx-xxxx 
V: vvvvvvvvvvvvvvvvvvvvvvvvv 
YYYY-MM-DD 
YYYY-MM-DD 
S: sssssssssssssssssssssss 
xxx-xxxx 
P: pppppppppppppppppp 
xxx-xxxx 
V: vvvvvvvvvvvvvvvvvvvvvvvvv 
YYYY 
Ongoing 
S: sssssssssssssssssssssss 
xxx-xxxx 
P: pppppppppppppppppp 
xxx-xxxx 
V: vvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvv 
YYYY-MM-DD 
Ongoing 
S: sssssssssssssssssssssssssssssssss 
xxx-xxxx 
P: ppppppppppppppppppppppppppp 
V: vvvvvvvvvvvvvvvvvvvvvvvvv 
YYYY-MM 
Ongoing 
S: sssssssssssssssssssssssssssssssssssssss 
P: pppppppppppppppppp 
xxx-xxxx 
V: vvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvv 
YYYY-MM-DD 
YYYY-MM-DD 
S: ssssssssss 
P: pppppppppppp 
Programming note: For subjects with multiple records, present in the order of onset date. 
[1] MedDRA vxx.x. 
Source: list SAS datasets used to create table 
M:\402C409\production\programs\tlf\L16_2-6.sas 
DateTime 


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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-409 
Listing 16.2-7: Study Drug Exposure – All Subjects 
 
Treatment: 
Subject 
Date/ Day[1] 
Start 
Time 
Stop 
Time 
Total Volume 
(mL) 
XXX-YYYY 
yyyy-mm-dd/ xxx 
HH:MM 
HH:MM 
XXX 
 
 
 
 
 
 
 
 
 
 
 
[1]Day = Visit date – first dose date +1 if Visit is on/after first dose; Otherwise Day=Visit date – first dose date. 
 
Source: list SAS datasets used to create table 
M:\402C409\production\programs\tlf\L16_2-7.sas 
DateTime 


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Pacira Pharmaceuticals 
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Protocol: 402-C-409 
Listing 16.2-8: Visits – All Subjects 
Treatment: 
Subject 
Visit 
Visit Date/ Day[1] 
XXX-YYYY 
Screening 
yyyy-mm-dd/ xxx 
D1 (Preop) 
yyyy-mm-dd/ xxx 
D14 
yyyy-mm-dd/ xxx 
D30 Call 
yyyy-mm-dd/ xxx 
. . . 
. . . 
 
 
 
[1]Day = Visit date – first dose date +1 if Visit is on/after first dose; Otherwise Day=Visit date – first dose date. 
 
Source: list SAS datasets used to create table 
M:\402C409\production\programs\tlf\L16_2-8.sas 
DateTime 


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EXPAREL 
402-C-409 
Statistical Analysis Plan 
CONFIDENTIAL 
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5 March 2018 
 
 
 
 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-409 
Listing 16.2-9.1: Admission and Discharge – All Subjects 
Treatment: 
Subject 
Date of 
admission to 
surgical 
facility/ Day[1] 
Time of 
admission 
to surgical 
facility 
Date of 
admission to 
PACU/ Day[1] 
Time of 
admission 
to PACU 
Date of 
discharge from 
surgical 
facility/ Day[1] 
Time of 
discharge from 
surgical 
facility 
XXX-YYYY 
yyyy-mm-dd/ xxx 
hh:mm 
yyyy-mm-dd/ xxx hh:mm 
yyyy-mm-dd/ xxx 
hh:mm 
XXX-YYYY 
yyyy-mm-dd/ xxx 
hh:mm 
yyyy-mm-dd/ xxx hh:mm 
yyyy-mm-dd/ xxx 
hh:mm 
XXX-YYYY 
yyyy-mm-dd/ xxx 
hh:mm 
yyyy-mm-dd/ xxx hh:mm 
yyyy-mm-dd/ xxx 
hh:mm 
XXX-YYYY 
yyyy-mm-dd/ xxx 
hh:mm 
yyyy-mm-dd/ xxx hh:mm 
yyyy-mm-dd/ xxx 
hh:mm 
. . . 
. . . 
 
 
 
[1]Day = Visit date – first dose date +1 if Visit is on/after first dose; Otherwise Day=Visit date – first dose date. 
 
Source: list SAS datasets used to create table 
M:\402C409\production\programs\tlf\L16_2-9_1.sas 
DateTime 


Pacira Pharmaceuticals, Inc. 
EXPAREL 
402-C-409 
Statistical Analysis Plan 
CONFIDENTIAL 
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5 March 2018 
 
 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-409 
Listing 16.2-9.2: Surgery – All Subjects 
Treatment: 
Subject 
Date/ Day[1] 
Start 
Time 
End 
Time 
Procedure 
Name 
Level of 
Surgery 
Surgery 
performed by 
Total 
Incision 
Length 
Type of Anesthesia 
Intraoperative 
opioids 
administered? 
XXX-YYYY yyyy-mm-dd/ xxx 
hh:mm hh:mm 
Other:xxx_specify_ No 
XXX-YYYY yyyy-mm-dd/ xxx 
hh:mm hh:mm 
XXX-YYYY yyyy-mm-dd/ xxx 
hh:mm hh:mm 
XXX-YYYY yyyy-mm-dd/ xxx 
hh:mm hh:mm 
. . . 
. . . 
 
 
 
[1]Day = Visit date – first dose date +1 if Visit is on/after first dose; Otherwise Day=Visit date – first dose date. 
 
Source: list SAS datasets used to create table 
M:\402C409\production\programs\tlf\L16_2-9_2.sas 
DateTime 


Pacira Pharmaceuticals, Inc. 
EXPAREL 
402-C-409 
Statistical Analysis Plan 
CONFIDENTIAL 
26 of 44 
5 March 2018 
 
 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-409 
Listing 16.2-10: Pain Intensity - Visual Analog Scale – All Subjects 
Treatment: 
 
Subject 
Date/ Day[1] 
Timepoint 
Time 
Pain assessment [2] 
XXX-YYYY 
yyyy-mm-dd/ xxx 
PACU Arrival 
hh:mm 
xxx 
yyyy-mm-dd/ xxx 
4 Hours 
hh:mm 
xxx 
yyyy-mm-dd/ xxx 
6 Hours 
hh:mm 
xxx 
yyyy-mm-dd/ xxx 
8 Hours 
hh:mm 
xxx 
. . . 
. . . 
. . . 
 
 
[1]Day = Visit date – first dose date +1 if Visit is on/after first dose; Otherwise Day=Visit date – first dose date. 
[2] How much pain are you experiencing right now (in VAS, cm)? 
 
Source: list SAS datasets used to create table 
M:\402C409\production\programs\tlf\L16_2-10.sas 
DateTime 


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EXPAREL 
402-C-409 
Statistical Analysis Plan 
CONFIDENTIAL 
27 of 44 
5 March 2018 
 
 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-409 
Listing 16.2-11: Pain Interference – All Subjects 
Treatment: 
Subject 
Date/ Day[1] 
Timepoint Question 
Res 
ponse[2] 
XXX-YYYY yyyy-mm-dd/ xxx 24 Hours 
In the past seven days, 
1. How much did pain interfere with your enjoyment of life? 
2 
2. How much did pain interfere with your ability to concentrate? 
1 
3. How much did pain interfere with your day to day activities? 
1 
4. How much did pain interfere with your enjoyment of recreational 
activities 
4 
5. How much did pain interfere with doing your tasks away from home? 
5 
6. How often did pain keep you from socializing with others? 
3 
. . . 
[1]Day = Visit date – first dose date +1 if Visit is on/after first dose; Otherwise Day=Visit date – first dose date. 
[2] For questions 1 to 5, 1 = Not at all, 2 = A little bit, 3 = Somewhat, 4 = Quite a bit, 5 = Very much. 
For question 6, 1 = Never, 2 = Rarely, 3 = Sometimes, 4 = Often, 5 = Always. 
 
Source: list SAS datasets used to create table 
M:\402C409\production\programs\tlf\L16_2-11.sas 
DateTime 
 
Note to programmer: Sort by date and time within subject. 
Continue for Timepoint = 48 Hours, 72 Hours 


Pacira Pharmaceuticals, Inc. 
EXPAREL 
402-C-409 
Statistical Analysis Plan 
CONFIDENTIAL 
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5 March 2018 
 
 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-409 
Listing 16.2-12: Discharge Readiness – All Subjects 
 
Treatment: 
 
 
 
Subject 
Timepoint 
Date/ Day[1] 
Time 
Vital 
Sign[2] 
Ambu 
Lation[3] 
Nausea and 
Vomiting[4] Pain[4] 
Surgical 
Bleeding[4
] 
 
 
XXX-YYYY Day of Surgery 
yyyy-mm-dd/ xxx hh:mm 
2 
1 
0 
1 
2 
 
 
 
[1] Day = Visit date – first dose date +1 if Visit is on/after first dose; Otherwise Day=Visit date – first dose date. 
[2] 2 = <=20% of preoperative value, 1 = 20%-40% of preoperative value, 0 = >40% of preoperative value 
[3] 2 = Steady gait/no dizziness, 1 = With assistance, 0 = None/dizziness 
[4] 2 = Minimal, 1 = Moderate, 0 = Severe 
 
Source: list SAS datasets used to create table 
M:\402C409\production\programs\tlf\L16_2-12.sas 
DateTime 
 
Note to programmer: 
 
Sort by date and time within subject. 
 
Continue for Timepoint = Day 2 Morning, Day 2 Evening, Discharge 


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EXPAREL 
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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-409 
Listing 16.2-13: Nurse Satisfaction – All Subjects 
Treatment: 
Subject 
Date/ Day[1] 
Time 
Timepoint 
Nurse's Overall 
Satisfaction [2] 
XXX-YYYY 
yyyy-mm-dd/ xxx 
hh:mm 
24 Hours 
2 
. . . 
[1] Day = Visit date – first dose date +1 if Visit is on/after first dose; Otherwise Day=Visit date – first dose date. 
[2] Nurse's overall satisfaction with the pain medication received after surgery: 
1 = Extremely dissatisfied, 2 = Dissatisfied, 3 = Neither satisfied nor dissatisfied, 
4 = Satisfied, 5 = Extremely satisfied 
 
Source: list SAS datasets used to create table 
M:\402C409\production\programs\tlf\L16_2-13.sas 
DateTime 
 
Note to programmer: 
 
Sort by date and time within subject. 
Continue for Timepoint = 48 Hours, 72 Hours 


Pacira Pharmaceuticals, Inc. 
EXPAREL 
402-C-409 
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5 March 2018 
 
 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-409 
Listing 16.2-14: OBAS Questionnaire – All Subjects 
Treatment: 
Subject 
Date/ Day[1] 
Time 
Timepoint Question 
Res 
ponse 
XXX-YYYY yyyy-mm-dd/ xxx 
hh:mm 24 Hours 
1. Was the OBAS Questionnaire Completed? 
2. Please rate your current pain at rest 
3. Please grade any distress and bother from vomiting in the past 24 h 
4. Please grade any distress and bother from itching in the past 24 h 
5. Please grade any distress and bother from sweating in the past 24 h 
6. Please grade any distress and bother from freezing in the past 24 h 
7. Please grade any distress and bother from dizziness in the past 24 h 
8. How satisfied are you with your pain treatment during the past 24 h 
9. Number of days in the Nursing Facility 
. . . 
[1]Day = Visit date – first dose date +1 if Visit is on/after first dose; Otherwise Day=Visit date – first dose date. 
 
Source: list SAS datasets used to create table 
M:\402C409\production\programs\tlf\L16_2-14.sas 
DateTime 
 
Note to programmer: Sort by date and time within subject. 
Continue for Timepoint = 48 Hours, 72 Hours 


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EXPAREL 
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Statistical Analysis Plan 
CONFIDENTIAL 
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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-409 
Listing 16.2-15: Last Phone Call – All Subjects 
Treatment: 
Subject 
Date/ Day[1] 
Question 
Response 
XXX-YYYY 
yyyy-mm-dd/ xxx 
1. Was Day 29 Phone Call made to the subject? 
Yes 
2. Were there any unscheduled pain-related calls since subject discharge? 
Yes 
3. Number of pain-related phone calls 
2 
4. Were there any unscheduled pain-related visits since subject discharge? 
No 
5. Number of pain-related office visits 
0 
6. Were there any Emergency Department Visits since subject discharge? 
Yes 
7. Number of Emergency Department Visits 
1 
8. Was there any Skilled Nursing Facility admission since subject discharge? 
No 
9. Number of days in the Nursing Facility 
0 
10. Was there any hospital readmission since subject discharge? 
No 
11. Number of hospital readmission 
0 
. . . 
[1]Day = Visit date – first dose date +1 if Visit is on/after first dose; Otherwise Day=Visit date – first dose date. 
 
Source: list SAS datasets used to create table 
M:\402C409\production\programs\tlf\L16_2-15.sas 
DateTime 
 
Note to programmer: Sort by date within subject. 


Pacira Pharmaceuticals, Inc. 
EXPAREL 
402-C-409 
Statistical Analysis Plan 
CONFIDENTIAL 
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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-409 
Listing 16.2-16.1: All Adverse Events – All Subjects 
Treatmernt: 
Subject 
ID 
Start 
Date/ 
Day[1] 
Stop 
Date/ 
Day[1] 
Duration 
(Day)[2] TEAE 
V: Verbatim 
S: System Organ Class[3] 
P: Preferred Term[3] 
S: Severity 
R: Relationship 
SAE: Serious 
F: Frequency 
A: Action Taken 
O: Outcome 
I: AESI 
xxxxx 
YYYY-MM-DD/ YYYY-MM-DD/ XXX 
Yes V: vvvvvvvvvvvvvvvvvvvvvvvvv S: Moderate 
F: xxx 
XXX 
XXX 
S: sssssssssssssssssssssss 
R: Not Related 
A: Hospitalization 
P: pppppppppppppppppp 
SAE: Death 
O: Fatal 
YYYY-MM-DD/ YYYY-MM-DD/ XXX 
Yes V: vvvvvvvvvvvvvvvvvvvvvvvv 
S: Mild 
F: xxx 
XXX 
XXX 
S: sssssssssssssssssssssssss R: Possible 
A: Study Drug Disc 
P: pppppppppppppppppppppp 
SAE: Life 
Threatening 
O: Recovered 
xxxxx 
YYYY-MM-DD/ YYYY-MM-DD/ XXX 
No 
V: vvvvvvvvvvvvvvvvvv 
S: Severe 
F: xxx 
XXX 
XXX 
S: sssssssssssssssssssssss 
R: Probable 
A: Nonpharm Therapy 
P: ppppppppppppppppppppppppp SAE: Incapacity O: Recovered with 
Sequelae 
YYYY-MM-DD/ 
Yes V: vvvvvvvvvvvvvvvv 
S: Severe 
F: xxx 
XXX 
S: ssssssssssssss 
R: Definite 
A: Other: xxx 
P: pppppppppppppppppp 
SAE: Hospital 
O: Not Recovered 
Programming instructions: Sort by Subject ID, then Start Date. 
TEAE: Treatment-emergent AE (Yes=TEAE/No=Not TEAE) 
[1] Day=event date – first dose date +1 if event occurred on/after first dose; Otherwise Day=event date – first 
dose date. 
[2] Duration=Stop Date – Start Date +1. 
[5] MedDRA version 19.0. 
Source: list SAS datasets used to create table 
M:\402C409\production\programs\tlf\L16_2-16_1.sas 
DateTime 
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 16.2-16.2: All Serious Adverse Events – All Subjects 


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Listing 16.2-16.3: Treatment-emergent Serious Adverse Events – All Subjects 
Listing 16.2-16.4: Treatment-emergent Serious Adverse Events leading to study discontinuation – All Subjects 
Listing 16.2-16.5: Treatment-emergent Opioid-Related Adverse Events – All Subjects 
Listing 16.2-16.6.1: Cardiac Treatment-emergent Adverse Events of Special Interest – All Subjects 
Listing 16.2-16.6.2: Neurologic Treatment-emergent Adverse Events of Special Interest – All Subjects 
 
Note: 
Cardiac AEs of special interest include chest pain (angina, myocardial infarction), abnormal/irregular heart rate 
(bradycardia, tachycardia, extrasystoles), and shortness of breath requiring intervention. Neurologic AEs of special 
interest include altered mental status/altered sensorium, rigidity, dysarthria, seizure, tremors, metallic taste, 
tinnitus, perioral numbness, visual disturbance, and severe or worsening dizziness. In addition, the following events 
are of special interest if they persist or occur beyond 72-hours postdose: dizziness, hyperesthesia, muscular 
twitching, and tingling/paresthesia. 


Pacira Pharmaceuticals, Inc. 
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402-C-409 
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Pacira Pharmaceuticals 
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Protocol: 402-C-409 
Listing 16.2-17: Pharmacokinetics – All Subjects 
 
Treatment: 
 
 
 
Subject 
Collection 
Date/ Day[1] 
Collection 
Time 
Vaule 
Reason for PK 
Collection 
 
If Other, Specify 
 
XXX-YYYY 
yyyy-mm-dd/ xxx 
hh:mm 
xxx 
AE Special Interest 
hh:mm 
xxx 
Other 
xxxxxxxxxxxxx 
hh:mm 
xxx 
SAE 
hh:mm 
xxx 
. . . 
. . . 
[1]Day = Visit date – first dose date +1 if Visit is on/after first dose; Otherwise Day=Visit date – first dose date. 
Source: list SAS datasets used to create table 
M:\402C409\production\programs\tlf\L16_2-17.sas 
DateTime 


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Statistical Analysis Plan 
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5 March 2018 
 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-409 
Listing 16.2-18: Vital Signs Assessment – All Subjects 
Treatment: 
Heart 
Rate 
Oral 
Temperature 
Blood Pressure (mmHg) 
 
 
 
 
[1]Day = Visit date – first dose date +1 if Visit is on/after first dose; Otherwise Day=Visit date – first dose date. 
Source: list SAS datasets used to create table 
M:\402C409\production\programs\tlf\L16_2-18.sas 
DateTime 
 
Note to programmer: Sort by date and time within subject. 
Subject 
Date/ Day[1] 
Time 
Timepoint 
(bpm) 
(°C) 
Systolic 
Diastolic 
XXX-YYYY 
yyyy-mm-dd/ xxx hh:mm 
Screening 
XX 
XX.X 
XXX 
XX 
hh:mm 
Day 1 (Pre-op) 
XX 
XX.X 
XXX 
XX 


Pacira Pharmaceuticals, Inc. 
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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-409 
Listing 16.2-19.1: Concomitant Medications – All Subjects 
Treatment: 
Subject 
ID 
Start Date 
(day)[1] 
Stop Date 
(day)[1] 
V: Verbatim 
D: Generic Name[2] 
C: Medication Class[2] 
D: Dose & Unit 
R: Route & Form 
F: Frequency 
Indication 
AE: AE number 
MH: Medical History 
xxxxx 
YYYY-MM-DD (XX) 
V: mmmmmmmmmmmmmmm 
D: dddddddd uuuuuuu AE: xx 
Continuing 
D: nnnnnnnnnnnnnnnn 
R: rrrrrrrr 
C: ppppppppppp 
F: ffffffff 
xxxxx 
YYYY-MM-DD (XX) 
V: mmmmmmmmmmmmmmm 
D: dddddddd uuuuuuu MH: Hypertension 
YYYY-MM-DD (XX) 
D: nnnnnnnnnnnnnnnn 
R: rrrrrrrr 
C: ppppppppppp 
F: ffffffff 
YYYY-MM-DD (XX) 
V: mmmmmmmmmmmmmmm 
D: dddddddd uuuuuuu Prophylactic 
YYYY-MM-DD (XX) 
D: nnnnnnnnnnnnnnnn 
R: rrrrrrrr 
C: ppppppppppp 
F: ffffffff 
xxxxx 
YYYY 
V: mmmmmmmmmmmmmmm 
D: dddddddd uuuuuuu aaaaa bbbbbb ccccc 
Continuing 
D: nnnnnnnnnnnnnnnn 
R: rrrrrrrr 
C: ppppppppppp 
F: ffffffff 
YYYY-MM 
V: mmmmmmmmmmmmmmm 
D: dddddddd uuuuuuu aaaaa bbbbbb ccccc 
Continuing 
D: nnnnnnnnnnnnnnnn 
R: rrrrrrrr 
C: ppppppppppp 
F: ffffffff 
Programming note: Display ‘Ongoing’ for Stop Date if stop date is missing and the Ongoing tick box is 
checked. Within a subject, medications should be presented in order of earliest start date. Do not display 
day for incomplete dates. If Reason for Use is ‘Prophylactic’, display ‘Prophylactic’ in the respective 
Indication cell. If unit, route, and frequency is other, include other specify text 
[1] Day = Medication date – First dose date + 1. 
[2] Preferred Term and ATC4, WHODD version xxx. 
Source: list SAS datasets used to create table 
M:\402C409\production\programs\tlf\L16_2-19_1.sas 
DateTime 
 
 
Listing 16.2-19.2: Prior Medications – All Subjects 


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Replace foonote [1] with “Day = Medication date – First dose date” 
 
 
Listing 16.2-19.3: Intraoperative Opioids – All Subjects 
Listing 16.2-19.4: Rescue Medication – All Subjects 


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Pacira Pharmaceuticals 
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Protocol: 402-C-409 
Listing 16.2-20: Electrocardiogram Findings – Investigator Assessment – All Subjects 
Treatment: 
Subject 
Assessment 
Date/ Day[1] 
Assessment 
Time 
Visit 
Finding 
Specify 
XXX-YYYY 
yyyy-mm-dd/ xxx 
hh:mm 
Screening 
Normal 
XXX-YYYY 
yyyy-mm-dd/ xxx 
hh:mm 
Screening 
Abormal-CS xxxxxxxxxx 
[1]Day=Visit date – first dose date +1 if Visit is on/after first dose date; 
Otherwise Day=Visit date – first dose date. 
 
Source: list SAS datasets used to create table 
M:\402C409\production\programs\tlf\L16_2-20.sas 
DateTime 


Pacira Pharmaceuticals, Inc. 
EXPAREL 
402-C-409 
Statistical Analysis Plan 
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5 March 2018 
 
 
 
Pacira Pharmaceuticals 
 
(Page X of Y) 
Protocol: 402-C-409 
Listing 16.2-21: Physical Examination – All Subjects 
Treatment: 
Subject 
Visit 
Assessment 
Date /Day[1] 
Assessment 
time 
Body System 
Condition 
Abnormality 
XXX-YYYY 
Screening yyyy-mm-dd/ xxx 
hh:mm 
General Appearance 
Normal 
HEENT 
Abnormal 
L thyroid mass- 
2x3cm; immobile, 
nontender; NCS 
Cardiovascular 
Normal 
Bronchopulmonary 
No Change 
Abdomen/Gastrointestinal 
Normal 
Lymphatic 
Normal 
Musculoskeletal 
Normal 
Integumentary (skin, 
hair, nails, etc.) 
Normal 
Neurologic 
Normal 
Extremities 
Normal 
[1]Day=Visit date – first dose date +1 if Visit is on/after first dose date; 
Otherwise Day=Visit date – first dose date. 
 
Source: list SAS datasets used to create table 
M:\402C409\production\programs\tlf\L16_2-21.sas 
DateTime 


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402-C-409 
Statistical Analysis Plan 
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5 March 2018 
 
 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-409 
Listing 16.2-22: Urine Drug Screen – All Subjects 
Treatment: 
Subject 
Timepoint 
Date/ Day[1] 
Time 
Specimen 
Type 
Result 
XXX-YYYY Screening 
yyyy-mm-dd/ xxx 
hh:mm 
Urine 
Negative 
[1]Day = Visit date – first dose date +1 if Visit is on/after first dose; Otherwise Day=Visit date – first dose date. 
 
Source: list SAS datasets used to create table 
M:\402C409\production\programs\tlf\L16_2-22.sas 
DateTime 
 
Note to programmer: 
 
Sort by date and time within subject. 


Pacira Pharmaceuticals, Inc. 
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402-C-409 
Statistical Analysis Plan 
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5 March 2018 
 
 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-409 
Listing 16.2-23: pregnancy test for Women of Child Bearing Potential – All Subjects 
Treatment: 
Subject 
Timepoint 
Date/ Day[1] 
Time 
Specimen 
Type 
Result 
XXX-YYYY 
Screening 
yyyy-mm-dd/ xxx 
hh:mm 
Urine 
Negative 
[1]Day = Visit date – first dose date +1 if Visit is on/after first dose; Otherwise Day=Visit date – first dose date. 
 
Source: list SAS datasets used to create table 
M:\402C409\production\programs\tlf\L16_2-23.sas 
DateTime 
 
Note to programmer: 
 
Sort by date and time within subject. 


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EXPAREL 
402-C-409 
Statistical Analysis Plan 
CONFIDENTIAL 
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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-40 
Listing 16.2-24: Clinical Laboratory Tests-Hematology – All Subjects 
Treatment: 
Subject 
ID 
Parameter 
(Units) 
Reference 
Range 
Visit 
Date / Day[1] Result 
Normal Range Indicator 
XXX-YYYY 
Hemoglobin (g/dL) 
xxx – xxx Screening YYYY-MM-DD/-XX XXXXXXXXX Normal 
Hematocrit (%) 
xxx – xxx Screening YYYY-MM-DD/-XX XXXXXXXXX High 
... 
Programming note: Order the lab parameters the same as shown in CRF. Any unscheduled lab results should be presented 
with scheduled data in date order. Number of decimal places for results should be as reported by the lab. 
[1] Day = Visit date – first dose date +1 if Visit is on/after first dose; Otherwise Day=Visit date – first dose 
date. 
Source: list SAS datasets used to create table 
M:\402C409\production\programs\tlf\L16_2-24.sas 
DateTi 
 
 
Same shell for: 
 
Listing 16.2-25: Clinical Laboratory Tests-Chemistry – All Subjects 
 
 
Listing 16.2-26: Clinical Laboratory Tests-Urinalysis – All Subjects 


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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-409 
Listing 16.2-27: Unique Adverse Events Terms and Associated Coded Terms 
MedDRA Terms 
SOC 
Preferred Term 
Verbatim(s) 
SOC1 
XXXXXXXXXXXXXXXXXXXXXXXXXXX 
PT1.1 
XXXXXXXXXXXXXXXXXXXXXXXXXXX 
XXXXXXXXXXXXXXXXXXXXXXXXXXX 
XXXXXXXXXXXXXXXXXXXXXXXXXXX 
PT1.2 
XXXXXXXXXXXXXXXXXXXXXXXXXXX 
XXXXXXXXXXXXXXXXXXXXXXXXXXX 
SOC2 
PT2.1 
XXXXXXXXXXXXXXXXXXXXXXXXXXX 
XXXXXXXXXXXXXXXXXXXXXXXXXXX 
Coded using MedDRA 
Source: list SAS datasets used to create table 
M:\402C409\production\programs\tlf\L16_2-27.sas 
DateTime 
 
Note to programmer: Sort by SOC and preferred term in alphabetical order 


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Statistical Analysis Plan 
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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-409 
Listing 16.2-28: Unique Medication Terms and Associated Coded Terms 
Who Drug Dictionary Terms 
ACT1 
ACT2 
ACT3 
ACT4 
Preferred name 
Verbatim(s) 
ATC1 
ATC1.2 
PN1.2.1 
XXXXXXXXXXXXXXXXXXXXXXXXXX 
XXXXXXXXXXXXXXXXXXXXXXXXXX 
PN1.2.2 
XXXXXXXXXXXXXXXXXXXXXXXXXX 
ATC2 
ATC2.2 
ATC2.3 
ATC2.4 
PN2.2.3.4.1 
XXXXXXXXXXXXXXXXXXXXXXXXXX 
XXXXXXXXXXXXXXXXXXXXXXXXXX 
Coded using Who Drug Dictionary 
Source: list SAS datasets used to create table 
M:\402C409\production\programs\tlf\L16_2-28.sas 
DateTime 
 
Note to programmer: Sort by ATC1, ATC2, ATC3, ATC4 and preferred name in alphabetical order