Clinical trial NCT03927911
Conditions: Postoperative Pain Management
Sponsor: Pacira Pharmaceuticals, Inc
Start date: 2019-07-31; Completion date: 2020-08-04
Enrollment: 65 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Primary Objective: The primary objective of this study is to compare postsurgical opioid consumption through 72 hours postsurgery in patients receiving local infiltration analgesia (LIA) with EXPAREL and bupivacaine HCl (EXPAREL group) with that of patients receiving standard of care (SOC) (control group) in adult subjects undergoing posterior lumbar spine surgeries where both groups are receiving a multimodal pain regimen.

Secondary Objectives: The secondary objectives of this study are to:

1. Compare safety and effectiveness outcomes following LIA with EXPAREL and bupivacaine hydrochloride (HCl) versus SOC in adult subjects undergoing posterior lumbar spine surgeries through 72 hours, including time to first opioid and opioid-related adverse events (ORAEs).
2. Compare health outcomes following LIA with EXPAREL and bupivacaine hydrochloride (HCl) versus SOC in adult subjects undergoing posterior lumbar spine surgeries, including discharge readiness, hospital (or other facility) length of stay (LOS), discharge disposition, hospital readmissions, and health service utilization.

Detailed description:
This is a Phase 4, multicenter, prospective, active-controlled, real world, study in approximately 225 adult subjects undergoing posterior lumbar spine surgery under general anesthesia.

Subjects will be screened within 30 days prior to surgery; screening on the day of surgery will be allowed but is discouraged. If a subject can only be screened on the day of surgery, the informed consent process must still be started at least 24 hours prior to the conduct of any screening procedures that are not considered SOC at the institution and such procedures may not be performed until written informed consent is provided. All screening procedures that are not SOC must be performed and documented within the 30-day time window (inclusive of the day of surgery for those subjects who can only be screened on the day of surgery) as described here.

During the screening visit, subjects will be assessed for any past or present medical conditions that in the opinion of the investigator would preclude them from study participation. After the ICF is signed, the following information will be recorded and procedures done: medical history, surgical history, medication history, the subject's opioid use history will be recorded to calculate mean daily mg oral morphine equivalent dosing (MED PO) in the last 30 days, demographic and background information, height, weight and body mass index (BMI), a urine pregnancy test for women of childbearing potential, and the subject's current adverse experiences (AEs), if any.

Subjects will be asked questions and/or be asked to fill forms as part of the following assessments: Brief Pain Inventory - short form (BPI-sf), 5-item Opioid Compliance Checklist (OCC), Hospital Anxiety and Depression Scale (HADS), Survey of Pain Attitudes (SOPA), Numeric Rating Scale (NRS) ti assess pain and Opioid Related Symptom Distress Scale (ORSDS).

Based on the planned surgical procedure, subjects will be placed in one of three cohorts:

* Cohort 1 - Open lumbar spinal fusion technique; ("open" cohort)
* Cohort 2 - Minimally invasive tubular and/or percutaneous pedicle screw insertion for lumbar decompression with or without fusion;("tubular/percutaneous without midline incision" cohort)
* Cohort 3 - Lumbar decompression surgery (LDS) without fusion (discectomy or laminectomy outpatient cohort)

The initial sample size in each study cohort (i.e., cohort 1, cohort 2 and cohort 3) is estimated at 75 subjects (50 subjects with EXPAREL and 25 subjects with Control group), for a total of 225 subjects in all three cohorts. Within each assigned cohort, subjects will be allocated in a 2:1 ratio to the EXPAREL (50 subjects) and Control group (25 subjects).

The following sequence will be followed for all cohorts: First, the subjects who meet eligibility criteria will be treated according to the institution's SOC. Their data will be collected prospectively. Next, at each investigational site, the administration of EXPAREL and bupivacaine HCl to the first 1 to 3 subjects in each cohort will be observed to ensure that the correct procedure for infiltration as described in the infiltration guide is being followed. If the infiltration was performed correctly, the subject will be included in the study. If the infiltration was performed incorrectly, the subject will continue in the study but will be removed from statistical analysis and will be replaced to ensure at least 50 evaluable EXPAREL patients are enrolled per cohort. If subjects are discontinued for other reasons, they will be replaced such that a total sample size of 75 fully evaluable subjects is obtained in each study cohort, with 50 in the EXPAREL group and 25 in the Control group.

Arms: arm 1: Local infiltration Analgesia administered (with EXPAREL and bupivacaine HCl) in EXPAREL arm within cohort. EXPAREL arm to be compared to SOC arm within cohort arm 2: Local infiltration Analgesia administered (with EXPAREL and bupivacaine HCl) in EXPAREL arm within cohort. EXPAREL arm to be compared to SOC arm within cohort arm 3: Local infiltration Analgesia administered (with EXPAREL and bupivacaine HCl) in EXPAREL arm within cohort. EXPAREL arm to be compared to SOC arm within cohort
Interventions: intervention 1: EXPAREL and Bupivacaine intervention 2: Standard of Care
Intervention descriptions: intervention 1: Drug: EXPAREL and Bupivacaine HCl 0.5% intervention 2: Standard of Care

Protocol documents:
Prot_000.pdf: 
 
 
Clinical Study Protocol 
A multicenter, prospective, active controlled, real world, Phase 4 study of EXPAREL in 
multimodal regimens compared with standard of care for postsurgical pain management in 
subjects undergoing lumbar posterior spine surgeries (FUSION) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confidentiality Statement 
The information contained in this document is confidential and the property of Pacira Pharmaceuticals, Inc.  
It should not be reproduced, revealed, or sent to third parties other than Institutional Review Boards/Independent 
Ethics Committees and the Investigator’s research support staff participating in the conduct of the study without 
the prior written authorization of Pacira Pharmaceuticals, Inc. 
Protocol No.: 402-C-413 
IND No.: Not applicable 
EudraCT No.: Not applicable 
Study Phase: Phase 4 
Study Drug: EXPAREL® (bupivacaine liposome injectable 
suspension) 
Original Protocol Date: 08-November-2018 
Amendment 1 Date: 25-February-2019 
 Study Site(s): Multicenter study in the United States 
Sponsor: Pacira Pharmaceuticals, Inc. 
5 Sylvan Way 
Parsippany, NJ  07054 
Telephone: (973) 254-3560 
 


Pacira Pharmaceuticals, Inc. 
402-C-413 (FUSION) 
EXPAREL® 
Clinical Study Protocol Amendment 1 
 
 
CONFIDENTIAL 
2 of 83 
25 Feb 2019 
 
 
1. 
SIGNATURE PAGE 
 
 
 
 
 
 
 
 
 
Richard Scranton, MD, MPH 
Chief Medical Officer 
 
Date 
 
 
 
 
 
 
 
 
 
Julia Yang, MD 
Vice President, Clinical Research 
 
Date 
 
 
 
 
 
 
 
 
 
 
Igor Grachev, MD, PhD 
Senior Medical Director, Clinical Research 
 
 
Date 
 
 
 
 
 
 
 
Vincent Yu, PhD 
Senior Director, Biometrics 
 
Date 
 
 
 
 
 
 
 
 
Michael Rozycki, PhD 
Senior Vice President, Regulatory Affairs 
 
Date 
 
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Pacira Pharmaceuticals, Inc. 
402-C-413 (FUSION) 
EXPAREL® 
Clinical Study Protocol Amendment 1 
 
 
CONFIDENTIAL 
3 of 83 
25 Feb 2019 
 
 
2. 
SYNOPSIS 
Name of Sponsor/Company: 
Pacira Pharmaceuticals, Inc. 
5 Sylvan Way 
Parsippany, NJ  07054 
(973) 254-3560 
Individual Study Table Referring 
to Part of the Dossier 
Volume: 
Page: 
 
(For National Authority Use Only) 
Name of Finished Product: 
EXPAREL (bupivacaine 
liposome injectable suspension);  
266 mg in 20 mL 
Name of Active Ingredient: 
Bupivacaine, 1.3%, 13.3 mg/mL 
Title of Study: A multicenter, prospective, active controlled, real world, Phase 4 study of EXPAREL in 
multimodal regimens compared with standard of care for postsurgical pain management in subjects undergoing 
lumbar posterior spine surgeries (FUSION) 
 
Principal Investigator(s): To be determined 
 
Study Center(s): Multicenter study in the United States 
 
Publications (Reference): None 
 
Objectives:  
Primary Objective: The primary objective of this study is to compare postsurgical opioid consumption through 
72 hours postsurgery in patients receiving local infiltration analgesia (LIA) with EXPAREL and bupivacaine HCl 
(EXPAREL group) with that of patients receiving standard of care (SOC) (control group) in adult subjects 
undergoing posterior lumbar spine surgeries where both groups are receiving a multimodal pain regimen. 
 
Secondary Objectives: The secondary objectives of this study are to: 
1. Compare safety and effectiveness outcomes following LIA with EXPAREL and bupivacaine hydrochloride 
(HCl) versus SOC in adult subjects undergoing posterior lumbar spine surgeries through 72 hours, including 
time to first opioid and opioid-related adverse events (ORAEs). 
 
2. Compare health outcomes following LIA with EXPAREL and bupivacaine HCl versus SOC in adult subjects 
undergoing posterior lumbar spine surgeries, including discharge readiness, hospital (or other facility) length 
of stay (LOS), discharge disposition, hospital readmissions, and health service utilization. 
 
Methodology:  
This is a Phase 4, multicenter, prospective, active-controlled, real world, study in approximately 225 adult 
subjects undergoing posterior lumbar spine surgery under general anesthesia.  
Screening:  
Subjects will be screened within 30 days prior to surgery; screening on the day of surgery will be allowed but is 
discouraged. If a subject can only be screened on the day of surgery, the informed consent process must still be 
started at least 24 hours prior to the conduct of any screening procedures that are not considered SOC at the 
Institution and such procedures may not be performed until written informed consent is provided. All screening 
procedures that are not SOC must be performed and documented within the 30-day time window (inclusive of the 
day of surgery for those subjects who can only be screened on the day of surgery) as described here. 


Pacira Pharmaceuticals, Inc. 
402-C-413 (FUSION) 
EXPAREL® 
Clinical Study Protocol Amendment 1 
 
 
CONFIDENTIAL 
4 of 83 
25 Feb 2019 
 
 
Name of Sponsor/Company: 
Pacira Pharmaceuticals, Inc. 
5 Sylvan Way 
Parsippany, NJ  07054 
(973) 254-3560 
Individual Study Table Referring 
to Part of the Dossier 
Volume: 
Page: 
 
(For National Authority Use Only) 
Name of Finished Product: 
EXPAREL (bupivacaine 
liposome injectable suspension);  
266 mg in 20 mL 
Name of Active Ingredient: 
Bupivacaine, 1.3%, 13.3 mg/mL 
During the screening visit, subjects will be assessed for any past or present medical conditions that in the opinion 
of the investigator would preclude them from study participation. 
After the ICF is signed, the following information will be recorded and procedures done: 
x 
Medical history 
x 
Surgical history 
x 
Medication history 
x 
Opioid use history will be recorded to calculate mean daily mg oral morphine equivalent dosing (MED 
PO) in the last 30 days 
x 
Demographic and background information, and height, weight, and body mass index (BMI) 
x 
Urine pregnancy test for women of childbearing potential 
x 
Current adverse experiences (AEs), if any 
 
Subjects will be asked questions and/or be asked to complete the following assessments:  
x 
Brief Pain Inventory – short form (BPI-sf) 
x 
5-item Opioid Compliance Checklist (OCC) (Jamison 2014; Jamison 2016) 
x 
Hospital Anxiety and Depression Scale (HADS) 
x 
Survey of Pain Attitudes (SOPA); single item (7 questions) version 
x 
Numeric Rating Scale (NRS) to assess pain 
x 
Opioid Related Symptoms Distress Scale (OR-SDS) 
 
Based on the planned surgical procedure, subjects will be placed in one of three cohorts: 
x 
Cohort 1 – Open lumbar spinal fusion technique; (“open” cohort) 
x 
Cohort 2 – Minimally invasive tubular and/or percutaneous pedicle screw insertion for lumbar 
decompression with or without fusion; (“tubular/percutaneous without midline incision” cohort) 
x 
Cohort 3 – Lumbar decompression surgery (LDS) without fusion (discectomy or laminectomy outpatient 
cohort) 
 
The initial sample size in each study cohort (i.e., cohort 1, cohort 2 and cohort 3) is estimated at 75 subjects 
(50 subjects with EXPAREL and 25 subjects with Control group), for a total of 225 subjects in all three cohorts. 
Within each assigned cohort, subjects will be allocated in a 2:1 ratio to the EXPAREL (50 subjects) and Control 
group (25 subjects). 


Pacira Pharmaceuticals, Inc. 
402-C-413 (FUSION) 
EXPAREL® 
Clinical Study Protocol Amendment 1 
 
 
CONFIDENTIAL 
5 of 83 
25 Feb 2019 
 
 
Name of Sponsor/Company: 
Pacira Pharmaceuticals, Inc. 
5 Sylvan Way 
Parsippany, NJ  07054 
(973) 254-3560 
Individual Study Table Referring 
to Part of the Dossier 
Volume: 
Page: 
 
(For National Authority Use Only) 
Name of Finished Product: 
EXPAREL (bupivacaine 
liposome injectable suspension);  
266 mg in 20 mL 
Name of Active Ingredient: 
Bupivacaine, 1.3%, 13.3 mg/mL 
 
The following sequence will be followed for all cohorts: First, the subjects who meet eligibility criteria will be 
treated according to the institution’s SOC. Their data will be collected prospectively. Next, at each investigational 
site, the administration of EXPAREL and bupivacaine HCl to the first 1 to 3 subjects in each cohort will be 
observed to ensure that the correct procedure for infiltration as described in the infiltration guide is being 
followed. If the infiltration was performed correctly, the subject will be included in the study. If the infiltration 
was performed incorrectly, the subject will continue in the study but will be removed from statistical analysis and 
will be replaced to ensure at least 50 evaluable EXPAREL patients are enrolled per cohort. If subjects are 
discontinued for other reasons, they will be replaced such that a total sample size of 75 fully evaluable subjects is 
obtained in each study cohort, with 50 in the EXPAREL group and 25 in the Control group. Criteria for fully 
evaluable will be defined in the statistical analysis plan (SAP). 
 
 
 
Blinding 
This will be an open-label study and neither subjects nor Investigators will be blinded for study group allocation. 
eDiary 
Subjects are to record their responses to subject questionnaires on an electronic device (an eDiary) from the time 
of screening, while in the hospital (or other facility), and after discharge. Every day after discharge through 
Day 14, subjects are to record any pain medication (date, time, and dose) taken in the prior 24 hours in addition to 
recording questionnaire responses at the specified time points. 
 
 


Pacira Pharmaceuticals, Inc. 
402-C-413 (FUSION) 
EXPAREL® 
Clinical Study Protocol Amendment 1 
 
 
CONFIDENTIAL 
6 of 83 
25 Feb 2019 
 
 
Name of Sponsor/Company: 
Pacira Pharmaceuticals, Inc. 
5 Sylvan Way 
Parsippany, NJ  07054 
(973) 254-3560 
Individual Study Table Referring 
to Part of the Dossier 
Volume: 
Page: 
 
(For National Authority Use Only) 
Name of Finished Product: 
EXPAREL (bupivacaine 
liposome injectable suspension);  
266 mg in 20 mL 
Name of Active Ingredient: 
Bupivacaine, 1.3%, 13.3 mg/mL 
Study interventions 
Control group 
Subjects in the Control group represented in each cohort will receive SOC as per the participating institution and 
Investigators. Subjects in the Control group in all three cohorts (cohort 1, cohort 2 and cohort 3) will receive the 
following recommended study interventions for analgesia: 
Pre-operative oral multimodal analgesia (within approximately 24-48 hours prior to surgery) 
a) Tylenol (acetaminophen) 1000 mg orally administered (PO) 
b) Gabapentin 300 mg PO 
c)  Robaxin 750 mg PO 
 
List of recommended pre-operative prophylactic medications (optional) for postoperative nausea and vomiting or 
pruritus: 
 For nausea and vomiting: 
a) Ondansetron 4 mg intravenously (IV) at approximately 15-30 min before emergence from anesthesia 
b) Decadron (dexamethasone) 8-12 mg IV after anesthesia induction 
c) Phenergan 25 mg IV PRN 
d) Metocopramide 10 mg PO PRN 
 For pruritus: 
a) Diphenhydramine 25 mg PO PRN 
b) Nalbuphine 2.5 mg IV PRN 
Intra-operative anesthesia and analgesia at the surgical site as per usual care. 
 
Post-operative multimodal analgesia in the control group (within approximately 72 hours postsurgery): 
a) Tylenol (acetaminophen) 1000 mg PO three times daily (TID); the total daily dose of acetaminophen is 
not to exceed 3000 mg. Intravenous (IV) acetaminophen can be used if the subject is unable to tolerate 
oral acetaminophen. 
b) Gabapentin 300 mg PO twice daily (BID); alternative medication is pregabalin 150 mg PO BID 
c) Robaxin 750 mg PO BID or TID 
The use of additional pre- or postsurgical pain medication (e.g., opioids) in cases of insufficient analgesia is 
permitted per the institution’s SOC. 
 
The investigative staff is responsible for recording all pain medications taken until discharge; the subject will then 
be responsible for recording their medications in the eDiary through Day 14. 
 


Pacira Pharmaceuticals, Inc. 
402-C-413 (FUSION) 
EXPAREL® 
Clinical Study Protocol Amendment 1 
 
 
CONFIDENTIAL 
7 of 83 
25 Feb 2019 
 
 
Name of Sponsor/Company: 
Pacira Pharmaceuticals, Inc. 
5 Sylvan Way 
Parsippany, NJ  07054 
(973) 254-3560 
Individual Study Table Referring 
to Part of the Dossier 
Volume: 
Page: 
 
(For National Authority Use Only) 
Name of Finished Product: 
EXPAREL (bupivacaine 
liposome injectable suspension);  
266 mg in 20 mL 
Name of Active Ingredient: 
Bupivacaine, 1.3%, 13.3 mg/mL 
EXPAREL group 
Subjects in the EXPAREL group in all three cohorts (cohort 1, cohort 2 and cohort 3) will receive the following 
strongly recommended study interventions for analgesia: 
1. Pre-operative oral multimodal analgesia (within approximately 24-48 hours prior to surgery) 
a) Tylenol (acetaminophen) 1000 mg PO 
b) Gabapentin 300 mg PO 
c)  Robaxin 750 mg PO 
 
2. List of recommended pre-operative prophylactic medications (optional) for postoperative nausea, vomiting, 
or pruritus: 
  For nausea and vomiting: 
a) Ondansetron 4 mg IV at approximately 15-30 min before emergence from anesthesia  
b) Decadron (dexamethasone) 8-12 mg IV after anesthesia induction 
c)   Phenergan 25 mg IV PRN 
d)   Metocopramide 10 mg PO PRN 
  For pruritus: 
a) Diphenhydramine 25 mg PO PRN 
b) Nalbuphine 2.5 mg IV PRN for pruritus 
 
3. Intra-operative anesthesia and analgesia at the surgical site as per usual care. 
Note: Subjects will not be permitted to receive any other local anesthetic for pre-, intra- (i.e., within 20 min 
before administering EXPAREL), or postoperative analgesia, other than the specified admixed bupivacaine 
for local infiltration at the surgical site per the infiltration guide. If administering lidocaine or other non-
bupivacaine-based local anesthetics is required per the institution’s SOC, wait 20 minutes before 
administering EXPAREL 
4. Post-operative scheduled multimodal analgesia (within approximately 72 hours postsurgery): 
a) Tylenol (acetaminophen) 1000 mg PO TID; the total daily dose of acetaminophen is not to exceed 
3000 mg. Intravenous (IV) acetaminophen can be used if the subject is unable to tolerate oral 
acetaminophen 
b) Gabapentin 300 mg PO BID; alternative medication is pregabalin 150 mg PO BID 
c) Robaxin 750 mg PO BID or TID 
Postsurgical Pain Management 
Subjects should receive opioid and non-opioid rescue pain medications only upon request for breakthrough pain. 
Rescue medications shall be provided based on the pain scores reported on the NRS. For pain scores of 1 to 3, 
subjects shall receive nonsteroidal anti-inflammatory drugs (NSAIDs), without exceeding the maximum daily 
dose. For pain scores of 4 or greater, immediate-release orally-administered (PO) oxycodone shall be 
administered as a rescue medication. For pain scores of 4 to 7, 5 mg PO oxycodone shall be provided PRN; for 
pain score of 8 to 10 on the NRS, 10 mg PO oxycodone will be provided PRN. 
 


Pacira Pharmaceuticals, Inc. 
402-C-413 (FUSION) 
EXPAREL® 
Clinical Study Protocol Amendment 1 
 
 
CONFIDENTIAL 
8 of 83 
25 Feb 2019 
 
 
Name of Sponsor/Company: 
Pacira Pharmaceuticals, Inc. 
5 Sylvan Way 
Parsippany, NJ  07054 
(973) 254-3560 
Individual Study Table Referring 
to Part of the Dossier 
Volume: 
Page: 
 
(For National Authority Use Only) 
Name of Finished Product: 
EXPAREL (bupivacaine 
liposome injectable suspension);  
266 mg in 20 mL 
Name of Active Ingredient: 
Bupivacaine, 1.3%, 13.3 mg/mL 
 
If a subject is unable to tolerate PO medication or fails the PO oxycodone rescue, IV morphine (initiated at 
1 to 2 mg) or hydromorphone (initiated at 0.3 to 0.5 mg) may be administered PRN. Initial rescue medications can 
be IV per Investigator’s discretion. Use of patient controlled analgesia pumps (PCA) is not recommended. 
Postoperative Assessments:  
The date, time, and doses of all opioid and non-opioid rescue medications, and all multimodal scheduled 
medications will be recorded. Additionally, the time that the subject spent in different hospital units (Post-
Anesthesia Care Unit [PACU], step down), date and time of discharge, discharge disposition, concomitant 
medications and AEs (if any) will be recorded.  
The following assessments will be made through 72 hours following surgery and, as specified below, at the follow 
up phone call or visit at 14 days after surgery for all subjects who received study drug as specified below: 
x 
Postsurgical opioid use (i.e., mg MED PO) at 6, 12, 18, 24, 30, 36, 42, 48, and 72 hours after the end of 
surgery, at discharge, and at the 14 day phone call (or visit)  
x 
Pain at the surgical site using an 11-point NRS at 6, 12, 18, 24, 30, 36, 42, 48, and 72 hours after the end 
of surgery, at discharge, and at the 14 day phone call (or visit) 
x 
BPI-sf: administered at screening/baseline; at 24, 48, and 72 hours , at discharge, and at the 14 day phone 
call (or visit) 
x 
Opioid related symptom distress scale (OR-SDS) at 24, 48, and 72 hours, at discharge,  and at the 14 day 
phone call (or visit) 
x 
Discharge readiness using Modified Post-Anesthesia Discharge Scoring System (MPADSS) at 24, 48, 
and 72 hours or discharge or until the subject attains a score of 9, whichever occurs first  
x 
Adverse events and medications used to treat AEs 
The following are also to be documented: 
x 
Unscheduled phone calls or office visits related to pain (Day 14 call or visit)  
x 
Requests for refills for opioid medication (Day 14 call or visit) 
x 
Hospital readmission(s) related to pain (Day 30 call) 
x 
Hospital readmission(s) for any reason (Day 30 call) 
x 
Unscheduled  Emergency Room (ER) visits related to pain (Day 30 call) 
x 
Persistent opioid use by asking the subject at the 30 day (± 3 days) phone call “Are you currently taking 
opioid medication to manage pain from your spine surgery?”  


Pacira Pharmaceuticals, Inc. 
402-C-413 (FUSION) 
EXPAREL® 
Clinical Study Protocol Amendment 1 
 
 
CONFIDENTIAL 
9 of 83 
25 Feb 2019 
 
 
Name of Sponsor/Company: 
Pacira Pharmaceuticals, Inc. 
5 Sylvan Way 
Parsippany, NJ  07054 
(973) 254-3560 
Individual Study Table Referring 
to Part of the Dossier 
Volume: 
Page: 
 
(For National Authority Use Only) 
Name of Finished Product: 
EXPAREL (bupivacaine 
liposome injectable suspension);  
266 mg in 20 mL 
Name of Active Ingredient: 
Bupivacaine, 1.3%, 13.3 mg/mL 
Number of Subjects (Planned):  
A sufficient number of subjects will be screened to provide a total of 225 evaluable subjects, with 150 in the 
EXPAREL group and 75 in the Control group.  
 
Interim analyses may be conducted to adjust to variability. Adaptive study design will be used which incorporates 
adjustment of sample size, cohort sequence, type of surgical procedure, endpoints, etc.  
Eligibility Criteria: 
Inclusion Criteria:  
 
Subjects must meet all of the following inclusion criteria to be eligible for participation: 
1. 18-75 years old at the time of screening 
2. Primary surgical indication is related to spinal degenerative disease, including any of the following: 
a) Spinal stenosis 
b) Spondylolisthesis 
c) Radiculopathy/instability disc disorders 
d) Degenerative disc disease 
3. Medically cleared for elective spine surgery 
4. Scheduled to undergo: 
a) Elective (i.e., not emergency) 
b) Lumbosacral (i.e., L1-S1) 
c) Posterior approach with posterior instrumentation 
5. Cohort 1 – Open cohort only: (Open or mini-open surgical technique with): 
a) 1-level (i.e., spanning 2 vertebrae) or 2-level (i.e., spanning 3 contiguous vertebrae) 
b) Primary fusion or revision fusion 
c) Open or mini-open surgical technique  
6. Cohort 2 – Tubular or percutaneous cohort only: 
a) 1-level (i.e., spanning 2 vertebrae) or 2-level (i.e., spanning 3 contiguous vertebrae) 
b) Primary fusion or revision fusion 
c) Tubular or percutaneous surgical technique  
7. Cohort 3 – Lumbar decompression without fusion outpatient cohort only:  
a) Radiculopathy 
b) Spinal stenosis 
8. Able to provide informed consent and adhere to all study assessments and visit schedule  
 
Exclusion Criteria: 
Subjects who meet any of the following exclusion criteria will not be eligible for participation in this study: 
1. Serious spinal pathology determined by the Investigator that might meaningfully affect postsurgical 
outcomes, including any of the following: 
a) Suspected cauda equina syndrome (e.g., bowel/bladder involvement) 


Pacira Pharmaceuticals, Inc. 
402-C-413 (FUSION) 
EXPAREL® 
Clinical Study Protocol Amendment 1 
 
 
CONFIDENTIAL 
10 of 83 
25 Feb 2019 
 
 
Name of Sponsor/Company: 
Pacira Pharmaceuticals, Inc. 
5 Sylvan Way 
Parsippany, NJ  07054 
(973) 254-3560 
Individual Study Table Referring 
to Part of the Dossier 
Volume: 
Page: 
 
(For National Authority Use Only) 
Name of Finished Product: 
EXPAREL (bupivacaine 
liposome injectable suspension);  
266 mg in 20 mL 
Name of Active Ingredient: 
Bupivacaine, 1.3%, 13.3 mg/mL 
b) Infection  
c) Tumor 
d) Fracture 
e) Systemic inflammatory spondyloarthropathy 
2. Contraindication to local anesthesia according to the clinical judgment of the Investigator and based on the 
EXPAREL label.  
3. Patients who most likely will require PCA pumps in EXPAREL group 
4. Anterior surgical approaches, including any of the following: 
a) Anterior lumbar interbody fusion (ALIF) 
b) Oblique lumbar interbody fusion (OLIF) 
c) Anterior-posterior or 360º fusion 
5. Lateral surgical approaches, including any of the following: 
a) Extreme lateral interbody fusion (XLIF) 
b) Direct lateral interbody fusion (DLIF) 
6. High-dose presurgical opioid use 
a) Mean daily intake greater than 100 mg mEq PO in the past 30 days 
7. Known allergy, hypersensitivity, or contraindication to any of the following study medications: 
a) Bupivacaine 
b) EXPAREL 
c) Tylenol (acetaminophen) 
d) Robaxin 
e) 2 or more NSAIDs 
f) 
2 or more gabapentinoids 
g) 2 or more rescue opioids (e.g., oxycodone, morphine, hydromorphone) 
h) 2 or more medications for postoperative nausea, vomiting, or pruritus (e.g., dexamethasone, ondansetron) 
8. History of severely impaired renal or hepatic function  
9. Severe chronic pain that requires analgesic treatment and, in the opinion of the principal Investigator, is likely 
to meaningfully affect postsurgical outcomes 
10. Subjects that have implanted spinal cord stimulator or intrathecal drug pump 
11. Any neurologic or psychiatric disorder that might affect postsurgical pain or interfere with study assessments 
per Investigator discretion  
12. Malignancy in the last 2 years 
13. History of misuse, abuse, or dependence on opioid analgesics, other prescription drugs, illicit drugs, or 
alcohol as defined in DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition). 
Dependence or chronic opioid use will be defined as use of more than 30 morphine equivalents per day 
during the prior 90 days 
14. Currently pregnant, nursing, or planning to become pregnant during the study or within 1 month after study 
drug administration 
15. Body Mass Index < 17 kg/m2 or >44 kg/m2 at screening 
16. Subjects receiving Worker’s Compensation for disability or who are involved in other litigation related to the 


Pacira Pharmaceuticals, Inc. 
402-C-413 (FUSION) 
EXPAREL® 
Clinical Study Protocol Amendment 1 
 
 
CONFIDENTIAL 
11 of 83 
25 Feb 2019 
 
 
Name of Sponsor/Company: 
Pacira Pharmaceuticals, Inc. 
5 Sylvan Way 
Parsippany, NJ  07054 
(973) 254-3560 
Individual Study Table Referring 
to Part of the Dossier 
Volume: 
Page: 
 
(For National Authority Use Only) 
Name of Finished Product: 
EXPAREL (bupivacaine 
liposome injectable suspension);  
266 mg in 20 mL 
Name of Active Ingredient: 
Bupivacaine, 1.3%, 13.3 mg/mL 
spine 
17. Planned concurrent surgical procedure 
18. Previous participation in an EXPAREL study 
19. Administration of any 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 
 
In addition, the subject might be excluded from the study prior to study drug infiltration if one of the following 
criteria during the surgical procedure is met:  
a) Unable to place planned surgical instrumentation  
b) Poor fixation at the time of surgical instrumentation 
 
In addition, the subject must be considered an early termination if one of the following criteria after the surgical 
procedure is met: 
1. An incision size >20 cm 
2. Autograft taken from a harvest site other than surgical site (i.e., iliac crest autograft) 
3. Intraoperative complications likely to meaningfully affect postsurgical outcomes, including any of the 
following: 
a) Clinically significant and prolonged (i.e., >24 hours) neurologic deficit (e.g., foot drop) 
b) Dural tear or suspected dural tear requiring bed rest (exception: subject will be allowed if the dural tear is 
fixed as per SOC of the institution during surgery) 
c) Extensive bleeding (i.e., >1,000 mL blood loss) 
d) Symptomatic epidural hematoma 
Whenever possible, subjects discontinuing the study should complete end of study (EoS) assessments. Subjects 
discontinuing prior to 72 hours are to complete the 72 hour assessments as EoS assessments. If early termination 
occurs after discharge but prior to Day 14, Day 14 assessments are to be completed as EoS assessments.  If early 
termination occurs after Day 14 but prior to Day 30, Day 30 assessments are to be completed as EoS assessments. 
Test Product, Dose, Mode of Administration, and Lot Number:  
EXPAREL group (EXPAREL admixed with Bupivacaine HCl) 
 
Medication 1 
Medication 2 
Name 
EXPAREL (bupivacaine liposome 
injectable suspension) 
Bupivacaine HCl 
Active Ingredient 
Bupivacaine 
Bupivacaine HCl 
Dosage 
266 mg 
150 mg 
Lot Number 
To be determined 
To be determined 
Mode of administration 
Local infiltration at the surgical 
site 
Local infiltration at the surgical 
site 
 
 


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Name of Sponsor/Company: 
Pacira Pharmaceuticals, Inc. 
5 Sylvan Way 
Parsippany, NJ  07054 
(973) 254-3560 
Individual Study Table Referring 
to Part of the Dossier 
Volume: 
Page: 
 
(For National Authority Use Only) 
Name of Finished Product: 
EXPAREL (bupivacaine 
liposome injectable suspension);  
266 mg in 20 mL 
Name of Active Ingredient: 
Bupivacaine, 1.3%, 13.3 mg/mL 
Reference Product, Dose, Mode of Administration, and Lot Number:  
Institutional site SOC for postsurgical analgesia. 
 
Duration of Subject Participation in Study:  
Participation in the study will begin upon signing the study ICF, which must occur no more than 30 days prior to 
the expected date of surgery. Follow-up will continue for 30 days (± 3 days) after discharge. Study subjects may 
therefore participate for a maximum of 63 days. 
 
Efficacy Assessments:  
The following assessments will be performed to determine efficacy: 
1. Postsurgical opioid use (i.e., mg MED PO) from end of surgery (closure of wound/incision) to 72 hours 
postsurgery   
2. Opioid related adverse events (ORAEs) using the OR-SDS at 24, 48, and 72 hours, at discharge, and at 
14 days. 
3. BPI-sf, administered at screening/baseline; at 24, 48, and 72 hours, at discharge, and at 14 days.  
4. NRS, used to assess pain at the surgical site at 6, 12, 18, 24, 30, 36, 42, 48, and 72 hours, at discharge, and at 
14 days.  
 


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Name of Sponsor/Company: 
Pacira Pharmaceuticals, Inc. 
5 Sylvan Way 
Parsippany, NJ  07054 
(973) 254-3560 
Individual Study Table Referring 
to Part of the Dossier 
Volume: 
Page: 
 
(For National Authority Use Only) 
Name of Finished Product: 
EXPAREL (bupivacaine 
liposome injectable suspension);  
266 mg in 20 mL 
Name of Active Ingredient: 
Bupivacaine, 1.3%, 13.3 mg/mL 
Efficacy Endpoints:  
The endpoints listed below will be assessed based on the efficacy measurements conducted at the times specified 
after the end of surgery. End of surgery is defined as the time when the last incision/wound is closed. All post-
surgical measures/assessments will be recorded from this point forward. 
 
Primary efficacy endpoint: 
The primary efficacy endpoint is postsurgical opioid consumption in mg MED PO from 0 hours (end of surgery) 
to 72 hours postsurgery 
 
Secondary endpoints: 
1. Post-surgical opioid consumption in mg MED PO at 14 days after surgery 
2. Time to first opioid rescue through 72 hours or discharge 
3. Opioid related adverse events will be assessed by using the Opioid Related Symptoms Distress Scale 
(OR-SDS) at 24, 48, and 72 hours postsurgery, at discharge, and at 14 days 
 
Exploratory endpoints: 
1. The NRS pain intensity score at surgical site at each assessed time point during the hospital (or other facility) 
stay (at 6, 12, 18, 24, 30, 36, 42, 48,  and 72 hours), at discharge, and at 14 days 
2. BPI-sf – short form (BPI-sf) at screening/baseline; daily for the first 3 days (24 hours, 48 hours and 72 hours 
or discharge), at discharge, and at 14 days.  
3. OCC, SOPA and HADS at the baseline visit.  
4. The area under the curve (AUC) of the NRS pain intensity scores at surgical site from 0 to 24, 0 to 48, and 
0 to 72 hours  
Safety Assessments: Adverse events will be monitored and recorded from the time the ICF is signed through 
Day 30. Safety assessments will be measured at multiple time points throughout the study. 
 
Safety Endpoints: 
Any adverse events (AEs) reported while subjects are in the hospital (or other facility), or at any time during the 
30 day study follow-up, will be assessed as safety outcomes. 
 


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Name of Sponsor/Company: 
Pacira Pharmaceuticals, Inc. 
5 Sylvan Way 
Parsippany, NJ  07054 
(973) 254-3560 
Individual Study Table Referring 
to Part of the Dossier 
Volume: 
Page: 
 
(For National Authority Use Only) 
Name of Finished Product: 
EXPAREL (bupivacaine 
liposome injectable suspension);  
266 mg in 20 mL 
Name of Active Ingredient: 
Bupivacaine, 1.3%, 13.3 mg/mL 
Health Outcomes Assessments: 
1. Time as hours spent in PACU and stepdown unit 
2. Total length of stay (i.e., recorded in hours) in the hospital (or other facility) 
3. Discharge readiness (measured via the MPADSS) at 24, 48, and 72 hours or  discharge or until the subject 
attains a score of 9, whichever occurs first 
4. Discharge disposition (i.e., home, outpatient rehabilitation facility, inpatient rehabilitation facility, skilled 
nursing facility, other) 
5. 30 days all cause readmissions 
6. 30 days readmissions related to pain  
7. 30 days Emergency Room (ER) visits related to pain 
8. 14days office visits related to pain 
9. 14 days call to doctor  related to pain 
10. 30 days persistent opioid use by asking the subject “Are you currently taking opioid medication to manage 
pain from your spine surgery?” 
 
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 and bupivacaine HCl (EXPAREL group) to treatment 
with SOC (Control group) will be determined using an analysis of variance (ANOVA) with treatment as the main 
effect on postoperative opioid consumption through 72 hours. Secondary efficacy endpoints will be analyzed 
using ANOVA, logistic regression model, chi-square tests, and log-rank tests, as appropriate. Safety endpoints 
will be summarized descriptively by treatment group.  
 
Interim Analysis 
Interim analyses may be conducted to adjust to variability. Adaptive study design (i.e., adjustment of sample size, 
cohort sequence, type of surgical procedure, endpoints, etc.) will be used. 
 
 
 


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Table 1. 
Time and Events Schedule of Study Procedures (Part 1) 
Abbreviations: AE = Adverse event; BMI = Body mass index; BPI-sf = Brief Pain Inventory – short form; HADS = Hospital Anxiety and Depression Scale; ICF = Informed consent 
form; MED = Morphine equivalent dosing; OCC = 5-item Opioid Compliance Checklist (Jamison 2014; Jamison 2016); PACU = Post-anesthesia care unit; PO = per os (oral); SOC = 
standard of care; SOPA = Survey of Pain Attitude; UPT = urine pregnancy test. 
a No more than 30 days should pass between signing of the ICF and performance of the surgery. Subjects will be screened within 30 days prior to surgery; screening on the day of 
surgery will be allowed but is discouraged. If a subject can only be screened on the day of surgery, the informed consent process must still be started at least 24 hours prior to the 
Study Procedure 
Screening/ Baseline  
(1-30 days prior to surgery) 
Pre-op 
Intra-op 
PACU 
Post-op 
Screening and Baseline 
Obtain signed ICFa 
X 
 
 
 
 
Record medical and surgical history  
X 
 
 
 
 
Record medication historyb 
X 
 
 
 
 
Record demographics and baseline characteristics 
X 
 
 
 
 
Record opioid use in last 30 days to determine mg MED PO/day average 
X 
 
 
 
 
Record height, weight, and BMI 
X 
 
 
 
 
Confirm eligibility  
X 
 
 
 
 
Urine pregnancy test (UPT) (for women of childbearing potential) 
X 
 
 
 
 
NRS for pain at the pre-surgical area 
X 
 
 
 
 
Survey of Pain Attitudes (Single-item SOPA) 
X 
 
 
 
 
Brief Pain Inventory – short form (BPI-sf) 
X 
 
 
 
 
Hospital Anxiety and Depression Scale (HADS) 
X 
 
 
 
 
5-item Opioid Compliance Checklist (OCC)c  
X 
 
 
 
 
Record AEs and medications to treat AEs from the time ICF was signed 
 
 
 
 
 
Day of surgery 
Confirm eligibility; UPT does not need to be repeated  
 
X 
 
 
 
Administer scheduled presurgical medications 
 
X 
 
 
 
Record surgery start and stop times  
 
 
X 
 
 
Prepare study drug 
 
 
X 
 
 
Administer study drug; record start and stop times  
 
 
X 
 
 
Record intraoperative opioids administered and doses, and all concomitant medications 
 
 
X 
 
 
Record times and doses of all opioid and non-opioid rescue medications administered  
 
 
X 
 
 
Post-surgeryd 
Record date, time, and dose of rescue postsurgical analgesics 
 
 
 
 
X 
Record date, times, and doses of all multimodal scheduled medications administered 
 
 
 
 
X 
Record date, time of admission to, and time of discharge from different hospital units 
(PACU, step-down) 
 
 
 
X 
 
Record concomitant medications 
 
 
 
 
 


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conduct of any screening procedures that are not considered SOC at the institution and such procedures may not be performed until written informed consent is provided. All 
screening procedures that are not SOC must be performed and documented within the 30-day time window (inclusive of the day of surgery for those subjects who can only be screened 
on the day of surgery) as described here. During the screening visit, subjects will be assessed for any past or present medical conditions that in the opinion of the investigator would 
preclude them from study participation.  
b Record any medications for the condition for which the procedure is being performed that were administered within 30 days prior to screening. 
c Sources for 5-item OCC are Jamison 2014 and Jamison 2016. 
d All assessments conducted after baseline (prior to the study drug administration) will be timed from the end of surgery. Postsurgical is defined as a period after the end of surgery. End 
of surgery is defined as the time (when the last incision/wound is closed). 
 


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Table 2. 
Time and Events Schedule of Study Procedures after PACU Arrival (Part 2) 
 
From End of Surgery 
6-72 Hoursa 
 
Dischargeb
Phone 
call or 
Visita 
Phone 
 callb 
Time Point 
± Time window 
6 hrs 
±1 hr 
12 hrs 
±1 hr 
18 hrs 
±1 hr 
24 hrs 
±1 hr 
30 hrs 
±2 hr 
36 hrs 
±2 hr 
42 hrs  
±2 hr 
48 hrs 
±2 hr 
72 hrs 
±4 hrb 
 
14 days 
±3 daysa
30 days 
±3 days 
Study Procedure 
NRS for pain at surgical site  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
BPI-sf 
 
 
 
X 
 
 
 
X 
X 
X 
X 
 
Record date and time of all opioid and non-opioid rescue  
medicationsa  
 
 
 
 
 
 
 
 
 
 
 
 
OR-SDS 
 
 
 
X 
 
 
 
X 
X 
X 
X 
 
MPADSSc 
 
 
 
X 
 
 
 
X 
X 
Xc 
 
 
Record date and time of discharge  
 
 
 
 
 
 
 
 
 
X 
 
 
Record subject discharge disposition 
 
 
 
 
 
 
 
 
 
X 
 
 
Document any unscheduled phone calls or office visits related to 
 pain 
 
 
 
 
 
 
 
 
 
 
X 
 
Document any requests for refills for opioid medication 
 
 
 
 
 
 
 
 
 
 
X 
 
Record persistent opioid use by asking the subject “Are you  
currently taking opioid medication to manage pain from your  
spine surgery?” 
 
 
 
 
 
 
 
 
 
 
 
X 
Document any hospital readmissions related to pain 
 
 
 
 
 
 
 
 
 
 
 
X 
Document hospital readmissions for any cause  
 
 
 
 
 
 
 
 
 
 
 
X 
Document any unscheduled visits to the ER related to pain 
 
 
 
 
 
 
 
 
 
 
 
X 
Record date and time of AEs and medications to treat AEs 
 (with dosage) 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: AE=adverse event; BPI-sf = Brief Pain Inventory – short form; ER = Emergency room; hr/hrs = hour(s); MPADSS = Modified Post-Anesthesia 
Discharge Scoring System; NRS=numeric rating scale; OR-SDS = Opioid-Related Symptom Distress Scale. 
a Subjects are to record their responses to subject questionnaires on an electronic device (eDiary) at screening, while in the hospital (or other facility), and at Day 14. 
Every day from discharge through Day 14, subjects are to record in the eDiary any pain medication (date, time, and dose) taken in the prior 24 hours in addition to 
recording questionnaire responses. Subjects who were lent an eDiary will have to return to the site at 14 days at which time they are to return the device. Subjects who 
used their own device will have a follow-up phone call at Day 14. All subjects will have a follow up call at 30 days after the surgery. 
b For all subjects, if discharge occurs prior to 72 hours postsurgery, all Discharge assessments are to be performed at the time of discharge.  After discharge, all scheduled 
assessments should be performed at the scheduled time points (i.e., NRS pain assessments at 6, 12, 18, 24, 30, 36, 42, 48, and 72 hours postsurgery; BPI-sf and OR-
SDS at 24, 48, and 72 hours; and date, time, and dose of all opioid and non-opioid rescue medications) and recorded in the eDiary. 
c Discharge readiness via the MPADSS will be assessed at 24, 48, and 72 hours and/or discharge or until the subject attains a score of 9, whichever occurs first. 
 


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Note: Early Termination: Whenever possible, subjects discontinuing the study should complete end of study (EoS) assessments. Subjects discontinuing prior to 72 hours are to 
complete the 72 hour assessments as EoS assessments. If early termination occurs after discharge but prior to Day 14, Day 14 assessments are to be completed as EoS assessments.  
If early termination occurs after Day 14 but prior to Day 30, Day 30 assessments are to be completed as EoS assessments. 
 
 


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3. 
TABLE OF CONTENTS 
1. 
SIGNATURE PAGE .................................................................................................... 2 
2. 
SYNOPSIS ................................................................................................................... 3 
3. 
TABLE OF CONTENTS ........................................................................................... 19 
4. 
LIST OF ABBREVIATIONS .................................................................................... 23 
5. 
ETHICS ...................................................................................................................... 25 
5.1. 
Institutional Review Board/Independent Ethics Committee ...................................... 25 
5.2. 
Ethical Conduct of the Study ..................................................................................... 25 
5.3. 
Subject Information and Consent ............................................................................... 25 
6. 
INVESTIGATORS AND STUDY ADMINISTRATION STRUCTURE ................. 25 
7. 
INTRODUCTION ...................................................................................................... 25 
7.1. 
Indication .................................................................................................................... 26 
7.2. 
Current Therapies/Treatments .................................................................................... 26 
7.3. 
EXPAREL (Bupivacaine Liposome Injectable Suspension) ..................................... 27 
7.4. 
Summary of Human Experience with EXPAREL ..................................................... 28 
7.5. 
Postmarketing Exposure............................................................................................. 29 
8. 
OBJECTIVES ............................................................................................................ 29 
8.1. 
Primary Objective ...................................................................................................... 29 
8.2. 
Secondary Objective(s) .............................................................................................. 30 
9. 
OVERALL STUDY DESIGN AND PLAN .............................................................. 30 
9.1. 
Study Design .............................................................................................................. 30 
9.1.1. 
Duration of the Study and Subject Participation ........................................................ 35 
9.1.2. 
Study Stopping Rules ................................................................................................. 36 
9.2. 
Discussion of Study Design ....................................................................................... 36 
10. 
STUDY POPULATION ............................................................................................ 36 
10.1. 
Inclusion Criteria ........................................................................................................ 36 
10.2. 
Exclusion Criteria ...................................................................................................... 37 
10.3. 
Removal of Subjects from Therapy or Assessment ................................................... 39 
10.3.1. 
Withdrawal Secondary to Adverse Events ................................................................. 40 


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10.3.2. 
Voluntary or Study Investigator Withdrawal ............................................................. 40 
11. 
TREATMENTS ......................................................................................................... 41 
11.1. 
Treatment to be Administered .................................................................................... 41 
11.1.1. 
Control Group ............................................................................................................ 41 
11.1.2. 
EXPAREL Group ....................................................................................................... 42 
11.2. 
Administration Instructions/Procedures ..................................................................... 44 
11.2.1. 
EXPAREL Administration Considerations ................................................................ 44 
11.3. 
Identity of the Investigational Products ...................................................................... 44 
11.3.1. 
Description of EXPAREL .......................................................................................... 44 
11.3.2. 
Description of Reference Product .............................................................................. 44 
11.3.3. 
Description of Diluents .............................................................................................. 45 
11.4. 
Method of Assigning Subjects to Treatment .............................................................. 45 
11.4.1. 
Two-step Subject Allocation ...................................................................................... 45 
11.4.2. 
Replacement of Subjects ............................................................................................ 45 
11.5. 
Selection of Doses in the Study.................................................................................. 45 
11.6. 
Blinding ...................................................................................................................... 45 
11.7. 
Prior and Concomitant Therapy and Medications ...................................................... 45 
11.7.1. 
Prior Therapy and Medications .................................................................................. 46 
11.7.2. 
Permitted and Restricted Therapy and Medications During Surgery ......................... 47 
11.7.3. 
Permitted and Restricted Therapy or Medications After Surgery .............................. 48 
11.8. 
Treatment Compliance ............................................................................................... 49 
11.9. 
Accountability of Study Drug .................................................................................... 49 
12. 
STUDY ENDPOINTS AND MEASUREMENTS .................................................... 49 
12.1. 
Efficacy Assessments ................................................................................................. 49 
12.2. 
Efficacy Endpoints ..................................................................................................... 50 
12.3. 
Pharmacokinetic Measurements (Not Applicable) .................................................... 50 
12.4. 
Pharmacokinetic Endpoints (Not Applicable) ........................................................... 51 
12.5. 
Health Outcomes Assessments .................................................................................. 51 
12.6. 
Safety Assessments .................................................................................................... 51 


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12.7. 
Safety Endpoints ........................................................................................................ 51 
12.8. 
Appropriateness of Measures ..................................................................................... 51 
13. 
STUDY PROCEDURES ........................................................................................... 51 
13.1. 
Instructions for Conducting Procedures and Measures .............................................. 52 
13.1.1. 
eDiary ......................................................................................................................... 52 
13.1.2. 
Pain Intensity Assessments ........................................................................................ 52 
13.1.3. 
Brief Pain Inventory-short form (BPI-sf) ................................................................... 53 
13.1.4. 
Opioid Related Symptoms Distress Scale (OR-SDS) ................................................ 53 
13.1.5. 
Hospital Anxiety and Depression Scale (HADS) ...................................................... 53 
13.1.6. 
Survey of Pain Attitudes (SOPA)............................................................................... 53 
13.1.7. 
5-item Opioid Compliance Checklist (OCC) ............................................................. 53 
13.1.8. 
Vital Signs .................................................................................................................. 53 
13.1.9. 
Clinical Laboratory Tests ........................................................................................... 53 
13.1.10. 
Discharge Readiness .................................................................................................. 54 
13.2. 
Obtaining Informed Consent ...................................................................................... 54 
13.3. 
Screening/Baseline Procedures .................................................................................. 54 
13.4. 
Preoperative procedures ............................................................................................. 55 
13.5. 
Intra-operative Procedures: ........................................................................................ 57 
13.6. 
Postoperative Procedures Through Discharge from the Hospital (or Other 
Facility) ...................................................................................................................... 57 
13.7. 
After Discharge from the Hospital (or Other Facility) ............................................... 59 
13.8. 
Day 14 Phone Call or Visit ........................................................................................ 59 
13.9. 
Day 30 Phone Call...................................................................................................... 60 
14. 
ADVERSE EVENT REPORTING ............................................................................ 60 
14.1. 
Adverse Events ........................................................................................................... 60 
14.1.1. 
Definitions .................................................................................................................. 60 
14.1.2. 
Recording Adverse Events ......................................................................................... 61 
14.1.3. 
Severity of Adverse Events ........................................................................................ 62 
14.1.4. 
Relationship of Adverse Events to Study Drug ......................................................... 62 
14.1.5. 
Outcome of Adverse Events ....................................................................................... 63 


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14.1.6. 
Action Taken with Subject due to an Adverse Event................................................. 63 
14.2. 
Serious Adverse Events .............................................................................................. 64 
14.2.1. 
Definition of a Serious Adverse Event ....................................................................... 64 
14.2.2. 
Reporting Serious Adverse Events ............................................................................. 65 
15. 
STATISTICAL METHODS ...................................................................................... 66 
15.1. 
Study Objective .......................................................................................................... 66 
15.2. 
Study Endpoints ......................................................................................................... 66 
15.3. 
Determination of Sample Size ................................................................................... 66 
15.4. 
Analysis Populations .................................................................................................. 67 
15.5. 
Handling Subject Dropouts and Discontinuations ..................................................... 67 
15.6. 
Statistical Analyses .................................................................................................... 67 
15.6.1. 
Baseline Characteristics ............................................................................................. 67 
15.6.2. 
Study Compliance ...................................................................................................... 67 
15.6.3. 
Efficacy Analyses ....................................................................................................... 67 
15.6.4. 
Safety Analyses .......................................................................................................... 67 
15.7. 
Significance Testing ................................................................................................... 68 
15.8. 
Interim Analyses......................................................................................................... 68 
16. 
REFERENCES ........................................................................................................... 68 
17. 
APPENDICES ............................................................................................................ 72 
17.1. 
Appendix 1: Subject’s Reported Pain (Numeric Rating Scale) at Surgical  Site ....... 73 
17.2. 
Appendix 2: Brief Pain Inventory - Short Form (BPI-sf) ........................................... 74 
17.3. 
Appendix 3:   The Opioid Related Symptom Distress Scale (OR-SDS) ................... 77 
17.4. 
Appendix 4: Hospital Anxiety and Depression Scale (HADS) .................................. 78 
17.5. 
Appendix 5: Single-item Survey of Pain Attitudes (SOPA) ...................................... 80 
17.6. 
Appendix 6: 5-item Opioid Compliance Checklist .................................................... 81 
17.7. 
Appendix 7: Modified Post-Anaesthetic Discharge Scoring System (MPADSS) ..... 82 
17.8. 
Appendix 8: Persistent Opioid Use ............................................................................ 83 
 
 


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LIST OF TABLES 
Table 1. 
Time and Events Schedule of Study Procedures (Part 1) ........................................... 15 
Table 2. 
Time and Events Schedule of Study Procedures After PACU Arrival (Part 2) ......... 17 
 
LIST OF FIGURES 
Figure 1 
Study Schema ............................................................................................................. 31 
 
4. 
LIST OF ABBREVIATIONS 
 
AE 
Adverse event 
ALIF 
Anterior lumbar interbody fusion 
ALT 
Alanine transaminase 
ANOVA 
Analysis of variation 
AST 
Aspartate transaminase 
AUC 
Area under the plasma concentration-versus-time curve 
BID 
Bis in die (twice a day) 
BMI 
Body mass index 
BPI-sf 
Brief Pain Inventory-short form 
CFR 
Code of Federal Regulations 
Cmax 
Maximum plasma concentration 
Cm 
Centimeters 
CRF 
Case Report Form 
CV 
Coefficient of variation 
DLIF 
Direct lateral interbody fusion 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition 
EoS 
End of study 
ER 
Emergency room 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transpeptidase 
HADS 
Hospital Anxiety and Depression Scale 
HCl 
Hydrochloride 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IV 
Intravenous 
JCAHO 
Joint Commission on Accreditation of Healthcare Organizations 


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L 
Lumbar (e.g., L5 vertebra) 
LDS 
Lumbar decompression surgery 
LIA 
Local infiltration analgesia 
LOS 
Length of stay 
MCID 
Minimum clinically important difference 
MED 
Morphine equivalent dosing 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
mL 
Milliliter 
MPADSS 
Modified Post-Anesthesia Discharge Scoring System 
NRS 
Numeric rating scale 
NSAIDs 
 
Non-steroidal anti-inflammatory drugs 
OCC 
Opioid compliance checklist 
OLIF 
Oblique lumbar interbody fusion 
OR-SDS 
Opioid Related Symptoms Distress Scale 
ORAE 
Opioid related adverse event 
PACU 
Post-anesthesia care unit 
PCA 
Patient controlled analgesia 
PO 
Per os (orally administered) 
POD 
Postoperative day 
PRN 
Pro re nata (as needed) 
PTAE 
Pretreatment adverse event 
S 
Sacral (e.g., S5 vertebra) 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SNRIs 
Serotonin and norepinephrine reuptake inhibitors 
SOC 
Standard of care 
SOPA 
Survey of Pain Attitudes 
SSRIs 
Selective serotonin reuptake inhibitors 
TAP 
Transversus abdominis plane 
TEAE 
Treatment-emergent adverse event 
TID 
Ter in die (three times a day) 
ULN 
Upper limit of normal 
UPT 
Urine pregnancy test 
US 
United States (of America) 
XLIF 
Extreme lateral lumbar interbody fusion 
 
 


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5. 
ETHICS 
5.1. Institutional Review Board/Independent Ethics Committee 
Prior to enrolling subjects into this study, each study site will obtain the approval of an Institutional 
Review Board (IRB) that complies with the International Council for 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 (if applicable) 312, and the ICH GCP.  Study documents 
will be maintained in accordance with applicable regulations. 
5.3. Subject Information and Consent 
Before a subject undergoes any study-specific screening procedures, the Investigator or designee 
will thoroughly explain to the subject the purpose of the study, the associated procedures, and any 
expected effects and potential adverse reactions. A copy of the IRB-approved 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 participate. The subject, and the 
study staff with whom he or she discusses the ICF, will sign and date the ICF. A photocopy of the 
signed ICF will be given to the subject. 
The Investigator will explain to the subject that he or she is completely free to decline entry into the 
study and may withdraw from the study at any time, for any reason, without risking his or her 
medical care. Similarly, the Investigator and/or Pacira Pharmaceuticals, Inc. (Pacira) 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 IRBs/IECs and regulatory agencies. 
7. 
INTRODUCTION 
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 


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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). Current therapies have a variety of side effects (see Section 7.2) and there 
is an unmet medical need for agents that provide better and safer postsurgical pain control. 
EXPAREL® (bupivacaine liposome injectable suspension) is a long-acting, non-opioid, analgesic. 
Bupivacaine, the active pharmaceutical ingredient in EXPAREL, is a local anesthetic that has been 
used to produce local analgesia via a field block (also referred to as infiltration) and to produce 
regional analgesia via a peripheral nerve block for decades in the United States (US) and around the 
world.  
7.1. Indication 
EXPAREL was initially approved by the US Food and Drug Administration (FDA) in 2011 for 
single-dose administration into the surgical site to produce postsurgical analgesia. The indication 
was amended and approved by the US FDA in 2018 to read: “EXPAREL is indicated for single-
dose infiltration in adults to produce postsurgical local analgesia and as an interscalene brachial 
plexus block to produce postsurgical regional analgesia. Safety and efficacy have not been 
established in other nerve blocks.” 
Since its approval, EXPAREL has been administered to over 4 million patients in the US. 
7.2. Current Therapies/Treatments 
Current modalities of postoperative analgesia include wound infiltration and nerve block with local 
anesthetics, 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; 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 (e.g., delay in regaining bowel function or an inability to 
tolerate liquid and solid oral intake, etc.), and conserves healthcare resources. As such, the Joint 
Commission on Accreditation of Healthcare Organizations (JCAHO) requires that all healthcare 


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facilities practice safe and quality pain management, promote safe opioid prescribing and use, 
minimize the risks associated with treatment (The Joint Commission), 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. Opioid-only regimens are common and intravenous (IV) patient-controlled analgesia is a 
widely used delivery system for morphine sulfate. AEs related to opioid administration (e.g., nausea, 
vomiting, ileus, confusion), however, represent one important reason that there is a need to develop 
opioid-sparing strategies. Indeed, fear of gastrointestinal side effects such as nausea and vomiting, 
as well as respiratory depression, present major limitations for the widespread use of opioid 
analgesics. (Chernin 2001 and Viscusi 2009) Furthermore, management of opioid-related events 
often requires medical attention (e.g., opioid antagonists, antiemetic agents) and increased 
pharmacy/nursing time, which may raise healthcare expenses (Carroll 1994).  
Postsurgical opioid use has also been linked to subsequent persistent opioid use. A recent large 
study of claims data found that approximately 6% of opioid-naïve patients who underwent surgery 
and received opioids continued to use opioids 90 days after surgery (Brummett 2017). Extrapolated 
to the US population, this translates to approximately 3 million patients each year. In addition, the 
incidence of persistent opioid use did not differ among patients undergoing minor (5.9%) or major 
(6.5%) surgeries, suggesting that many patients are likely continuing opioid therapy for reasons 
other than the intensity of their pain (Brummett 2017). 
EXPAREL could provide physicians with a long-acting analgesic for procedures that are more 
amenable to brachial plexus nerve block than field block, an indication for which EXPAREL has an 
extensive history of safe and effective use in over 4 million patients in the US. Moreover, the 
analgesic effects of a local anesthetic when administered as a brachial plexus nerve block could be 
prolonged via a single-shot technique without the risks and difficulty of placing 1 or more 
continuous nerve block catheters. Finally, this approach also has the potential to reduce the exposure 
of surgical patients to opioids and their associated AEs, as well as reduce the number of opioids 
available for abuse and diversion in the community. 
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 (Balocco 2018). EXPAREL 
(Pacira Pharmaceuticals, Inc., Parsippany, New Jersey) is a bupivacaine liposome injectable 
suspension. It consists of microscopic spherical, multivesicular liposomes (DepoFoam® drug 
delivery system), organized in a honeycomb-like structure comprising numerous non-concentric 
internal aqueous chambers containing a bupivacaine base at a concentration of 13.3 mg/mL. Each 
chamber is separated from adjacent chambers by lipid membranes. The lipids (phospholipids, 
cholesterol, and triglycerides) are naturally occurring or close analogs of endogenous lipids. 
Bupivacaine is slowly released from the DepoFoam particles by a complex mechanism involving 


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reorganization of the barrier lipid membranes and subsequent diffusion of the drug over an extended 
period of time. A small amount of extra-liposomal bupivacaine (i.e., not bound within the 
DepoFoam particles) enables EXPAREL to have a similar onset of action to standard bupivacaine 
hydrochloride (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 to 2 hours and a 
second peak at approximately 24-48 hours (Hu 2013). 
Following the initial approval of EXPAREL, numerous clinical studies were conducted in which 
EXPAREL was administered via various routes of administration, including infiltration into the 
transversus abdominis plane (TAP) (Sternlicht 2014, Feierman 2014).  
Please see the EXPAREL Full Prescribing Information (2018) for complete safety information 
regarding EXPAREL (liposome bupivacaine injectable suspension): 
https://www.exparel.com/hcp/prescriptioninformation.pdf.  
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: 
x 
Bupivacaine HCl solution, a well-characterized anesthetic/analgesic, with more than 
35 years of its use in the US. 
x 
DepoFoam, a liposomal extended-release formulation contained in the marketed product 
DepoCyt® (1999). The form of DepoFoam used in EXPAREL – has a slightly different 
mixture of lipid components than DepoCyt.  
7.4. Summary of Human Experience with EXPAREL 
The EXPAREL clinical development program, which includes 31 clinical studies (13 Phase 1, 
7 Phase 2, and 11 Phase 3), assessed the efficacy and safety across a wide range of body regions and 
applications, investigating its use in pain management when administered as a peripheral nerve 
block for regional analgesia and as a field block for local analgesia. A total of 3,644 subjects were 
studied in these 31 clinical studies, of which 2,141 subjects received EXPAREL. 
In terms of efficacy, 5 positive Phase 3 studies, 316, 317, 323, 327, and 331 demonstrated 
statistically significant improvements in pain intensity scores compared to placebo or IR 
bupivacaine in the postoperative period. All 5 studies also showed a statistically significant 
reduction compared to placebo or bupivacaine in total opioid consumption; Studies 327, 316, 317, 
and 331 additionally showed a significantly higher percentage of opioid-free subjects and a 
significantly longer time to first opioid use compared to placebo or IR bupivacaine. 
The safety of EXPAREL was evaluated in 10 randomized, double-blind, local administration into 
the surgical site clinical studies involving 823 subjects undergoing various surgical procedures.  


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Subjects were administered a dose ranging from 66 to 532 mg of EXPAREL. In these studies, the 
most common adverse reactions (incidence ≥10%) following EXPAREL administration were 
nausea, constipation, and vomiting. The common adverse reactions (incidence ≥2% to <10%) 
following EXPAREL administration were pyrexia, dizziness, edema peripheral, anemia, 
hypotension, pruritus, tachycardia, headache, insomnia, anemia postoperative, muscle spasms, 
hemorrhagic anemia, back pain, somnolence, and procedural pain.  
The less common/rare adverse reactions (incidence <2%) following EXPAREL administration were 
chills, erythema, bradycardia, anxiety, urinary retention, pain, edema, tremor, dizziness, postural, 
paresthesia, syncope, incision site edema, procedural hypertension, procedural hypotension, 
procedural nausea, muscular weakness, neck pain, pruritus generalized, rash pruritic, hyperhidrosis, 
cold sweat, urticaria, palpitations, sinus bradycardia, supraventricular extrasystoles, ventricular 
extrasystoles, ventricular tachycardia, hypertension, pallor, anxiety, confusional state, depression, 
agitation, restlessness, hypoxia, laryngospasm, apnea, respiratory depression, respiratory failure, 
body temperature increased, blood pressure increased, blood pressure decreased, oxygen saturation 
decreased, urinary incontinence, vision blurred, tinnitus, drug hypersensitivity, and hypersensitivity. 
Across the 31 completed studies in the clinical program, safety data were collected on 
3,644 subjects (2,141 subjects received EXPAREL, 850 subjects received IR bupivacaine alone, and 
653 subjects received placebo). Doses administered ranged from 10 mg to 750 mg. There were 
adequate numbers in the ≥65 years of age category (171 subjects) as well as the American Society of 
Anesthesiologists Class 3-4 category (135 subjects). Overall, the type and frequency of safety events 
were consistent across various surgical procedures performed and with the well-established safety 
profile of local anesthetics. The safety of EXPAREL was also assessed for any evidence of 
neurotoxicity, impaired wound healing, and the potential for systemic local anesthetic toxicity. 
There is no evidence of any local adverse effects specific to EXPAREL. 
Please refer to the Investigator’s Brochure for additional information regarding the completed 
studies. Please see the EXPAREL Full Prescribing Information for complete safety information 
regarding EXPAREL (liposome bupivacaine injectable suspension) in the setting of wound 
infiltration (https://www.exparel.com/hcp/prescriptioninformation.pdf). 
7.5. Postmarketing Exposure 
The extensive supportive safety database generated by 4 million exposures (as of 07 May 2018) in 
the US supports the safety profile of EXPAREL.  
8. 
OBJECTIVES 
8.1. Primary Objective 
The primary objective of this study is to compare postsurgical opioid consumption through 72 hours 
postsurgery in patients receiving local infiltration analgesia (LIA) with EXPAREL and bupivacaine 


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HCl  (EXPAREL group) with that of patients receiving standard of care (SOC) (control group) in 
adult subjects undergoing posterior lumbar spine surgeries where both groups are receiving a 
multimodal pain regimen. 
8.2. Secondary Objective(s) 
The secondary objectives are to: 
1. 
Compare safety and effectiveness outcomes following LIA with EXPAREL and bupivacaine 
hydrochloride (HCl) versus SOC in adult subjects undergoing posterior lumbar spine 
surgeries through 72 hours, including time to first opioid, opioid-related adverse events 
(ORAEs). 
2. 
Compare health outcomes following LIA with EXPAREL and bupivacaine HCl versus SOC 
in adult subjects undergoing posterior lumbar spine surgeries, including discharge readiness, 
hospital (or other facility) length of stay (LOS), discharge disposition, hospital readmissions, 
and health service utilization. 
9. 
OVERALL STUDY DESIGN AND PLAN 
9.1. Study Design  
This is a Phase 4, multicenter, prospective, active-controlled, real world study in approximately 
225 adult subjects undergoing posterior lumbar spine surgeries under general anesthesia. This will 
be an open-label study and neither subjects nor Investigators will be blinded for study group 
allocation. This study will include three cohort groups: cohort 1 – open lumbar spinal fusion 
technique (“open”); cohort 2 – minimally invasive tubular and/or percutaneous pedicle screw 
insertion for lumbar decompression with or without fusion (“tubular/percutaneous without midline 
incision”); and cohort 3 – lumbar decompression surgery (LDS) without fusion (discectomy or 
laminectomy) outpatient cohort.  
 
The initial sample size in each study cohort (i.e., cohort 1, cohort 2 and cohort 3) is estimated at 
75 subjects (50 subjects with EXPAREL and 25 subjects with Control group), for a total of 
225 subjects in all three cohorts. Within each assigned cohort, subjects will be allocated in a 
2:1 ratio to the EXPAREL (50 subjects) and Control group (25 subjects). 
 
The following sequence will be followed for all cohorts: First, the subjects who meet eligibility 
criteria will be treated according the institution’s SOC. Their data will be collected prospectively. 
Next, at each investigational site, the administration of EXPAREL and bupivacaine HCl to the first 
1 to 3 subjects in each cohort will be observed to ensure that the correct procedure for infiltration as 
described in the infiltration guide is being followed. If the infiltration was performed correctly, the 
subject will be included in the study. If the infiltration was performed incorrectly, the subject will 
continue in the study but will be removed from statistical analysis and will be replaced to ensure at 
least 50 evaluable EXPAREL patients are enrolled per cohort. If subjects are discontinued for other 


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reasons, they will be replaced such that a total sample size of 75 fully evaluable subjects is obtained 
in each study cohort, with 50 in the EXPAREL group and 25 in the Control group. Criteria for fully 
evaluable will be defined in the statistical analysis plan (SAP).  
Figure 1 
Study Schema 
 
Obtaining Informed Consent 
Potential participants may provide informed consent up to 30 days before their scheduled surgery. 
Subjects will be screened within 30 days prior to surgery; screening on the day of surgery will be 
allowed but is discouraged. If a subject can only be screened on the day of surgery, the informed 
consent process must still be started at least 24 hours prior to the conduct of any screening 
procedures that are not considered SOC at the institution and such procedures may not be performed 
until written informed consent is provided. All screening procedures that are not SOC must be 
performed and documented within the 30-day time window (inclusive of the day of surgery for those 
subjects who can only be screened on the day of surgery) as described here. During the screening 
visit, subjects will be assessed for any past or present medical conditions that in the opinion of the 
investigator would preclude them from study participation.  
Screening 
Subjects will be screened within 30 days prior to surgery. During the screening visit, subjects will be 
assessed for past or present medical conditions that, in the opinion of the Investigator, would 
preclude them from study participation. After the ICF is signed, a medical history, surgical history, 
medication history, opioid use history, and current adverse experiences (if any) will be collected. 
Height, weight, and BMI will be recorded, and a urine pregnancy test (UPT) for women of 
childbearing potential will be conducted. 
 


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Subjects will be asked questions and/or be asked to fill forms to complete the following 
assessments:  
x 
Brief Pain Inventory – short form (BPI-sf) 
x 
5-item Opioid Compliance Checklist (OCC) (Jamison 2014; Jamison 2016) 
x 
Hospital Anxiety and Depression Scale (HADS) 
x 
Survey of Pain Attitudes (SOPA); single item (7 questions) version 
x 
Numeric rating scale (NRS) to assess pain 
x 
Opioid Related Symptoms Distress Scale (OR-SDS) 
Day of Surgery 
Control Group: Subjects in the Control group will receive SOC as per the participating institutions 
and Investigators. Subjects in the Control group in all three cohorts (cohort 1, cohort 2, and 
cohort 3) will receive the following recommended study interventions for analgesia: 
 
Pre-operative oral multimodal analgesia (within approximately 24-48 hours prior to surgery) 
a) Tylenol (acetaminophen) 1000 mg PO 
b) Gabapentin 300 mg PO 
c)  Robaxin 750 mg PO 
 
List of recommended pre-operative prophylactic medications (optional) for postoperative nausea 
and vomiting or pruritus: 
  Nausea and vomiting: 
a) Ondansetron 4 mg IV at approximately 15-30 min before emergence from anesthesia  
b) Decadron (dexamethasone) 8-12 mg IV after anesthesia induction 
c) Phenergan 25 mg PRN 
d) Metocopramide 10 mg PO PRN 
Pruritus: 
a) Diphenhydramine 25 mg PO PRN 
b) Nalbuphine 2.5 mg IV PRN for pruritus 
 
Intra-operative anesthesia and analgesia at the surgical site as per usual care. 
 
Post-operative multimodal analgesia in the control group (within approximately 72 hours 
postsurgery): 
a) Tylenol (acetaminophen) 1000 mg PO TID; the total daily dose of acetaminophen is not 
to exceed 3000 mg. Intravenous (IV) acetaminophen can be used if the subject is unable 
to tolerate oral acetaminophen. 
b) Gabapentin 300 mg PO BID; alternative medication is pregabalin 150 mg PO BID 


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c) Robaxin 750 mg PO BID or TID 
 
The use of additional pre- or postsurgical pain medication (e.g., opioids) in cases of insufficient 
analgesia is permitted per the institution’s SOC. 
 
The investigative staff is responsible for recording all pain medications taken until the hospital (or 
other facility) discharge; the subject will then be responsible for recording their medications in the 
eDiary through Day 14. 
 
EXPAREL Group: All eligible subjects in EXPAREL group will receive the following strongly 
recommended study interventions for analgesia:  
1. 
Pre-operative oral multimodal analgesia (within approximately 24-48 hours prior to 
surgery): 
a) Tylenol (acetaminophen) 1000 mg PO 
b) Gabapentin 300 mg PO 
c) Robaxin 750 mg PO 
 
2. 
List of recommended pre-operative prophylactic medications (optional) for postoperative 
nausea and vomiting or pruritus: 
  Nausea and vomiting: 
a) Ondansetron 4 mg IV at approximately 15-30 min before emergence from anesthesia  
b) Decadron (dexamethasone) 8-12 mg IV after anesthesia induction 
c) Phenergan 25 mg PRN 
d) Metocopramide 10 mg PO PRN 
Pruritus: 
a) Diphenhydramine 25 mg PO PRN 
b) Nalbuphine 2.5 mg IV PRN for pruritus 
 
3. 
Intraoperative anesthesia and analgesia at the surgical site as per usual care  
Note: Subjects will not be permitted to receive any other local anesthetic for preoperative, 
intraoperative (i.e., within 20 min before administering EXPAREL), or postoperative 
analgesia, other than the specified admixed bupivacaine for local infiltration at the surgical 
site per the infiltration guide. If administering lidocaine or other non-bupivacaine-based 
local anesthetics is required per the institution’s SOC, wait 20 min before administering 
EXPAREL. 
 
Post-operative Medications 
Postsurgically, all eligible subjects from the EXPAREL group are required to receive the following 
scheduled postoperative multimodal analgesia (within approximately 72 hours postsurgery):  
x Tylenol (acetaminophen) 1000 mg PO TID; the total daily dose of acetaminophen is not to 
exceed 3000 mg. Intravenous (IV) acetaminophen can be used if the subject is unable to 
tolerate oral acetaminophen. 


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x Gabapentin 300 mg PO BID; alternative medication is pregabalin 150 mg PO BID. 
x Robaxin 750 mg PO BID or TID 
 
No additional skeletal muscle relaxants should be used in the hospital in the EXPAREL group. 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 receive opioid and non-opioid rescue pain medications only upon request for 
breakthrough pain.  
 
Rescue medications shall be provided based on the pain scores reported on the NRS. For pain scores 
of 1 to 3, subjects shall receive nonsteroidal anti-inflammatory drugs (NSAIDs), without exceeding 
the maximum daily dose. For pain scores of 4 or greater, immediate- release orally-administered 
(PO) oxycodone shall be administered as a rescue medication. For pain scores of 4 to 7, 5 mg PO 
oxycodone shall be provided as needed (PRN); for pain score of 8 to 10 on the NRS, 10 mg PO 
oxycodone will be provided PRN. 
 
If a subject is unable to tolerate PO medication or fails the PO oxycodone rescue, IV morphine 
(initiated at 1 to 2 mg) or hydromorphone (initiated at 0.3 to 0.5 mg) may be administered PRN. 
 
Optional: The initial rescue medication can be IV per Investigator’s discretion. 
 
Post-discharge Analgesia 
Upon discharge from the hospital (or other facility), subjects will receive prescriptions for 30 tablets 
of Tylenol (acetaminophen) 500 mg (1000 mg up to TID; not to exceed 3000 mg or 6 tablets daily) 
and 30 tablets of oxycodone 5 mg (PRN, not to exceed 3 tablets per day). If refills for opioid 
medication are requested by subjects from discharge up to Day 14, the time and date of the 
request(s) will be noted as one of the outcomes measured in this study related to postsurgical opioid 
use.  
 
The subject should record pain medication taken (date, time and dose) in the eDiary from discharge 
through Day 14. 
 
Postoperative Assessments 
The date, time, and doses of all opioid and non-opioid rescue medications (if needed) and all 
multimodal scheduled medications will be recorded. Additionally, the time that the subject spent in 
different hospital units (Post-Anesthesia Care Unit [PACU], step down), date and time of discharge, 
discharge disposition, concomitant medications and AEs (if any) will be recorded.  
 


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The following assessments will be made through 72 hours following surgery and, as specified 
below, at the follow up phone call or visit at 14 days after surgery for all subjects who received 
study drug as specified below: 
x Postsurgical opioid use (i.e., mg MED PO) at 6, 12, 18, 24, 30, 36, 42, 48, and 72 hours after 
the end of surgery, at discharge, and at the 14 day phone call (or visit) 
x Pain at the surgical site using an 11-point NRS at 6, 12, 18, 24, 30, 36, 42, 48, and 72 hours 
after the end of surgery, at discharge, and at the 14 day follow-up call (or visit) (see 
Appendix 1)  
x BPI-sf: administered at screening/baseline; at 24, 48, and 72 hours, at discharge, and at the 
14 day follow-up phone call (or visit) 
x Opioid related symptom distress scale (OR-SDS) at 24, 48, and 72 hours, at discharge, and 
at the 14 day follow-up call (or visit) (see Appendix 3)  
x Discharge readiness using Modified Post-Anesthesia Discharge Scoring System (MPADSS) 
at 24, 48, and 72 hours or discharge or until the subject attains a score of 9, whichever 
occurs first  
x Adverse events and medications used to treat AEs through Day 30 
 
The following are also to be documented: 
x Unscheduled phone calls or office visits related to pain (Day 14 call or visit)  
x Requests for refills for opioid medication (Day 14 call or visit) 
x Hospital readmission(s) related to pain (Day 30 call) 
x Hospital readmission(s) for any reason (Day 30 call) 
x Unscheduled  Emergency Room (ER) visits related to pain (Day 30 call) 
x Adverse events and medications used to treat AEs 
x Persistent opioid use by asking the subject at the 30 day (± 3 days) phone call “Are you 
currently taking opioid medication to manage pain from your spine surgery?”  
 
Follow-up Visit and Phone calls 
Two follow up phone calls will be scheduled at 14 days (±3 days) and 30 days (±3 days) after the 
surgery for all subjects. Subjects who were lent an eDiary will have to return to the site at 14 days at 
which time they are to return the device; they will have a follow-up phone call at 30 days. Subjects 
who used their own device will have follow-up phone calls at 14 and 30 days after the surgery. 
9.1.1. Duration of the Study and Subject Participation 
Participation in the study will begin upon signing the study ICF, which must occur no more than 
30 days prior to the expected date of surgery. Follow-up will continue for 30 days (± 3 days) after 
the discharge. Study subjects may therefore participate for up to 63 days from ICF to the final study 
follow-up. 


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9.1.2. Study Stopping Rules 
If Pacira, the Investigator, or officials from regulatory authorities discover conditions during the 
study that indicate that the study or study site should be terminated, this action may be taken after 
Pacira has consulted with appropriate regulatory authorities and notified the Investigator(s). 
The Pacira Medical Monitor and Pharmacovigilance team review all serious adverse events (SAEs) 
reported from Pacira clinical studies on an ongoing basis and in real time (i.e., as the events are 
reported). The Medical Monitor is responsible for temporarily halting the study if the type, 
frequency, or seriousness/severity of such events suggests a potential threat to the safety of the study 
participants. If such action is taken, a thorough review of all available data will be done. 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, multicenter, active-
controlled study is designed to compare postsurgical opioid consumption following local infiltration 
with EXPAREL with bupivacaine HCl versus SOC in adult subjects undergoing posterior lumbar 
spine surgeries. 
This study is designed to assess the effectiveness of EXPAREL infiltration in a multimodal setting 
to reduce total postsurgical opioid consumption. All subjects in the study will be eligible to receive 
a non-opioid or opioid analgesic, if needed, to control breakthrough postsurgical pain as part of the 
multimodal approach to pain management. 
Adverse events (AEs) and SAEs will be recorded by the investigator or staff from the time the ICF 
is signed through postoperative Day (POD) 30. 
10. 
STUDY POPULATION 
Subjects must meet all eligibility criteria to be enrolled in this study. 
10.1. Inclusion Criteria 
Subjects must meet all of the following criteria to be eligible for study entry: 
1. 
Subjects 18-75 years old at time of screening 
2. 
Primary surgical indication is related to spinal degenerative disease, including any of the 
following: 
a) Spinal stenosis 
b) Spondylolisthesis 
c) Radiculopathy/instability disc disorders 
d) Degenerative disc disease 


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3. 
Medically cleared for elective spine surgery 
4. 
Scheduled to undergo: 
a) Elective (i.e., not emergency) 
b) Lumbosacral (i.e., L1-S1) 
c) Posterior approach with posterior instrumentation 
5. 
Cohort 1- Open only: 
Open or mini-open surgical technique with: 
a) 1-level (i.e., spanning vertebrae) or 2-level (i.e., spanning 3 contiguous vertebrae) 
b) Primary fusion or revision fusion 
c) Open or mini-open surgical technique  
6. 
Cohort 2- Tubular or percutaneous cohort only: 
a)  1-level (i.e., spanning 2 vertebrae) or 2-level (i.e., spanning 3 contiguous vertebrae) 
b)  Primary fusion or revision fusion 
c)  Tubular or percutaneous surgical technique  
7. 
Cohort 3- Lumbar decompression without fusion outpatient cohort only: 
a) Radiculopathy 
b) Spinal stenosis 
8. 
Able to provide informed consent and adhere to all study assessments and visit schedule 
10.2. Exclusion Criteria 
Subjects who meet any of the following exclusion criteria will not be eligible for participation in 
this study: 
1. 
Serious spinal pathology determined by the Investigator that might meaningfully affect 
postsurgical outcomes, including any of the following: 
a) Suspected cauda equina syndrome (e.g., bowel/bladder involvement) 
b) Infection  
c) Tumor 
d) Fracture 
e) Systemic inflammatory spondyloarthropathy 
2. 
Contraindication to local anesthesia according to the clinical judgment of the Investigator 
and based on the EXPAREL label.  
3. 
Patients who most likely will require patient-controlled analgesia (PCA) pumps in 
EXPAREL group 
4. 
Anterior surgical approaches, including any of the following: 
a) Anterior lumbar interbody fusion (ALIF) 
b) Oblique lumbar interbody fusion (OLIF) 
c) Anterior-posterior or 360º fusion 


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5. 
Lateral surgical approaches, including any of the following: 
a. Extreme lateral interbody fusion (XLIF) 
b. Direct lateral interbody fusion (DLIF) 
6. 
High-dose presurgical opioid use 
a. Mean daily intake greater than 100 mg mEq PO in the past 30 days 
7. 
Known allergy, hypersensitivity, or contraindication to any of the following study 
medications: 
a) Bupivacaine 
b) EXPAREL 
c) Tylenol (acetaminophen) 
d) Robaxin 
e) 2 or more NSAIDs 
f) 2 or more gabapentinoids 
g) 2 or more rescue opioids (e.g., oxycodone, morphine, hydromorphone) 
h) 2 or more medications for postoperative nausea, vomiting, or pruritus (e.g., 
dexamethasone, ondansetron) 
8. 
History of severely impaired or hepatic function  
9. 
Severe chronic pain that requires analgesic treatment, and in the opinion of the principal 
Investigator, is likely to meaningfully affect postsurgical outcomes 
10. Subjects that have implanted spinal cord stimulator or intrathecal drug pump 
11. Any neurologic or psychiatric disorder that might affect postsurgical pain or interfere with 
study assessments per Investigator discretion  
12. Malignancy in the last 2 years 
13. History of misuse, abuse, or dependence on opioid analgesics, other prescription drugs, 
illicit drugs, or alcohol as defined in DSM-5 (Diagnostic and Statistical Manual of Mental 
Disorders, Fifth Edition). Dependence or chronic opioid use will be defined as use of more 
than 30 morphine equivalents per day during the prior 90 days 
14. Currently pregnant, nursing, or planning to become pregnant during the study or within 
1 month after study drug administration 
15. Body Mass Index < 17 kg/m2 or >44 kg/m2 at screening 
16. Subjects receiving Worker’s Compensation for disability or who are involved in other 
litigation related to the spine 
17. Planned concurrent surgical procedure 
18. Previous participation in an EXPAREL study 
19. Administration of any 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 
In addition, the subject might be excluded from the study prior to study drug infiltration if one of the 
following criteria during the surgical procedure is met:  


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a) Unable to place planned surgical instrumentation  
b) Poor fixation at the time of surgical instrumentation 
In addition, the subject must be considered an early termination if one of the following criteria after 
the surgical procedure is met: 
1. An incision size >20 cm 
2. Autograft taken from a harvest site other than surgical site (i.e., iliac crest autograft) 
3. Intraoperative complications likely to meaningfully affect postsurgical outcomes, including any 
of the following: 
a) Clinically significant and prolonged (i.e., >24 hours) neurologic deficit (e.g., foot drop) 
b) Dural tear or suspected dural tear requiring bed rest (exception: subject will be allowed if the 
dural tear is fixed as per SOC of the institution during surgery) 
c) Extensive bleeding (i.e., >1,000 mL blood loss) 
d) Symptomatic epidural hematoma 
10.3. Removal of Subjects from Therapy or Assessment 
Every reasonable effort shall be made to maintain subject compliance and participation in the study. 
Reasons for discontinuation of any subject from the study will be recorded. If a subject withdraws 
from the study and has an ongoing AE, the subject may be monitored for safety through Day 30 or 
until satisfactory resolution is obtained at the investigator’s discretion. Whenever possible, subjects 
discontinuing the study should complete EoS assessments. Subjects discontinuing prior to 72 hours 
are to complete the 72 hour assessments as EoS assessments. If early termination occurs following 
discharge but prior to Day 14, the subject will be asked to complete the Day 14 assessments as EoS 
assessments. If early termination occurs after Day 14 but prior to Day 30, the subject will be asked 
to complete the Day 30 assessments as EoS assessments. 
Subject might be excluded from the study prior to study drug infiltration if one of the following 
criteria during the surgical procedure is met: 
a) Unable to place planned surgical instrumentation 
b) Poor fixation at the time of surgical instrumentation 
If any clinically significant event or condition is uncovered during or after the surgery, such as the 
ones listed below, the subject should be withdrawn from the study and the event or condition should 
be reported as an AE or SAE: 
1. An incision size >20 cm 
2. Autograft taken from harvest site other than surgical site (i.e., iliac crest autograft) 
3. Intraoperative complications likely to meaningfully affect postsurgical outcomes, including 
any of the following: 
a) Clinically significant and prolonged (i.e., >24 hours) neurologic deficit (e.g., foot drop) 
b) Dural tear or suspected dural tear requiring bed rest 


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c) Extensive bleeding (i.e., >1,000 mL blood loss) 
d) Symptomatic epidural hematoma 
10.3.1. Withdrawal Secondary to Adverse Events 
If a subject experiences an AE that renders him/her incapable of continuing with the remaining 
study assessments, then he/she will be discontinued from further participation in the study. If such a 
subject discontinues prior to 72 hours, all assessments to be conducted at 72 hours should be 
completed. If such a subject discontinues following discharge but prior to Day 14, the subject will 
be asked to complete the Day 14 assessments. If the subject withdraws after Day 14 but before Day 
30, the subject will be asked to complete the Day 30 assessments. 
Any subject who discontinues because of an AE should be instructed to notify the study personnel 
of any abnormalities and to come to the study site if medical evaluation is needed and the urgency of 
the situation permits. Any subject exhibiting undesirable side effects will receive appropriate 
treatment at the discretion of the Investigator.  
This study involves a single infiltration of study drug; therefore, subjects should not be terminated 
from the ongoing study assessments as long as they are willing and able to continue with the follow-
up schedule according to the protocol. For emergencies and other unscheduled visits to a medical 
facility other than the study site, medical records must be obtained by the Investigator and 
appropriate information captured in the subject’s case report form (CRF). 
10.3.2. Voluntary or Study Investigator Withdrawal 
Subjects are free to discontinue from the study at any time, without prejudice to future treatment. 
Nevertheless, subjects will be encouraged to complete the end of study 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 EoS assessments. If the subject 
withdraws before 72 hours postsurgery, he or she will be asked to complete the 72 hour assessments 
as EoS assessments. If the subject withdraws following discharge but prior to Day 14, he or she will 
be asked to complete the Day 14 assessments as EoS assessments. If the subject withdraws after 
Day 14 but before Day 30, he or she will be asked to complete the Day 30 assessments as EoS 
assessments. 
After termination from the study, the subject may be monitored for safety including monitoring of 
AEs through Day 30 at the investigator’s discretion. 


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11. 
TREATMENTS 
11.1. Treatment to be Administered 
11.1.1. Control Group 
Subjects in the Control group in each cohort will receive SOC as per the participating institution and 
Investigators. Subjects in the Control group in all three cohorts (cohort 1, cohort 2 and cohort 3) will 
receive the following recommended study interventions for analgesia: 
Pre-operative oral multimodal analgesia (within approximately 24 to 48 hours prior to surgery): 
a) Tylenol (acetaminophen) 1000 mg PO 
b) Gabapentin 300 mg PO 
c) Robaxin 750 mg PO 
Intra-operative anesthesia and analgesia at the surgical site as per usual care. 
List of recommended pre-operative prophylactic medications (optional) for postoperative nausea 
and vomiting or pruritus: 
For nausea and vomiting: 
a) Ondansetron 4 mg intravenously (IV) at approximately 15-30 min before emergence 
from anesthesia 
b) Decadron 8-12 mg IV after anesthesia induction 
c) Phenergan 25 mg IV PRN 
d) Metocopramide 10 mg PO PRN 
 For pruritus: 
a) Diphenhydramine 25 mg PO PRN  
b) Nalbuphine 2.5 mg IV PRN 
Post-operative multimodal analgesia in the control group: 
a) Tylenol (acetaminophen) 1000 mg PO TID; the total daily dose of acetaminophen is not 
to exceed 3000 mg. Intravenous (IV) acetaminophen can be used if the subject is unable 
to tolerate oral acetaminophen. 
b) Gabapentin 300 mg PO BID; alternative medication is pregabalin 150 mg PO BID 
c) Robaxin 750 mg PO BID or TID 


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The use of additional pre- or postsurgical pain medication (e.g., opioids) in cases of insufficient 
analgesia is permitted per the institution’s SOC. 
The investigative staff is responsible for recording all pain medications taken until the discharge; the 
subject will then be responsible for recording their medications in the eDiary. 
Postsurgical Pain Management 
Subjects should receive opioid and non-opioid rescue pain medications only upon request for 
breakthrough pain.  
Rescue medications shall be provided based on the pain scores reported on the NRS. For pain scores 
of 1 to 3, subjects shall receive additional unscheduled nonsteroidal anti-inflammatory drugs 
(NSAIDs), without exceeding the maximum daily dose. For pain scores of 4 or greater, immediate-
release orally-administered (PO) oxycodone shall be administered as a rescue medication. For pain 
scores of 4 to 7, 5 mg PO oxycodone shall be provided; for pain score of 8 to 10 on the NRS, 10 mg 
PO oxycodone will be provided.  
If a subject is unable to tolerate PO medication or fails the PO oxycodone rescue, IV morphine 
(initiated at 1 to 2 mg) or hydromorphone (initiated at 0.3 to 0.5 mg) may be administered PRN. 
Initial rescue medication can be IV per Investigator’s discretion. Use of patient controlled analgesia 
pumps (PCA) is not recommended. 
The investigative staff is responsible for recording all pain medications taken until discharge; the 
subject will then be responsible for recording their medications in the eDiary from discharge 
through Day 14. 
11.1.2. EXPAREL Group 
Subjects in the EXPAREL group in all three cohorts (cohort 1, cohort 2 and cohort 3) will receive 
the following strongly recommended study interventions for analgesia: 
1. Pre-operative oral multimodal analgesia (within approximately 24-48 hours prior to surgery) 
a) Tylenol (acetaminophen) 1000 mg PO 
b) Gabapentin 300 mg PO 
c) Robaxin 750 mg PO 
2. List of recommended pre-operative prophylactic medications (optional) for postoperative nausea 
and vomiting or pruritus: 
For nausea and vomiting: 


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a) Ondansetron 4 mg intravenously (IV) at approximately 15-30 min before emergence 
from anesthesia 
b) Decadron 8-12 mg IV after anesthesia induction 
c) Phenergan 25 mg IV PRN 
d) Metocopramide 10 mg PO PRN 
 
 
For pruritus: 
a) Diphenhydramine 25 mg PO PRN 
b) Nalbuphine 2.5 mg IV PRN 
3. Intra-operative anesthesia and analgesia at the surgical site as per usual care  
(Note: Subjects will not be permitted to receive any other local anesthetic for pre-, intra- (i.e., 
within 20 min. before administering EXPAREL), or postoperative analgesia, other than the 
specified admixed bupivacaine for local infiltration at the surgical site per infiltration guide. If 
administering lidocaine or other non-bupivacaine-based local anesthetics is required per the 
institution’s SOC, wait 20 min before administering EXPAREL). 
4. Post-operative scheduled multimodal analgesia (within approximately 72 hours postsurgery): 
a) Tylenol (acetaminophen) 1000 mg PO TID; the total daily dose of acetaminophen is not 
to exceed 3000 mg. Intravenous (IV) acetaminophen can be used if the subject is unable 
to tolerate oral acetaminophen. 
b) Gabapentin 300 mg PO BID; alternative medication is pregabalin 150 mg PO BID 
c) Robaxin 750 mg PO BID or TID 
Postsurgical Pain Management 
Subjects should receive opioid and non-opioid rescue pain medications only upon request for 
breakthrough pain. 
Rescue medications shall be provided based on the pain scores reported on the NRS. For pain scores 
of 1 to 3, subjects shall receive nonsteroidal anti-inflammatory drugs (NSAIDs), without exceeding 
the maximum daily dose. For pain scores of 4 or greater, immediate- release orally-administered 
(PO) oxycodone shall be administered as a rescue medication. For pain scores of 4 to 7, 5 mg PO 
oxycodone shall be provided PRN; for pain score of 8 to 10 on the NRS, 10 mg PO oxycodone will 
be provided PRN. 
If a subject is unable to tolerate PO medication or fails the PO oxycodone rescue, IV morphine 
(initiated at 1 to 2 mg) or hydromorphone (initiated at 0.3 to 0.5 mg) may be administered PRN. 


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Initial rescue medication can be IV per Investigator’s discretion. Use of patient controlled analgesia 
pumps (PCA) is not recommended. 
The investigative staff is responsible for recording all pain medications taken until the discharge; the 
subject will then be responsible for recording their medications in the eDiary from discharge 
through Day 14. 
11.2. Administration Instructions/Procedures 
Please refer to cohort-specific infiltration guide for technique. 
11.2.1. EXPAREL Administration Considerations 
Because of the potential risk of severe adverse effects associated with the administration of 
bupivacaine, the study sites must be equipped to manage subjects with any evidence of cardiac, 
neurological, or respiratory toxicity. 
Subjects will not be permitted to receive any other local anesthetic for pre-, intra- (i.e., within 
20 min before administering EXPAREL), or postoperative analgesia, other than the specified 
admixed bupivacaine for local infiltration at the surgical site per the infiltration guide. If 
administering lidocaine or other non-bupivacaine-based local anesthetics is required per the 
institution’s SOC wait 20 min before administering EXPAREL. 
EXPAREL may not be administered to a subject if the vial has been open for more than 4 hours. In 
order to prevent EXPAREL from settling, gently inverting and re inverting the syringe prior to 
administration is recommended. 
11.3. Identity of the Investigational Products 
11.3.1. Description of EXPAREL 
EXPAREL (bupivacaine liposome injectable suspension) is formulated as a sterile, non-pyrogenic, 
white to off-white, preservative-free homogenous suspension of bupivacaine encapsulated into 
multivesicular lipid-based (the DepoFoam drug delivery system). Bupivacaine is present at a 
nominal concentration of 13.3 mg/mL. For the purposes of this study, EXPAREL will be provided 
in 20 mL, 1.3% (13.3 mg/mL) single-use, and clear glass vials. EXPAREL vials should be stored 
refrigerated between 2°C to 8°C (36°F to 46°F). 
11.3.2. Description of Reference Product 
The reference therapy will be the institutional site’s SOC for post-surgical analgesia. 


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11.3.3. Description of Diluents 
Normal saline (0.9% sodium chloride solution) for injection will be used for the dilution (volume 
expansion) of study drug. 
11.4. Method of Assigning Subjects to Treatment 
11.4.1. Two-step Subject Allocation 
This study will not have a randomized design, but rather two-step subject allocation. Study subjects 
will be allocated in a 2:1 ratio to the EXPAREL or SOC group. This study will be done in 2 steps: 
step 1 – including 25 subjects managed by institutional SOC (Control group), and step 2 – including 
50 subjects managed by multimodal regimen with local infiltration of EXPAREL and bupivacaine 
HCl into the surgical site (EXPAREL group). 
11.4.2. Replacement of Subjects 
Given that this study will have a case observation period for the first 1 to 3 subjects in EXPAREL 
group, the total number of subjects included in this group may further increase when accounting for 
the number of subjects that will be excluded from data analysis if the infiltration guide was not 
properly followed. Subjects enrolled to replace those excluded subjects from data analysis will be 
assigned unique subject numbers. 
11.5. 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 100 mg. Clinical studies have shown that for wound infiltration a total dose of 
266 mg (20 mL) of EXPAREL is safe and efficacious. Based on this experience, the FDA-approved 
marketed dose of 266 mg was deemed appropriate for this study. 
11.6. Blinding 
This will be an open-label study and neither subjects nor Investigators will be blinded for study 
group allocation. 
11.7. Prior and Concomitant Therapy and Medications 
Any medications for the condition for which the procedure is being performed administered within 
30 days prior to screening will be recorded on the case report form (CRF), as well all medications 
though Day 14 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.  


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11.7.1. Prior Therapy and Medications 
The following multimodal pain regimen will be used for all cohorts that receive EXPAREL: 
Permitted Prior Medications and Therapy  
Prophylactic antibiotics are permitted, according to the surgeon’s preference.  
On the day of surgery (Day 1), all eligible subjects will receive the following medications:  
x Tylenol (acetaminophen) 1000 mg PO; the total daily dose of acetaminophen is not to 
exceed 3000 mg. Intravenous acetaminophen can be used per investigator’s discretion if 
the subject is unable to tolerate oral acetaminophen.  
x Gabapentin 300 mg PO; alternative medication is pregabalin 150 mg PO 
x Robaxin 750 mg PO 
List of recommended pre-operative prophylactic medications (optional) for postoperative nausea 
and vomiting or pruritus: 
 
For nausea and vomiting: 
a) Ondansetron 4 mg intravenously (IV) at approximately 15-30 min before emergence 
from anesthesia 
b) Decadron 8-12 mg IV after anesthesia induction 
c) Phenergan 25 mg IV PRN 
d) Metocopramide 10 mg PO PRN 
 
 
For pruritus: 
a) Diphenhydramine 25 mg PO PRN 
b) Nalbuphine 2.5 mg IV PRN 
 
Restricted Prior Medications and Therapy  
Use of the medications listed below is restricted or prohibited within the specified time frames. 
Subjects will not be permitted to receive any other local anesthetic for pre-, intra-, or postoperative 
analgesia, other than admixed bupivacaine HCl for local infiltration at the surgical site. 
 
Before screening 
x Bupivacaine and any other local anesthetics are not permitted within 7 days of screening  
 


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Within 3 days pre-op  
x Long-acting opioid medication (e.g., morphine including MS Contin (morphine sulfate 
extended-release tablets), hydromorphone [Dilaudid], oxycodone [Oxycontin], 
methadone) daily for more than 3 months duration or within 3 days pre-op  
x NSAIDs, aspirin (except for low-dose aspirin used for cardioprotection), or 
acetaminophen within 3 days pre-op.  
x Dexmedetomidine HCl (Precedex) within 3 days post-op 
Note: 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 (e.g., 
4 Percocet) within 24 hours of surgery. 
 
Within 1 month pre-op 
Initiation of treatment with any of the following medications is prohibited within 1 month of study 
drug administration or if the medication(s) are being given to control pain:   
x Selective serotonin reuptake inhibitors (SSRIs), serotonin and selective norepinephrine 
reuptake inhibitors (SNRIs), gabapentin, pregabalin (Lyrica), 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.  
x Dermal or systemic glucocorticosteroids (e.g., Decadron) are prohibited within 1 month 
of enrollment in this study.  
x 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.  
11.7.2. Permitted and Restricted Therapy and Medications During Surgery 
Permitted Medications and Therapy  
x Propofol for induction and/or intraoperatively 
x Fentanyl or short-acting analogues  
x Any medication for nausea/vomiting or pruritus prevention can be given at the 
physician’s discretion.  
 
Restricted Medications and Therapy 
x As described in the EXPAREL package insert, no drugs are to be admixed with study 
drug other that bupivacaine HCl (e.g., epinephrine, dexamethasone, clonidine).  
x When a topical antiseptic is applied to the surgical site, the solutions are not to come in 
contact with each other (e.g., the area must be dry before EXPAREL is administered).  
x The use of long-acting opioids (e.g., morphine, hydromorphone HCl), acetaminophen/ 
paracetamol, ketorolac, or other NSAIDs will not be permitted intraoperatively except 
for emergency use to treat an AE.  


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x Avoid additional use of local anesthetics within 96 hours following administration of 
EXPAREL. 
Upon discovering use of any prohibited therapy and/or medication during or after surgery, the 
Investigator should document all events that led to the deviation, write a note to file, and notify the 
Pacira Medical Monitor accordingly.  
11.7.3. Permitted and Restricted Therapy or Medications After Surgery 
Permitted Medications and Therapy 
x Tylenol (acetaminophen) 1000 mg PO TID; the total daily dose of acetaminophen is not to 
exceed 3000 mg. Intravenous acetaminophen can be used if the subject is unable to tolerate 
oral acetaminophen. 
x Gabapentin 300 mg PO BID; alternative medication is pregabalin 150 mg PO BID. 
x Robaxin 750 mg BID or TID. 
 
Postsurgical Pain Management 
Subjects should receive opioid and non-opioid rescue pain medications only upon request for 
breakthrough pain. 
Rescue medications shall be provided based on the pain scores reported on the NRS. For pain scores 
of 1 to 3, subjects shall receive nonsteroidal anti-inflammatory drugs (NSAIDs), without exceeding 
the maximum daily dose. For pain scores of 4 or greater, immediate- release orally-administered 
(PO) oxycodone shall be administered as a rescue medication. For pain scores of 4 to 7, 5 mg PO 
oxycodone shall be provided PRN; for pain score of 8 to 10 on the NRS, 10 mg PO oxycodone will 
be provided PRN. 
If a subject is unable to tolerate PO medication or fails the PO oxycodone rescue, IV morphine 
(initiated at 1 to 2 mg) or hydromorphone (initiated at 0.3 to 0.5 mg) may be administered PRN. The 
initial rescue medication can be IV per Investigators' discretion.  
Use of patient controlled analgesia pumps (PCA) is not recommended. 
Restricted Medications and Therapy 
x No other analgesics, including fentanyl, are permitted up to 72 hours after study drug 
administration or discharge from the hospital (or other facility).  
x Anesthetics in the “caine” family, which may interfere with the bupivacaine pharmacokinetic 
profile, are prohibited through 96 hours following administration of EXPAREL .  


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For study purposes, it is important to standardize pain management modalities through discharge 
from the hospital (or other facility). Therefore, the study staff must adhere closely to the treatment 
options and requirements noted in the protocol. After discharge, the analgesic regimen may be 
adjusted for each subject individually as deemed appropriate by the physician responsible for the 
postsurgical care. 
11.8. Treatment Compliance 
Study drug will be administered by the study staff and, thus, treatment compliance is ensured. 
11.9. Accountability of Study Drug 
Shipment of EXPAREL for the study will contain an investigational drug transmittal and receipt 
form to assist the Investigator or designee (e.g., pharmacist) in maintaining current and accurate 
inventory records. At a minimum, the Investigator or designee will maintain accurate records 
demonstrating dates and units of drug received, lot numbers, subjects to whom drug was 
administered, and accounts of any drug destroyed accidentally or deliberately. The Investigator must 
retain vials containing used, unused, or expired EXPAREL for return or destruction, as instructed by 
Pacira, following confirmation of drug accountability data by a study monitor. A record of drug 
return or destruction will be maintained and provided to Pacira. Inventory records must be readily 
available for inspection by the study monitor and/or appropriate regulatory authorities at any time. A 
copy of the inventory records, drug accountability information, and notice of return or destruction 
will be returned to Pacira at the end of the study. Only authorized personnel identified by the 
Investigator will have the ability to access and administer the drug. 
12. 
STUDY ENDPOINTS AND MEASUREMENTS 
12.1. Efficacy Assessments 
The following efficacy measurements will be conducted:   
1. Postsurgical opioid use in milligrams of oral morphine equivalent dosing (i.e., mg MED PO) 
from the end of surgery (closure of wound/incision) until 72 hours postsurgery. Although 
pre-operative and intra-operative opioids will be recorded for study subjects, they will not be 
included in the definition of this primary outcome. 
2. Opioid related adverse events (ORAEs) will be assessed by using the Opioid Related 
Symptoms Distress Scale (OR-SDS) (see Appendix 3) at 24, 48, and 72 hours, discharge, 
and at 14 days.  
3. BPI-sf will be administered at screening/baseline; at 24, 48, and 72 hours, discharge, and at 
14 days (see Appendix 2). 
4. NRS: The pain intensity score at surgical site will be assessed using an 11-point NRS during 
the hospital (or other facility) stay at 6, 12, 18, 24, 30, 36, 42, 48,  and 72 hours, discharge, 
and then once at 14 days (see Appendix 1).  
 


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For all subjects, if discharge occurs prior to 72 hours postsurgery, all Discharge assessments 
are to be performed at the time of discharge. After discharge, all scheduled assessments 
should be performed at the scheduled time points (i.e., NRS pain assessments at 6, 12, 18, 
24, 30, 36, 42, 48, and 72 hours postsurgery; BPI-sf and OR-SDS at 24, 48, and 72 hours; 
and date, time, and dose of all opioid and non-opioid rescue medications) and recorded in 
the eDiary. 
 
Note: if the subject is sleeping, do not wake him or her for an assessment of pain. If he or 
she awakens within the assessment window (i.e., ±1 hour for all time points up to 24 h, 
±2 hours for the 30 to 48 hour assessments, and ±4 hours for the 72-hour assessment), a pain 
score may be collected then. 
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. End of surgery is defined as the time when the last 
incision/wound is closed. 
Primary efficacy endpoint: The primary efficacy endpoint is postsurgical opioid consumption in mg 
MED PO from 0 hours (end of surgery) to 72 hours postsurgery. 
 
Secondary endpoints: 
1. Post-surgical opioid consumption in mg MED PO at 14 days after surgery 
2. Time to first opioid rescue through 72 hours or discharge 
3. Opioid related adverse events will be assessed by using the Opioid Related Symptoms Distress 
Scale (OR-SDS) at 24, 48, and 72 hours postsurgery, at discharge, and at 14 days. 
Exploratory endpoints: 
1. The NRS pain intensity score at surgical site at each assessed time point during the hospital (or 
other facility) stay (at 6, 12, 18, 24, 30, 36, 42, 48, and 72 hours), at discharge, and then once at 
14 days (±3 days) 
2. Brief Pain Inventory – short form (BPI-sf) at screening/baseline,  daily for the first 3 days 
(24 hours, 48 hours, and 72 hours), at discharge, and at 14 days (±3 days).  
3. OCC, SOPA and HADS at the baseline visit.  
4. The area under the curve (AUC) of the NRS pain intensity scores at surgical site from 0 to 24, 
0 to 48, and 0 to 72 hours  
12.3. Pharmacokinetic Measurements (Not Applicable) 
Not Applicable. 


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12.4. Pharmacokinetic Endpoints (Not Applicable) 
Not Applicable. 
12.5. Health Outcomes Assessments 
x Time in hours spent in PACU and stepdown unit 
x Total length of stay (i.e., recorded in hours) in the hospital (or other facility) 
x Discharge readiness, measured via the Modified Post-Anesthesia Discharge Scoring System 
(MPADSS) at 24, 48 and 72 hours or discharge or until the subject attains a score of 9, 
whichever occurs first (see Appendix 7) 
x Discharge disposition (i.e., home, outpatient rehabilitation facility, inpatient rehabilitation 
facility, skilled nursing facility, other) 
x 30 days readmissions related to pain  
x 30 days all cause readmissions 
x 30 days Emergency Room (ER) visits related to pain 
x 14 days office visits related to pain 
x 14 days call to doctor related to pain 
x 30 days “Are you currently taking opioid medication to manage pain from your spine 
surgery?” 
12.6. Safety Assessments  
Adverse events will be monitored and recorded from the time the ICF is signed through Day 30 or 
until termination from the study. Safety assessments will be measured at multiple time points 
throughout the study. Treatment-emergent AEs should be managed per the Investigator’s discretion 
and the site’s SOC.  
12.7. Safety Endpoints 
Any adverse events (AEs) reported while subjects are in the hospital (or other facility), at any time 
up to the Day 30 visit, or until termination from the study, will be assessed as safety outcomes.  
12.8. 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 all study procedures is provided in Table 1 and Table 2. 


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13.1. Instructions for Conducting Procedures and Measures 
Baseline is when the first assessments are done after informed consent is obtained, and is defined 
for statistical analyses purposes as the last non-missing assessment of a given endpoint prior to first 
dose of trial drug unless otherwise specified. 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 (prior to the study drug administration) will be timed from the end of 
surgery. Postsurgical is defined as a period after the end of surgery. End of surgery is defined as the 
time when the last incision/wound is closed. 
Subjects can be discharged from the hospital (or other facility) based on current clinical practice but, 
at a minimum, should: 
x No longer require parenteral pain management 
x Be able to tolerate a liquid diet 
x Demonstrate safe mobility as determined with occupational therapy/physical therapy input 
per hospital (or other facility) standards 
The study will not require limitations with respect to hospitalization duration. Study staff will 
monitor and record postsurgical analgesia and will collect study data (other than subject 
assessments/questionnaires) through discharge. Following discharge, the subject will record use of 
pain medication, if any, in the eDiary. Additionally, the subject will record pain at surgical site using 
the NRS pain scale in the eDiary daily through 72 hours postoperation, at discharge, and at Day 14. 
The subject will record responses to the BPI-sf in the eDiary at 24, 48, and 72 hours, at discharge, 
and at Day 14. 
13.1.1. eDiary 
Subjects are to record their responses to subject questionnaires on an electronic device (an eDiary) 
at screening, while in the hospital (or other facility), and after discharge. Every day after discharge 
through Day 14, subjects are to record any pain medication (date, time, and dose) taken in the prior 
24 hours in addition to recording questionnaire responses at the specified time points. Subjects can 
use their own device or be lent a device from the time of the screening visit. 
13.1.2. Pain Intensity Assessments 
Pain intensity scores at the surgical site will be assessed using an 11-point NRS at 
screening/baseline; at 6, 12, 18, 24, 30, 36, 42, 48, and 72 hours after surgery, at discharge, and at 
Day 14 (Carlsson 1983;  McCormack 1988, and Scott 1976) (see Appendix 1). For all subjects, if 
discharge occurs prior to 72 hours postsurgery, all Discharge assessments are to be performed at the 
time of discharge. After discharge, all scheduled assessments should be performed at the scheduled 
time points (i.e., NRS pain assessments at 6, 12, 18, 24, 30, 36, 42, 48, and 72 hours postsurgery; 
BPI-sf and OR-SDS at 24, 48, and 72 hours; and date, time, and dose of all opioid and non-opioid 
rescue medications) and recorded in the eDiary. 


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13.1.3. Brief Pain Inventory-short form (BPI-sf) 
The BPI-sf (See Appendix 2) will be completed at the screening/baseline visit; daily for the first 
3 days (24, 48 and 72 hours), at discharge, and on Day 14 (Tan 2004). For all subjects, if discharge 
occurs prior to 72 hours postsurgery, all Discharge assessments are to be performed at the time of 
discharge. After discharge, all scheduled assessments should be performed at the scheduled time 
points (i.e., NRS pain assessments at 6, 12, 18, 24, 30, 36, 42, 48, and 72 hours postsurgery; BPI-sf 
and OR-SDS at 24, 48, and 72 hours; and date, time, and dose of all opioid and non-opioid rescue 
medications) and recorded in the eDiary. 
13.1.4. Opioid Related Symptoms Distress Scale (OR-SDS) 
Opioid related adverse events will be assessed by using the Opioid Related Symptoms Distress 
Scale (OR-SDS) (See Appendix 3) at 24, 48, and 72 hours after surgery, at discharge, and at 14 days 
(Apfelbaum 2004 and Yadeau 2011). For all subjects, if discharge occurs prior to 72 hours 
postsurgery, all Discharge assessments are to be performed at the time of discharge. After discharge, 
all scheduled assessments should be performed at the scheduled time points (i.e., NRS pain 
assessments at 6, 12, 18, 24, 30, 36, 42, 48, and 72 hours postsurgery; BPI-sf and OR-SDS at 24, 48, 
and 72 hours; and date, time, and dose of all opioid and non-opioid rescue medications) and 
recorded in the eDiary. 
13.1.5. Hospital Anxiety and Depression Scale (HADS) 
Hospital anxiety and depression will be assessed using Hospital Anxiety and Depression Scale 
(HADS) at the screening/baseline visit (Turk 2015) (See Appendix 4). 
13.1.6. Survey of Pain Attitudes (SOPA) 
Pain attitudes will be assessed using Survey of Pain Attitudes (SOPA) (See Appendix 5) at the 
screening/baseline visit (Jensen 2003). 
13.1.7.  5-item Opioid Compliance Checklist (OCC)  
5-item Opioid Compliance Checklist (See Appendix 6) will be assessed at the screening/ baseline 
visit (Jamison 2014; Jamison 2016).  
13.1.8. Vital Signs 
Height, weight, and body mass index (BMI) will be recorded at screening/baseline.  
13.1.9. Clinical Laboratory Tests 
Clinical laboratory evaluations are to be conducted as per SOC of the institution. 


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13.1.10. Discharge Readiness 
The subject’s discharge readiness will be assessed using the Modified Post-Anesthesia Discharge 
Scoring System criteria (MPADSS) (Chung 1995a; Chung 1995b) (see Appendix 7). The discharge 
readiness assessment will be used for data collection only and is not intended to interfere with the 
investigational site’s policy for determining when the subject should be discharged from the hospital 
(or other facility). Discharge readiness will be assessed at 24, 48, and 72 hours or discharge or until 
the subject attains a score of 9, whichever occurs first. 
13.2. Obtaining Informed Consent  
Potential participants may provide informed consent up to 30 days before their scheduled surgery, 
and at least 1 day prior to surgery, in order to ensure ample time for the subject to review the ICF 
and have all his or her questions answered by the Investigator/study staff prior to providing 
informed consent. Screening procedures that are SOC at the institution may be completed prior to 
written informed consent. Any screening procedures that are not SOC must be completed after 
written informed consent is provided and prior to surgery. (See Section 13.3- Screening/Baseline 
Procedures) 
13.3. Screening/Baseline Procedures  
Subjects will be screened within 30 days prior to surgery. If a subject can only be screened on the 
day of surgery, the informed consent process must still be started at least 24 hours prior to the 
conduct of any screening procedures that are not considered SOC at the institution and such 
procedures may not be performed until written informed consent is provided. All screening 
procedures that are not SOC must be performed and documented within the 30-day time window 
(inclusive of the day of surgery for those subjects who can only be screened on the day of surgery) 
as described here. During the screening visit, subjects will be assessed for any past or present 
medical conditions that in the opinion of the investigator would preclude them from study 
participation. 
The following screening/baseline procedures should be performed within 30 days prior to surgery: 


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x Explain study purpose and procedures 
x Obtain written informed consent before performing any study-related procedures. 
x Assess and confirm eligibility  
x Record medical and surgical history 
x Record any prior and concomitant medications (medication history) for the condition for 
which the procedure is being perform administered within 30 days prior to screening 
x Record demographics and baseline characteristics 
x Explain to the subject that he or she is to use an electronic diary (eDiary) into which he 
or she will be expected to capture specific information at screening and at specified time 
points after surgery, including recording pain medications every day from discharge 
through Day 14.  
x Measure height, weight, and BMI 
x Conduct urine pregnancy test for women of childbearing potential 
x Record AEs starting when the ICF is signed 
x Record concomitant medications for treatment of AEs 
x 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. 
x Record baseline NRS pain intensity score prior to any premedication (see Appendix 1).  
x Record opioid use history (i.e., to calculate mean daily mg MED PO in the last 30 days) 
x Complete Brief Pain Inventory-short form (BPI-sf) (Appendix 2) 
x Complete Hospital Anxiety and Depression Scale (HADS) (Appendix 4) 
x Complete Survey of Pain Attitudes (SOPA) (Appendix 5)  
x Complete 5-item Opioid Compliance Checklist (OCC) (Appendix 6) 
13.4. Preoperative procedures 
Control Group 
x 
Confirm eligibility; UPT does not need to be repeated  
x 
Record AEs and medications used to treat them from the time ICF is signed 
x Administer recommended pre-operative medications (within approximately 24 to 
48 hours of procedure) in all 3 cohorts (cohort 1, cohort 2, and cohort 3): 
a) Tylenol (acetaminophen) 1000 mg PO 
b) Gabapentin 300 mg PO 
c) Robaxin 750 mg PO 
Intra-operative anesthesia and analgesia at the surgical site as per usual care. 
o List of recommended pre-operative prophylactic medications (optional) for postoperative 
nausea and vomiting or pruritus: 


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For nausea and vomiting: 
a) Ondansetron 4 mg intravenously (IV) at approximately 15-30 min before 
emergence from anesthesia 
b) Decadron 8-12 mg IV after anesthesia induction 
c) Phenergan 25 mg IV PRN 
d) Metocopramide 10 mg PO PRN 
 
 For pruritus: 
a) Diphenhydramine 25 mg PO PRN 
b) Nalbuphine 2.5 mg IV PRN 
 
EXPAREL Group  
x Confirm eligibility; UPT does not need to be repeated 
x Record AEs and medications used to treat them from the time ICF is signed 
x Administer the following strongly recommended study interventions for analgesia to 
subjects in all three cohorts (cohort 1, cohort 2 and cohort 3): 
o Pre-operative oral multimodal analgesia (within approximately 24-48 hours prior to 
surgery) 
a) Tylenol (acetaminophen) 1000 mg PO 
b) Gabapentin 300 mg PO 
c) Robaxin 750 mg PO 
o List of recommended pre-operative prophylactic medications (optional) for 
postoperative nausea and vomiting or pruritus: 
For nausea and vomiting: 
a) Ondansetron 4 mg intravenously (IV) at approximately 15-30 min before 
emergence from anesthesia 
b) Decadron 8-12 mg IV after anesthesia induction 
c) Phenergan 25 mg IV PRN 
d) Metocopramide 10 mg PO PRN 
 
For pruritus: 
a) Diphenhydramine 25 mg PO PRN 
b) Nalbuphine 2.5 mg IV PRN 


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13.5. Intra-operative Procedures: 
Note: Subjects will not be permitted to receive any other local anesthetic for pre-, intra- (i.e., within 
20 min before administering EXPAREL), or postoperative analgesia, other than the specified 
admixed bupivacaine for local infiltration at the surgical site per infiltration guide. If administering 
lidocaine or other non-bupivacaine-based local anesthetics is required per the institution’s SOC wait 
20 min before administering EXPAREL. 
x Prepare study drug (no earlier than 4 hours before administration) 
x Record surgery start and stop times 
x Administer study drug; Record start and stop times of study drug administration  
x Record dosage of study drug administered and total volume 
x Record all intraoperative medications 
x Record times and doses of all opioid and non-opioid rescue medications administered 
x Record AEs and any treatment(s) for the events 
 
If an AE or SAE occurs during the study, the event should be managed per the Investigator’s 
discretion and the site’s SOC. 
13.6. Postoperative Procedures Through Discharge from the Hospital (or Other 
Facility)  
For all subjects, if discharge occurs prior to 72 hours postsurgery, all Discharge assessments are to 
be performed at the time of discharge. After discharge, all scheduled assessments should be 
performed at the scheduled time points (i.e., NRS pain assessments at 6, 12, 18, 24, 30, 36, 42, 48, 
and 72 hours postsurgery; BPI-sf and OR-SDS at 24, 48, and 72 hours; and date, time, and dose of 
all opioid and non-opioid rescue medications) and recorded in the eDiary. 
Control Group:  
x Administer the following scheduled multimodal analgesia within approximately 72 hours 
postsurgery): 
a) Tylenol (acetaminophen) 1000 mg PO TID; the total daily dose of acetaminophen is not 
to exceed 3000 mg. Intravenous (IV) acetaminophen can be used if the subject is unable 
to tolerate oral acetaminophen. 
b) Gabapentin 300 mg PO BID; alternative medication is pregabalin 150 mg PO BID 
Robaxin 750 mg PO BID or TID 
 
x Administer additional postsurgical pain medication (e.g., opioids) in cases of insufficient 
analgesia as permitted per your institution’s SOC. 
x Record times and doses of all multimodal scheduled medication administered 
 


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EXPAREL Group 
x Administer the following postoperative scheduled multimodal analgesia (within 
approximately 72 hours postsurgery): 
a) Tylenol (acetaminophen) 1000 mg PO TID; the total daily dose of acetaminophen 
is not to exceed 3000 mg. Intravenous (IV) acetaminophen can be used if the 
subject is unable to tolerate oral acetaminophen. 
b) Gabapentin 300 mg PO BID; alternative medication is pregabalin 150 mg PO 
BID 
c) Robaxin 750 mg PO BID or TID 
x Record times and doses of all multimodal scheduled medication administered 
x Administer rescue postsurgical analgesics 
Both Treatment Groups 
x Record dates, times, and doses of all opioid and non-opioid rescue medications 
administered 
x Record all pain medications taken until discharge 
x Complete OR-SDS questionnaire at 24, 48 and 72 hours after the surgery, and at 
discharge 
x Record NRS pain intensity score upon arrival at the PACU; at 6, 12, 18, 24, 30, 36, 42, 
48, and 72 hours; at discharge; 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. If he or she awakens within the assessment 
window (i.e., 1 hour for all time points up to 24 hours, 2 hours for the 30 to 48 hour 
assessments, and 4 hours for the 72-hour assessment), a pain score may be collected 
then. 
x Complete BPI-sf at 24, 48, and 72 hours after the surgery and at discharge 
x Administer postoperative rescue medication only upon request, as needed (see Section 
11.1- Treatment to be Administered) 
x Record other concomitant medications 


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x Record time of admission to and discharge from the PACU 
x Record time of admission to and discharge from the step-down unit 
x Complete MPADSS at 24, 48 and 72 hours after the surgery or discharge or until the 
subject attains a score of 9, whichever occurs first 
x Record date and time of discharge 
x Record discharge disposition (home, outpatient rehabilitation facility, inpatient 
rehabilitation facility, and skilled nursing facility) 
x Instruct the subject about use of the eDiary to record daily opioid pain management 
medication use, pain scores, and BPI-sf responses. If the subject is being provided an 
eDiary, remind the subject that the completed eDiary should be returned to the clinic at 
the end of their participation in the study. 
x Record AEs or SAEs and any treatment(s) for the events 
x 
If an AE and/or SAE occurs during the study, the event should be managed per the 
Investigator’s discretion and the site’s SOC. 
13.7. After Discharge from the Hospital (or Other Facility) 
x Subject is to record the use of pain medication, if any, in the eDiary daily from discharge 
through Day 14 
x Assessments to be completed on Day 14 are presented in Section 13.8 
x Assessments to be completed on Day 30 are presented in Section 13.9 
13.8. Day 14 Phone Call or Visit 
x Record pain at surgical site using NRS (Appendix 1) 
x Complete BPI-sf (see Appendix 2) 
x Complete OR-SDS (see Appendix 3) 
x Review and record date and amount of all opioid pain management medication used up 
to Day 14. (Note: upon discharge, the patient will continue to record daily opioid pain 
management medication use in the eDiary)  
x Document any requests for refills for opioid medication 
x Document whether the subject has made any unscheduled phone calls or office visits 
related to pain  
x Record any AEs or SAEs and any treatment(s) for the events 
x Collect the eDiary (if the subject was lent an eDiary for the course of the study) 


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If an AE or SAE occurs during the study, the event should be managed per the Investigator’s 
discretion and the site’s SOC. 
13.9. Day 30 Phone Call  
x Record persistent opioid use by asking the subject “Are you currently taking opioid 
medication to manage pain from your spine surgery?”  (see Appendix 8) 
x Document if the subject has had any hospital readmissions for pain  
x Document if the subject has had any hospital readmisions for any cause 
x Document whether the subject has made any unscheduled visits to the ER related to pain 
since discharge 
x Record any AEs and medications used to treat AEs 
 
If an AE or SAE occurs during the study, the event should be managed per the Investigator’s 
discretion and the site’s SOC. 
14. 
ADVERSE EVENT REPORTING  
Consistent with the current regulatory guidance provided by the US CFR and the ICH GCP, AE and 
SAE are defined in Section 14.1.1 and Section 14.2.1, respectively. 
The concepts of AE and SAE represent regulatory instruments used to evaluate and monitor the 
safety of clinical study subjects. Therefore, these terms only apply in light of their regulatory 
definition. The term serious, in a regulatory sense, does not necessarily mean severe. The SAE 
concept is primarily used to identify, during the conduct of the study, those SAEs that may require 
expedited reporting to regulatory authorities. 
14.1. Adverse Events 
14.1.1. Definitions  
Definition of an Adverse Event (AE): Any untoward medical occurrence associated with the use of 
a drug in humans, whether or not considered drug related. An AE (also referred to as an adverse 
experience) can be any unfavorable and unintended sign (e.g., abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a drug, without any judgment about 
causality. An AE can arise from any use of the drug (e.g., off-label use in combination with another 
drug) and from any route of administration, formulation, or dose, including an overdose. 
An AE can be any unfavorable and unintended change in a body structure or body function.  
Adverse events include any clinically significant deterioration of a subject’s medical status. The AE 
may involve any organ or system and can be represented by the new onset or the deterioration of a 
disease, a syndrome, a symptom, a physical sign, as well as by findings and results of instrumental 
examinations and laboratory tests. Any medically relevant and untoward change after the subject 


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signs the ICF, including frequency or pattern changes for a fluctuating condition (e.g., migraine) is 
considered an AE.  
An AE that occurs after the ICF has been signed and before the start of the study drug 
administration is identified as a pretreatment AE (PTAE). An AE that occurs after the first 
administration of a study treatment is considered a treatment emergent adverse event (TEAE). All 
AEs must be recorded and reported accordingly, whether they appear causally related to the study 
drug, or not. Adverse events will be followed until the outcome is known or until the Investigator 
feels no further medical follow-up is warranted. 
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 with an onset after the subject signs 
the ICF (i.e., PTAEs and TEAEs). For the purpose of this study, all AEs that occur through Day 30 
after study drug administration must be recorded regardless of whether or not they are considered 
related to the study drug. Whenever feasible, AEs should be documented as medical diagnoses 
(highest possible level of integration). Otherwise, when they do not appear clearly interrelated, 
individual signs or symptoms may be reported as separate AEs. Record one AE per line in the CRF; 
for example, the AE of nausea and vomiting should be listed as two separate events: the event of 
nausea and the event of vomiting. Whenever possible, abnormal laboratory results should be 
reported as their clinical corollary (e.g., low potassium should be recorded as hypokalemia). 
All AEs will be followed through progression and regression of their severity. For example, if an 
AE is reported as mild in severity but changes to moderate, the AE of mild will have an outcome of 
changed AE characteristic and the AE will be re-entered. The AE with a moderate severity must 
have the same start date as the mild event stop date. If the AE then becomes mild, the AE with a 
moderate severity will have an outcome of changed AE characteristic and the AE will be re-entered 
with a severity of mild; the start date of the mild AE must be the same as the stop date of the 
moderate AE.  
A continuous AE with varying grades of severity must be recorded as one AE. The highest grade of 
severity experienced by that subject during the course of the continuous AE must be recorded. 


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Any condition noted before the ICF is signed will be listed as Medical History and will be 
considered a pre-existing condition. If a pre-existing condition changes (i.e., becomes more severe 
or more frequent), at any time after the ICF is signed, or after study drug administration, it will be 
considered an AE. Note: A change in treatment for a pre-existing condition (e.g., new high blood 
pressure medication), does not necessarily indicate an AE. 
Information recorded on the appropriate AE CRF will include AE term, the date and time of onset, 
severity, seriousness, relationship to the study drug, action taken with study drug, action taken for 
the AE, and the outcome of the AE including the date and time of resolution (if applicable).  
14.1.3. Severity of Adverse Events 
In general, the severity of an AE should be categorized using the following guidelines:  
Mild: 
An AE that is easily tolerated by the subject, causing minimal discomfort and 
not interfering with everyday activities. 
Moderate: 
An AE that is discomforting and interferes with normal everyday activities. 
Severe: 
An AE that prevents normal everyday activities. 
 
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 must assess the relationship of the AE to study drug after careful medical 
consideration on a case-by-case basis. General guidelines for determining the AE’s causality to the 
study drug are provided below. 
Unrelated: A causal relationship between the study drug and the AE can be easily ruled out (e.g., 
based on the temporal sequence, absence of a reasonable pathophysiological mechanism, or direct 
evidence of actual cause); 
    Unlikely: A clinical event with a temporal relationship to study drug administration which makes a 
causal relationship improbable and in which other drugs, chemicals, or underlying disease provide a 
plausible explanation; 
Possible: A clinical event with a reasonable time sequence to administration of the study drug but 
which could also be explained by a concurrent disease or other drugs or chemicals; 


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


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x 
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 a Serious Adverse Event (SAE): An AE is considered “serious” if, in the view of 
either the Investigator or Sponsor, it results in any of the following outcomes: 
x 
Death1. 
x 
A life-threatening adverse event2.  
x 
Inpatient hospitalization or prolongation of existing hospitalization3. 
x 
A persistent or significant incapacity4. 
x 
Congenital anomaly/birth defect. 
x 
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.” 


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2Life-threatening: An AE is considered life-threatening if, in the view of either the Investigator or 
Sponsor, its occurrence places the subject at immediate risk of death. It does not include an AE that 
had it occurred in a more severe form might have caused death. 
3Hospitalization: It should be noted that hospitalization, in and of itself, does not represent an SAE. 
It is the AE leading to the subject’s hospitalization that becomes “serious” when it requires inpatient 
care. Consequently, an SAE should not be reported in case of preplanned hospitalizations for a 
pre-existing condition that did not worsen during the study. However, any medical condition that 
delays a subject’s discharge from the hospital (i.e., prolonged hospitalization) or requires the subject 
to be readmitted should be reported as an SAE. 
4Persistent or significant incapacity: A substantial disruption of a person’s ability to conduct 
normal life functions. 
5 Medically 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 by 
either email (drugsafety@pacira.com) or fax to 858-678-3962 within 24 hours of discovery. 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 patient-identifying information redacted prior to forwarding to Pacira. In the event 
of a fatal or life-threatening SAE, any required follow-up must be provided to Pacira Drug Safety or 
designee immediately. The Investigator will follow all SAEs until resolved or the condition 
stabilizes and further follow-up is not warranted. 
If the Investigator is made aware of any SAEs after Day 30, these should also be reported to Pacira 
Drug Safety or designee provided the SAE is considered related to EXPAREL. The site would then 
provide a completed SAE form within 1 business day and the event would be followed until 
resolution, or until adequate stabilization is met.  


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15. 
STATISTICAL METHODS 
A comprehensive statistical analysis plan (SAP) will be developed for this study. 
Interim analyses may be conducted to adjust to variability. Adaptive study design (i.e., adjustments 
of sample size, cohort sequence, type of surgical procedure, endpoints, etc.) will be used. 
15.1. Study Objective 
The primary objective of this study is to compare postsurgical opioid consumption through 72 hours 
postsurgery in patients receiving local infiltration analgesia (LIA) with EXPAREL and bupivacaine 
HCl (EXPAREL group) with those receiving SOC (Control group) in adult subjects undergoing 
posterior lumbar spine surgeries where both groups are receiving a multimodal pain regimen. 
15.2. Study Endpoints  
The endpoints to be assessed in this study are listed in Section 12.2, Efficacy Endpoints and Section 
12.7, Safety Endpoints. 
15.3. Determination of Sample Size  
The sample size for this study is based on the primary outcome measure of postsurgical opioid use 
in milligrams of oral morphine equivalent dosing (mg MED PO) from the end of surgery (closure of 
wound/incision) until 72 hours postsurgery. Based on preliminary data, the coefficient of variation 
(CV) is approximately 60%. The minimum clinically important difference (MCID) for this outcome 
was estimated at 40%.  
With these parameters and a beta of 0.2 (i.e., 80% power), an alpha of 0.05, a 2-sided test, and 
allocating subjects in a 2:1 ratio to the EXPAREL group or Control group to minimize barriers to 
enrolment for an approved and marketed medication, a total sample size of 75 fully evaluable 
subjects is required in each study cohort, with 50 in the EXPAREL group and 25 in the Control 
group. The same assumptions are made across all cohorts. Not fully evaluable subjects should be 
replaced. Criteria for fully evaluable will be defined in SAP. Given that this study will have a case 
observation period for the first few subjects in EXPAREL group, if observation is deemed correct 
and infiltration was performed correctly, subject can be included in the study. If observation is 
deemed incorrect and infiltration was performed incorrectly, subject will continue in the study but 
will be removed from statistical analysis and will be replaced to ensure at least 50 evaluable 
EXPAREL arm patients are enrolled per cohort. The total number of subjects in all three cohorts 
will be 225, with 150 in the EXPAREL group and 75 in the Control group. 
 


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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 allocated subjects who undergo the planned surgery. All 
analyses based on the efficacy analysis set will be by treatment groups. 
 
The per-protocol efficacy analysis set will include all subjects in the efficacy analysis set who do not 
have any important protocol deviations.  
15.5. Handling Subject Dropouts and Discontinuations 
Given that this study will have a case observation period for the first few subjects in EXPAREL 
group, the total number of subjects included in this group may further increase for the number of 
subjects that will be excluded from data analysis if the infiltration guide was not properly followed.  
Methods for dealing with missing data will be described in the SAP. 
15.6. Statistical Analyses 
15.6.1. Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively by treatment group. 
15.6.2. Study Compliance 
The percentage of subjects in each analysis set and the percentage who fail to complete the study (as 
well as the reasons for discontinuation) will be displayed by treatment group. 
15.6.3. Efficacy Analyses 
A comprehensive statistical analysis plan (SAP) will be developed for this study. All efficacy 
endpoint analyses will be conducted for the efficacy analysis set. The primary efficacy endpoint will 
also be analyzed using the per-protocol analysis set as a sensitivity analysis.  
Summary statistics (n, mean, median, standard deviation, minimum, maximum) will be shown for 
each continuous measure of efficacy by treatment group. Number and percentage of subjects in each 
category will be shown for each categorical measure of efficacy by treatment group. For time to 
event measures of efficacy, medians and Kaplan-Meier estimates will be shown by treatment group. 
15.6.4. Safety Analyses 
Adverse event verbatim terms will be mapped to preferred terms and related system/organ class 
using the Medical Dictionary for Regulatory Activities (MedDRA). All summaries of AEs will 


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include AEs that occur after the beginning of anesthesia. All summaries of AEs will be based on the 
safety analysis set. Events that start prior to anesthesia will be identified in listings only. Incidence 
rates of AEs after the start of anesthesia and the proportion of subjects prematurely withdrawn from 
the study due to an AE will be shown for each treatment group. Incidence rates will also be shown 
for each treatment group for study drug-related AEs after the start of anesthesia and by severity. 
Incidence rates of SAEs will also be shown for each treatment group. All incidence rates will be 
categorized and shown by system/organ class and preferred term. 
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. 
15.8. Interim Analyses 
Interim analyses may be conducted to adjust to variability. Adaptive study design (i.e., adjustment of 
sample size, cohort sequence, type of surgical procedure, endpoints, etc.) will be used. 
16. 
REFERENCES 
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Fifth 
Edition (DSM-5). Washington, DC. American Psychiatric Publishing; 2013. 
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. 
Apfelbaum JL, Gan TJ, Zhao S, Hanna DB, Chen C. Reliability and validity of the perioperative 
opioid-related symptom distress scale. Anesth Analg. 2004; 99:699–709. 
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(5):367–373. 
Balocco AL, Van Zundert PG, Gan SS, Gan TJ, Hadcic A.  Extended release bupivacaine 
formulations for postoperative analgesia: An update. Curr Opin Anesthesiol. 2018; 31(5)636-642. 
DOI: 10.1097/ACO.0000000000000642  


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Brummett CM, Waljee JF, Goesling J, Moser S, Lin P, Englesbe MJ, Bohnert ASB, Kheterpal S, 
Nallamothu BK. New persistent opioid use after minor and major surgical procedures in US adults. 
JAMA Surg. 2017;152(6):e17054. 
Carlsson A. Assessment of chronic pain. I. Aspects of the reliability and validity of the visual analog 
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 Anaesth 1995a; 42:1056–8. 
Chung F, Chan VW, Ong D. A post-anesthetic discharge scoring system for home readiness after 
ambulatory surgery. J Clin Anesth. 1995b; 7:500–506. 
Feierman DE, Kronenfeld M, Gupta PM. Liposomal bupivacaine infiltration into the transversus 
abdominis plane for postsurgical analgesia in open abdominal umbilical hernia repair: Results from 
a cohort of 13 patients.  J Pain Res.  2014;7:477-482. 
Hu D, Onel E, Singla N, Kramer WG, Hadzic A. Pharmacokinetic profile of liposome bupivacaine 
injection following a single administration at the surgical site. Clin Drug Investig. 2013;33:109–
115.  
Jamison RN, Martel MO, Edwards RR, Qian J, Sheehan KA, Ross EL. Validation of a brief opioid 
compliance checklist for patients with chronic pain. The Journal of Pain. 2014;15:1092-1101. ͒ 
Jamison RN, Martel MO, Huang, CC, Jurcik D, Edwards RR. Efficacy of the Opioid Compliance 
Checklist to monitor chronic pain patients receiving opioid therapy in primary care. J Pain 
2016;17:414-423 
Jensen MP, Keefe FJ, Lefebvre JC, Romano JM, Turner JA. One- and two-item measures of pain 
beliefs and coping strategies. Pain. 2003;104:453-469. 
McCormack HM, Horne DJ, Sheather S. Clinical applications of visual analogue scales: a critical 
review. Psychol Med. 1988;18:1007-1019 
Oderda GM, Said Q, Evans RS, et al. Opioid-related adverse drug events in surgical 
hospitalizations: impact on costs and length of stay. Ann Pharmacother. 2007;41:400–407. 
Scott J, Huskisson EC. Graphic representation of pain. Pain. 1976;2:175–184. 
Sternlicht A, Shapiro M, Robelen G, et al.  Infiltration of liposome bupivacaine into the transversus 
abdominis plane for postsurgical analgesia in robotic laparoscopic prostatectomy: A pilot study.  
Local Reg Anesth. 2014;7:69-74. 


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Tan G, Jensen MP, Thornby JI, Shanti BF. Validation of the Brief Pain Inventory for chronic 
nonmalignant pain. J Pain. 2004;5:133-137. 
Turk DC, Dworkin RH, Trudeau JJ, et al. Validation of the hospital anxiety and depression scale in 
patients with acute low back pain. Journal of Pain, 2015;16, 1012–1021.  
Viscusi ER, Gan TJ, Leslie JB, et al. Peripherally acting mu-opioid receptor antagonists and 
postoperative ileus: mechanisms of action and clinical applicability. Anesth Analg. 
2009;108:1811–1822. 
Yadeau JT, Liu SS, Rade MC, Marcello D, Liguori GA. Performance characteristics and validation 
of the Opioid-Related Symptom Distress Scale for evaluation of analgesic side effects after 
orthopedic surgery. Anesth Analg. 2011;113:369-377. 


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


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17. 
APPENDICES 
 


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17.1. Appendix 1: Subject’s Reported Pain (Numeric Rating Scale) at Surgical 
 
Site  
Subjects will be evaluated for pain intensity scores at rest using the 11-point NRS at rest at 6, 
12, 18, 24, 30, 36, 42, 48, and 72 hours after surgery, at discharge, and then once at 14 days 
(±3 days). If the subject is sleeping, do not wake him or her for an assessment of pain. If he or 
she awakens within the assessment window (i.e., ±1 hour for all time points up through 24 h,  
±2 hours for the 30- to 48-h assessments, and ±4 hours for the 72-hour assessment), a pain score 
may be collected then.  
The subject will either download the application onto their own device or an eDiary will be lent 
to the subject following surgery, which will have to be returned on the Day 14 visit. The subject 
will record pain at surgical site using the NRS pain scale in the eDiary through 72 hours 
postoperation.  
To assess pain intensity (NRS) at rest, the subject should rest quietly in a supine or seated 
position that does not exacerbate his or her postsurgical pain for 3-5 minutes before entering the 
pain score.   
Subjects are to assess, “How much pain are you experiencing at surgical site right now?” 
(“surgical site” meaning location on the body where the surgery was performed). They are 
advised to circle a number on the NRS to indicate the level of pain experienced at the time of 
assessment, with a number closer to zero (0) meaning little or no pain and a number closer to 10 
meaning much pain or pain as bad as it can be.   
Subject’s Reported Pain NRS 
Pain Intensity Scale 
On a scale of 0 to 10, where 0 = no pain and 10 = worst possible pain, circle the number that best 
describes how much pain you are experiencing at the surgical site right now. (Circle one number 
only) 
 
No 
Worst 
pain 
possible 
 
pain 
(For reference only; not for clinical use.) 
 


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17.2. Appendix 2: Brief Pain Inventory - Short Form (BPI-sf) 
The BPI-sf will be completed at screening/baseline; daily for the first 3 days (24 hours, 48 hours, 
72 hours), at discharge; and at Day 14 (± 3 days).  
Part A 
1. Throughout our lives, most of us have had pain from time to time (such as minor headaches, sprains, and 
toothaches). Have you had pain other than these everyday kinds of pain today?                
         ܆ Yes         ܆ No 
2. On the diagram, shade in the areas where you feel pain. Put an X on the area that hurts the most. 
 
Part B 
Describe the quality of your pain (0 to 10, where: 0 = no pain and 10 = pain as bad as you can imagine). 
3. Please rate your pain by marking the box beside the number that best describes your pain at its worst in the last 
24 hours. 
      ܆0
܆1
܆2
܆3
܆4
܆5
܆6
܆7
܆8
܆9
܆10 
 
No Pain  
 
 
 
 
 
 
 
           Pain As Bad As  
 
 
            
 
 
 
 
 
 
 
          You can Imagine 
4. Please rate your pain by marking the box beside the number that best describes your pain at its least in the last 
24 hours. 
      ܆0
܆1
܆2
܆3
܆4
܆5
܆6
܆7
܆8
܆9
܆10 
 
No Pain  
 
 
 
 
 
 
 
           Pain As Bad As  
 
 
          
 
 
 
 
 
 
 
          You can Imagine 
5. Please rate your pain by marking the box beside the number that best describes you pain on the average. 
      ܆0
܆1
܆2
܆3
܆4
܆5
܆6
܆7
܆8
܆9
܆10 


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No Pain  
 
 
 
 
 
 
 
           Pain As Bad As  
 
 
          
 
 
 
 
 
 
 
          You can Imagine 
6. Please rate your pain by marking the box beside the number that tells how much pain you have right now. 
              ܆0
܆1
܆2
܆3
܆4
܆5
܆6
܆7
܆8
܆9
܆10 
 
 No Pain  
 
 
 
 
 
 
 
           Pain As Bad As  
 
 
          
 
 
 
 
 
 
 
          You can Imagine 
7. What treatments or medications are you receiving for your pain? 
 
8. In the last 24 hours, how much relief have pain treatments or medications provided? Please mark the box below 
the percentage that most shows how much relief you have received. 
                 0%       10% 
20% 
30% 
40% 
50% 
60% 
70% 
80% 
90% 
100%    
                ܆
܆
܆
܆
܆
܆
܆
܆
܆
܆
܆ 
              No relief  
 
 
 
 
 
 
                              Complete Relief 
9. Mark the box beside the number that describes how, during the past 24 hours, pain has interfered with your: 
               General Activity 
               ܆0
܆1
܆2
܆3
܆4
܆5
܆6
܆7
܆8
܆9
܆10 
 
 Does Not 
 
 
 
 
 
 
 
             Completely     
 
 Interfere  
 
            
 
 
 
 
 
             Interferes 
 
 Mood 
               ܆0
܆1
܆2
܆3
܆4
܆5
܆6
܆7
܆8
܆9
܆10 
 
 Does Not 
 
 
 
 
 
 
 
             Completely     
 
 Interfere  
 
                            
 
 
 
 
             Interferes 
 
 Walking ability 
               ܆0
܆1
܆2
܆3
܆4
܆5
܆6
܆7
܆8
܆9
܆10 
 
 Does Not 
 
 
 
 
 
 
 
             Completely     
 
 Interfere  
 
                          
 
 
 
 
             Interferes 
 
 Normal Work (includes both work outside the home and housework) 
               ܆0
܆1
܆2
܆3
܆4
܆5
܆6
܆7
܆8
܆9
܆10 
 
 Does Not 
 
 
 
 
 
 
 
             Completely     
 
 Interfere  
 
                          
 
 
 
 
             Interferes 
 
 Relations with other people 
               ܆0
܆1
܆2
܆3
܆4
܆5
܆6
܆7
܆8
܆9
܆10 
 
 Does Not  
 
 
 
 
 
 
 
             Completely     
 
 Interfere  
 
                               
 
 
 
             Interferes 


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 Sleep 
               ܆0
܆1
܆2
܆3
܆4
܆5
܆6
܆7
܆8
܆9
܆10 
 
 Does Not 
 
 
 
 
 
 
 
             Completely     
 
 Interfere  
 
                     
 
 
 
 
             Interferes 
 
 Enjoyment of life 
               ܆0
܆1
܆2
܆3
܆4
܆5
܆6
܆7
܆8
܆9
܆10 
 
 Does Not 
 
 
 
 
 
 
 
             Completely     
 
 Interfere  
 
                        
 
 
 
 
             Interferes 


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17.3. Appendix 3:   The Opioid Related Symptom Distress Scale (OR-SDS) 
 
Opioid related adverse events will be assessed by using the Opioid Related Symptoms Distress 
Scale (OR-SDS) at 24 hour postsurgery (postoperative Day [POD] 1), 48 hours postsurgery 
(POD 2), 72 hours postsurgery (POD 3), at discharge, and at 14 days (± 3 days). 
We have listed 10 symptoms below. Read each one carefully. If you have had the symptom 
during the past 24 hours, let us know how OFTEN you had it, how SEVERE it was usually and 
how much it DISTRESSED OR BOTHERED you by placing an "X" in the appropriate box. If 
you DID NOT HAVE the symptoms, please place an "X" in the box marked "Did not have." For 
the symptoms "retching/vomiting" below, you will indicate the actual number of episodes you 
experienced. During the last 24 hours, did you have any of the following: 
 
 
 


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17.4. Appendix 4: Hospital Anxiety and Depression Scale (HADS) 
 
Hospital anxiety and depression will be assessed using Hospital Anxiety and Depression Scale 
(HADS) at the baseline visit. 
 
Tick the box beside the reply that is closest to how you have been feeling in the past week. 
Don't take too long over your replies: your immediate is best. 
 
 
 D 
A 
 
D 
A 
 
 
 
I feel tense or 'wound 
up': 
 
 
I feel as if I am 
slowed down: 
 
3 
Most of the time 
3 
 
Nearly all the time 
 
2 
A lot of the time 
2 
 
Very often 
 
1 
From time to time, 
occasionally 
1 
 
Sometimes 
 
0 
Not at all 
0 
 
Not at all 
 
 
 
 
 
 
 
 
I still enjoy the things 
I used to enjoy: 
 
 
I get a sort of 
frightened feeling like 
'butterflies' in my 
stomach 
0 
 
Definitely as much 
 
0 
Not at all 
1 
 
Not quite so much 
 
1 
Occasionally 
2 
 
Only a little 
 
2 
Quite Often 
3 
 
Hardly at all 
 
3 
Very Often 
 
 
 
 
 
 
 
 
I get a sort of 
frightened feeling as 
if something awful is 
about to happen: 
 
 
I have lost interest in 
my appearance: 
 
3 
Very definitely and 
quite badly  
3 
 
Definitely 
 
2 
Not quite so much 
now 
2 
 
I don't take as much 
care as I should 
 
1 
Definitely not so much 
now 
1 
 
I may not take quite as 
much care 
 
0 
Not at all 
0 
 
I take just as much 
care as ever 
 
 
 
 
 
 
 
 
I can laugh and see 
the funny side of 
things: 
 
 
I feel restless as I 
have to be on the 
move: 
0 
 
As much as I always 
could 
 
3 
Very much indeed 
1 
 
Not quite so much 
 
2 
Quite a lot 


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 D 
A 
 
D 
A 
 
now 
2 
 
Definitely not so much 
now 
 
1 
Not very much 
3 
 
Not at all 
 
0 
Not at all 
 
 
Worrying thoughts 
go through my mind 
 
 
I look forward with 
enjoyment of things: 
 
3 
A great deal of the 
time 
0 
 
As much as I ever did 
 
2 
A lot of the time 
1 
 
Rather less than I used 
to 
 
1 
From time to time, but 
not too often 
2 
 
Definitely less than I 
used to 
 
0 
Only occasionally 
3 
 
Hardly at all 
 
 
 
 
 
 
 
 
I feel cheerful: 
 
 
I get sudden feelings 
of panic: 
3 
 
Not at all 
 
3 
Very often indeed 
2 
 
Not often 
 
2 
Quite often 
1 
 
Sometimes 
 
1 
Not very often 
0 
 
Most of the time 
 
0 
Not at all 
 
 
 
 
 
 
 
 
I can sit at ease and 
feel relaxed: 
 
 
I can enjoy a good 
book or radio or TV 
program: 
 
0 
Definitely 
0 
 
Often 
 
1 
Usually 
1 
 
Sometimes 
 
2 
Not often 
2 
 
Not often 
 
3 
Not at all 
3 
 
Very seldom 
 


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17.5. Appendix 5: Single-item Survey of Pain Attitudes (SOPA) 
 
Pain attitudes will be assessed using Survey of Pain Attitudes (SOPA) at the baseline visit.  
Instructions: Please indicate how much you agree with each of the following statements about 
your pain problem by using the following scale: 
 
0 = This is very untrue for me. 
1 = This is somewhat untrue for me. 
2 = This is neither true nor untrue for me (or it does not apply to me). 
3 = This is somewhat true for me. 
4 = This is very true for me. 
 
1. There is little I can do to ease my pain.................................................0  1  2  3  4 
2. My pain does not stop me from leading a physically active life..........0  1  2  3  4 
3. The pain I feel is a sign that damage is being done..............................0  1  2  3  4 
4. There is a connection between my emotions and my pain level..........0  1  2  3  4 
5. I will probably always have to take pain medications..........................0  1  2  3  4 
6. When I am hurting, I deserve to be treated with care and concern.......0  1  2  3  4 
7. I trust that doctors can cure my pain.....................................................0  1  2  3  4 
 


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17.6. Appendix 6: 5-item Opioid Compliance Checklist 
 
5-item Opioid Compliance Checklist (OCC) will be assessed at the baseline visit. 
Over the past month have you: 
1. Lost or misplaced your opioid medications?      
                ܆ Yes         ܆ No 
2. Run out of your pain medication early? 
                  
    ܆ Yes         ܆ No 
3. Missed any scheduled medical appointments? 
     
    ܆ Yes         ܆ No 
4. Used any illegal or unauthorized substances?        
   
   ܆ Yes         ܆ No 
5. Been completely honest about your personal drug use?            ܆ Yes         ܆ No 
 


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17.7. Appendix 7: Modified Post-Anaesthetic Discharge Scoring System 
(MPADSS) 
 
The subject’s discharge readiness will be assessed using the Modified Post Anesthesia Discharge 
Scoring System below (Chung 1995a; Chung 1995b). 
 
The discharge readiness assessment will be used for data collection only and is not intended to 
interfere with the investigational site’s policy for determining when the subject should be discharged 
from the hospital (or other facility). 
 
Discharge readiness will be assessed at 24, 48, and 72 hours or at discharge, or until the subject 
attains a score of 9, whichever occurs first. Once a score of 9 is reached, no further discharge 
readiness assessments are required. 
 
Modified Post Anesthesia Discharge Scoring System 
 
 


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17.8. Appendix 8: 
Persistent Opioid Use 
 
To be collected at Day 30 as part of the Day 30 phone call.  The subject will be asked the following 
question: 
1. Are you currently taking opioid medications to manage pain from your spine surgery? 
a. Yes 
b. No 
 
 
 

SAP_001.pdf: 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
A Multicenter, Prospective, Active Controlled, Real World, Phase 4 Study of EXPAREL® 
in Multimodal Regimens Compared with Standard of Care for Postsurgical Pain 
Management in Subjects Undergoing Lumbar Posterior Spine Surgeries (FUSION) 
 
 
 
 
Protocol No.: 402-C-413 
IND No.: Not applicable  
Study Phase: 4 
Study Drug: EXPAREL® (bupivacaine liposome injectable 
suspension) 
Date/Version: 19 October 2020/Version 1.0  
Prepared by: Ashley Pajak, MS 
Pacrira Pharmaceuticals, Inc. 
 
Sponsor: Pacira Pharmaceuticals, Inc. 
5 Sylvan Way 
Parsippany, NJ 07054 
Tel: 973-254-3560 
 
 
 
 
 
 
 
 
Confidentiality Statement 
The information contained in this document is confidential and the property of Pacira Pharmaceuticals, 
Inc. It should not be reproduced, revealed, or sent to third parties other than Institutional Review 
Boards/Independent Ethics Committees and the Investigator’s research support staff participating in the 
conduct of the study without the prior written authorization of Pacira Pharmaceuticals, Inc. 


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CONFIDENTIAL 
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SIGNATURE PAGE 
 
 
 
 
 
Approved by: 
Donald Manning, MD, PhD 
Chief Medical Office, Clinical Operations 
 
Date 
 
 
 
 
 
 
 
Approved by: 
Michael Rozycki, PhD 
Vice President, Regulatory Affairs 
 
Date 
 
 
 
 
Approved by: 
Gary Nevins, DC 
Executive Medical Director, Clinical Operations 
 
Date 
 
 
 
 
Approved by: 
Vincent Yu, PhD 
Vice President, Biometrics 
 
Date 
 
Do
D nald Manning, MD, PhD
Chief Medical Office, Clinical Operations


Ga
G ry Nevins, DC
Ex
E ecutive Medical Director, Clinical Operati

Mi
Mi
Mi
Mi
Mi
M chael Rozycki, PhD
Vi
V ce President, Regulatory Affairs
Vi
V ncent Yu, PhD
Vi
V ce President, Biometrics



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        19 October 2020 
TABLE OF CONTENTS 
1. 
INTRODUCTION ................................................................................................................................ 6 
2. 
STUDY OBJECTIVES ......................................................................................................................... 7 
2.1 
Primary Objective ....................................................................................................................... 7 
2.2 
Secondary Objectives ................................................................................................................. 7 
3. 
STUDY OVERVIEW ........................................................................................................................... 8 
4. 
DEFINITIONS ...................................................................................................................................... 9 
5. 
ANALYSIS SETS ................................................................................................................................. 9 
6. 
STATISTICAL METHODS ............................................................................................................... 10 
6.1 
General Principles ..................................................................................................................... 10 
6.1.1 
Handling Missing Values ........................................................................................... 10 
6.1.1.1 
Exposure, Surgery, and Rescue Opioid Medication Date or Time ............ 10 
6.2 
Subject Disposition ................................................................................................................... 10 
6.3 
Description of Demographics and Baseline Characteristics ..................................................... 11 
6.3.1 
Demographics ............................................................................................................. 11 
6.3.2 
Baseline Characteristics ............................................................................................. 11 
6.4 
Surgery Characteristics and Prior Staged Procedure ................................................................ 11 
6.5 
Intraoperative, Prior, Concomitant, and Other Mediciations .................................................... 11 
6.6 
Medicial History ....................................................................................................................... 12 
6.7 
Measurements of Treatment Compliance ................................................................................. 12 
6.8 
Study Drug Exposure ................................................................................................................ 12 
6.9 
Efficacy Analysis ...................................................................................................................... 12 
6.10 Health Outcomes Assessments ................................................................................................. 12 
6.11 Safety Analyses ........................................................................................................................ 12 
6.11.1 
Adverse Events ........................................................................................................... 12 
6.12 Interim Analysis ....................................................................................................................... 13 
7. 
SAMPLE SIZE REVIEW ................................................................................................................... 14 
8. 
REFERENCES .................................................................................................................................... 15 
9. 
TIME AND EVENTS SCHEDULE OF STUDY PROCEDURES .................................................... 16 
9.1 
Part 1 ......................................................................................................................................... 16 
9.2 
Part 2- After PACU Arrival ...................................................................................................... 17 
10. LAYOUT OF LISTINGS ................................................................................................................... 18 
11. TABLE OF CONTENTS FOR LISTING MOCK-UPS ..................................................................... 19 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Description 
ADL 
Activities of daily living 
AE 
Adverse event 
AICC 
Corrected Akaike information criterion 
ASA 
American Society of Anesthesiology 
ATC 
Anatomical therapeutic class 
AUC 
Area under the curve 
BIC 
Schwarz’s Bayesian information criterion 
BLOQ 
Below the limit of quantification 
BMI 
Body mass index 
BPI-sf 
Brief Pain Inventory – short form 
bpm 
Beats per minute 
CAS 
Color Analog Scale 
CI 
Confidence interval 
CMP 
Complete metabolic panel 
CRF 
Case report form 
CSR 
Clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Coefficient of variation 
EMA 
European Medicines Agency 
ER 
Emergency room 
GM 
Geometric mean 
HADS 
Hospital Anxiety and Depression Scale 
HCl 
Hydrochloride 
hr, h 
Hour 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IM 
Intramuscular 
IV 
Intravenous 
LIA 
Local infiltration analgesia 
LOS 
Length of stay 
MCID 
Minimum clinically important difference 
MedDRA 
Medical dictionary for regulatory affairs 
min 
Minutes 


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Abbreviation 
Description 
mg MED 
Morphine equivalent dose in mg 
mg 
Milligram 
MPADSS 
Modified Post-Anesthesia Discharge Scoring System 
n 
Number of subjects 
NCI 
National Cancer Institute 
NRS 
Numerical Rating Scale 
OCC 
5-item Opioid Compliance Checklist 
ORAE 
Opioid-related adverse events 
OR-SDS 
Opioid Related-Symptoms Distress Scale 
PACU 
Post-Anesthesia Care Unit 
PO 
Oral 
PT 
Preferred Term 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SC 
Subcutaneous 
SD 
Standard deviation 
SOC 
Standard of care 
SOPA 
Survey of Pain Attitudes 
TEAE 
Treatment-emergent adverse event 
TLF 
Tables, listings and figures 
USFDA 
United States Food and Drug Administration 
WHO 
World Health Organization 
WHO-DD 
World Health Organization – Drug Dictionary 
 


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1. INTRODUCTION 
This Statistical Analysis Plan (SAP) describes the planned statistical analysis and reporting of the clinical 
study 402-C-413 titled “A Multicenter, Prospective, Active Controlled, Real World, Phase 4 Study of 
EXPAREL® in Multimodal Regimens Compared with Standard of Care for Postsurgical Pain 
Management in Subjects Undergoing Lumbar Posterior Spine Surgeries (FUSION)”. This study is 
intended to evaluate postsurgical opioid consumption in adult subjects receiving EXPAREL and 
undergoing posterior lumbar spine surgeries. 
This study was prematurely terminated by the sponsor. At the time of termination, the study has enrolled 
65 subjects. 
The purpose of this SAP is to outline how the collected data will be summarized and presented for the 
abbreviated study report. 
The following documents were reviewed in preparation of this SAP: 
x 
Amendment 1 of Protocol 402-C-413 issued on 25 February 2019. 
x 
Case Report Form (CRF) final version 4.0 issued on 06 July 2020. 
x 
ICH Guidance on Statistical Principles for Clinical Trials (E9) 
The reader of this SAP is encouraged to also read the clinical protocol and other identified documents for 
details on the planned conduct of this study. Operational aspects related to the collection and timing of 
planned clinical assessments are not repeated in this SAP unless relevant to the planned analyses. 


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2. STUDY OBJECTIVES 
2.1 Primary Objective 
The primary objective of this study is to compare postsurgical opioid consumption through 72 hours 
postsurgery in patients receiving local infiltration analgesia (LIA) with EXPAREL and bupivacaine 
hydrochloride (HCl; EXPAREL group) with that of patients receiving standard of care (SOC; Control 
group) in adult subjects undergoing posterior lumbar spine surgeries where both groups are receiving a 
multimodal pain regimen. 
2.2 Secondary Objectives 
The secondary objectives are to: 
1. Compare safety and effectiveness outcomes following LIA with EXPAREL and bupivacaine HCl 
versus SOC in adult subjects undergoing posterior lumbar spine surgeries through 72 hours, 
including time to first opioid, opioid-related adverse events (ORAEs). 
2. Compare health outcomes following LIA with EXPAREL and bupivacaine HCl versus SOC in 
adult subjects undergoing posterior lumbar spine surgeries, including discharge readiness, 
hospital (or other facility) length of stay (LOS), discharge disposition, hospital readmissions, and 
health service utilization. 


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3. STUDY OVERVIEW 
This is a Phase 4, multicenter, prospective, active-controlled, real-world study in approximately 225 adult 
subjects undergoing posterior lumbar spine surgeries under general anesthesia. This will be an open-label 
study and neither subjects nor investigators will be blinded for study group allocation. This study will 
include three cohort groups: cohort 1 – open lumbar spinal fusion technique (“open” cohort); cohort 2 –
 minimally invasive tubular and/or percutaneous pedicle screw insertion for lumbar decompression with 
or without fusion (“tubular/percutaneous without midline incision” cohort); and cohort 3 – lumbar 
decompression surgery (LDS) without fusion (discectomy or laminectomy cohort) outpatient cohort. 
The initial sample size in each study cohort (i.e., cohort 1, cohort 2 and cohort 3) is estimated at 
75 subjects (50 subjects with EXPAREL and 25 subjects with Control group), for a total of 225 subjects 
in all three cohorts. Within each assigned cohort, subjects will be allocated in a 2:1 ratio to the EXPAREL 
(50 subjects) and Control group (25 subjects).  
The following sequence will be carried out for all cohorts: First, the subjects who meet eligibility criteria 
will be treated according to the institution’s SOC. Their data will be collected prospectively. Next, at each 
investigational center, the administration of EXPAREL and bupivacaine HCl to the first 1 to 3 subjects in 
each cohort will be observed to ensure that the correct procedure for infiltration as described in the 
infiltration guide is being followed. If the infiltration was performed correctly, the subject will be 
included in the study. If the infiltration was performed incorrectly, the subject will continue in the study 
but will be removed from statistical analysis and will be replaced to ensure at least 50 evaluable 
EXPAREL patients are enrolled per cohort. If subjects are discontinued for other reasons, they will be 
replaced such that a total sample size of 75 fully evaluable subjects is obtained in each study cohort, with 
50 in the EXPAREL group and 25 in the Control group. Criteria for being fully evaluable will be defined 
in detail in Section 5. 
Figure 1 
Study Schema 
 
Source:  Protocol, Amendment 1, 25 February 2019 
 
 
 


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4. DEFINITIONS 
Study Day 
Study Day is calculated as the date of the event minus the date of the start of surgery plus one (1), if the 
date of event is on or after the date of the start of surgery. If the date of the event is before the date of the 
start of surgery, study day is the date of the event minus the date of the start of surgery. 
Time 0 (zero) 
Time 0 is defined as the date and time of the end of surgery. 
Treatment-emergent Adverse Events 
Treatment-emergent adverse events (TEAEs) are those with onset between the end date and time of 
surgery, and the end of the study (Study Day 30 or until termination from the study). 
Baseline 
Baseline measurement or assessment is defined as the last available non-missing measurement or 
assessment prior to the start of surgery. 
5. ANALYSIS SETS 
All Subjects: all the listings presented in this SAP will be based on all enrolled subjects. Includes the 
following subjects who enrolled but did not undergo surgery; 101-01-0013, 101-03-0034, 109-02-0001, 
113-03-0039. 


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6. STATISTICAL METHODS 
6.1 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. 
6.1.1 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. 
6.1.1.1 
Exposure, Surgery, and Rescue Opioid Medication Date or Time 
It is expected that all necessary information on study drug exposure and surgery (dates and times) will be 
complete. Any such information that is missing and cannot be obtained through query resolution may be 
imputed, on a case-by-case basis, in a conservative manner that minimizes bias. 
6.1.1.2 Adverse Event or Concomitant Medications Dates or Time. 
For adverse events (AEs) or concomitant medications with missing or partially missing start/stop 
date/time, the following imputation rules will be applied: 
For partial start date/time: 
x 
If the year is unknown, then the date will be assigned the year of the start of surgery.  
x 
If the month is unknown, then: 
o If the year matches the year of start of surgery, then the month and day of the dose of study drug 
date will be used to impute the missing month and corresponding day. 
o Otherwise, ‘January’ will be assigned. 
x 
If the day is unknown, then: 
o If the month and year match the month and year of the dose of start of surgery, then the day of the 
start of surgery date will be imputed. 
o Otherwise, ‘01’ will be assigned. 
x 
If the time is unknown, then: 
o If the date (day, month, and year) matches the date of the start of surgery, then the end time of the 
surgery will be imputed. 
o Otherwise, ’00:00’ will be assigned. 
For partial stop date/time: 
x 
If the year is unknown, then the date will be assigned the year that subject had surgery, and time will 
be set to the last time of the day (‘23:59’). 
x 
If the month is unknown, then month of start of surgery will be assigned. 
x 
If the day is unknown, then the last day of the month will be assigned. 
x 
If the time is unknown, then the last time of the day will be assigned (‘23:59’), with the exception of 
end times for epoch in any CDISC dataset, where next day and ’00:00’ would be assigned. 
 
6.2 Subject Disposition 
A listing of subject disposition will be provided, which will include information on study completion 
status among others.  


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6.3 Description of Demographics and Baseline Characteristics 
6.3.1 Demographics  
Listing of demographic data will include: 
x 
Initals 
x 
Date of Birth (DOB) 
x 
Age (years) 
x 
Sex  
x 
Ethnicity  
x 
Race  
 
6.3.2 Baseline Characteristics 
Listing of baseline characteristic data will include: 
x 
Screening Survey of Pain Attitudes (Single-item SOPA) 
x 
Screening Hospital Anxiety and Depression Scale (HADS) 
x 
Screening 5-item Opioid Compliance Checklist (OCC) 
x 
Height (cm) 
x 
Weight (kg) 
x 
Body mass index (BMI;kg/m2) 
The formula for BMI isݓȀሺ݄ଶሻ, 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 meters using the conversion factor of 0.0254 meters to 1 inch.  
6.4 Surgery Characteristics and Prior Staged Procedure 
Surgery characteristics include duration of surgery, total incision length, and type of procedure. Duration 
of surgery is calculated as the difference between the end of surgery and start of surgery times and 
reported in hours. Surgical characteristics will be included in data listings.  
Prior staged procedue characteristics will be included in data listings. 
6.5 Intraoperative, Prior, Concomitant, and Other Mediciations 
Intraoperative, prior, and concomitant medications will be coded using the World Health Organization 
Drug Dictionary (WHODrug version: march 2019 B3) and will be classified according to the default 
anatomical therapeutic chemical (ATC 4) classification term and preferred term (PT). 
Intraoperative medications are defined as medications given as part of the surgical procedure. These may 
include anesthesia, opioids or other medications and are collected on the intraoperative medication page 
of the case report form. 
Prior medications are defined as medications with a stop date and time prior to the start of surgery and 
reported on the prior/concomitant medication page of the case report form. 
Concomitant medications are defined as medications taken after the start of surgery (i.e., started prior to 
the start of surgery and continued after or started after the start of surgery) and reported on the 
prior/concomitant medication page of the case report form. 
Data listings will be created for all medications, with separate listings for intraoperative, prior, 
concomitant, multimodal pain pre-operative, multimodal pain post-operative, prescription daily pain, and 
rescue medications. 


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A listing mapping the ATC class and PT to verbatim term will be presented. 
6.6 Medicial History  
Relevant medicial history and surgery will be presented in a by-subject listing. 
6.7 Measurements of Treatment Compliance 
Study treatment is administered by a party other than the subject, therefore compliance is assured. 
6.8 Study Drug Exposure 
A listing of study drug exposure, which includes volume of injection administered will be provided. 
6.9 Efficacy Analysis 
Listing of the following efficacy assessments will be provided: 
x 
Pain intensity score using the NRS  
x 
OR-SDS at 24, 48, and 72 hours postsurgery, at discharge, and at 14 days  
x 
Brief Pain Inventory – Short Form at screening/baseline, 24 hours, 48 hours, and 72 hours, at 
discharge, and at 14 days 
 
6.10 Health Outcomes Assessments 
Listing of the following health outcome assessments will be provided: 
x 
Post-Anesthesia Care Unit (PACU)- The date and time of admission and discharge, and the hours 
spent in the PACU will be provided in a listing. The hours spent in PACU will be computed as 
the date and time of discharge from PACU minus the date and time of admission to PACU. 
x 
Surgical Facility- The date and time of admission and discharge, and the hours spent in the step-
down and surgical facility will be provided in a listing.  
x 
Modified Post-Anesthesia Discharge Scoring System (MPADSS) at 24, 48, and 72 hours, or at 
discharge, or until the subject attains a score of 9, whichever occurs first. 
x 
Discharge Disposition 
x 
Day 14 Call to doctor and office visits related to pain 
x 
Day 30 Call to doctor and ER visits related to pain, and pain-related/all-casue 30-day 
readmissions 
 
6.11 Safety Analyses 
Safety assessments in this study consist of AEs. Adverse events will be collected from the time of 
informed consent through to the final Day 30 visit. 
6.11.1 Adverse Events 
All AEs will be mapped to PTs and related system/organ class using the Medical Dictionary for 
Regulatory Activities (MedDRA Version 22.0). 
An AE will be considered TEAE if the onset date and time is between the end time and date of surgery 
and the final Day 30 visit. An AE will be considered related to study drug if “Possible”, “Probable” and 
“Definite.  
 If an AE has a partial onset date and time the imputed start and stop dates and times will be used to 
determine treatment-emergence (e.g., stop date and time is before start time of surgery). If an AE has a 
missing relationship it will be assumed to be “Related”. 


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A listing of all AEs will be provided, with a flag indicating TEAEs. 
 
6.12 Interim Analysis 
Interim analysis may be conducted to adjust to variability. Adaptive study design (i.e., adjustment of 
sample size, cohort sequence, type of surgical procedure, endpints, etc.) will be used.  


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7. SAMPLE SIZE REVIEW 
The sample size for this study was based on the primary outcome measure of postsurgical opioid use in 
mg MED PO from the end of surgery (closure of wound/incision) until 72 hours postsurgery. Based on 
preliminary data, the coefficient of variation (CV) is approximately 60%. The minimum clinically 
important difference (MCID) for this outcome was estimated at 40%. 
With these parameters and a beta of 0.2 (i.e., 80% power), an alpha of 0.05, a 2-sided test, and allocating 
subjects in a 2:1 ratio to the EXPAREL group or Control group to minimize barriers to enrollment for an 
approved and marketed medication, a total sample size of 75 fully evaluable subjects is required in each 
study cohort, with 50 subjects in the EXPAREL group and 25 subjects in the Control group. The same 
assumptions are made across all cohorts. Subjects who undergo the planned surgery and whose 
infiltration is performed correctly and who are not discontinued early from the study for any other reasons 
will be fully evaluable. Not fully evaluable subjects should be replaced. Given that this study will have a 
case observation period for the first few subjects in EXPAREL group, if observation is deemed correct 
and infiltration was performed correctly, subject can be included in the study. If observation is deemed 
incorrect and infiltration was performed incorrectly, subject will continue in the study but will be 
removed from statistical analysis and will be replaced to ensure at least 50 evaluable EXPAREL arm 
patients are enrolled per cohort. The total number of subjects in all three cohorts will be 225, with 150 in 
the EXPAREL group and 75 in the Control group.  This is subject to adjustment per interim analysis if 
necessary.   
 
 


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8. REFERENCES 
 American Statistical Association. Ethical Guidelines for Statistical Practice. Prepared by the 
Committee on Professional Ethics, 07 August 1999. 
http://www.amstat.org/profession/ethicalstatistics.html 
 Rubin, DB. (1987). Multiple Imputation for Nonresponse in Surveys. New York: John Wiley & Sons. 
 US Federal Register. International Conference on Harmonisation; Guidance on Statistical Principles 
for Clinical Trials. Department of Health and Human Services: Food and Drug Administration 
[Docket No. 97D-0174]. Federal Register Volume 63, Number 179, pages 49583-49598. 16 
September 1998. 
 Royal Statistical Society. The Royal Statistical Society: Code of Conduct, August 1993. 
http://www.rss.org.uk/about/conduct.html. 


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9. TIME AND EVENTS SCHEDULE OF STUDY PROCEDURES 
9.1 Part 1 
 
 


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9.2 Part 2- After PACU Arrival 
 
 
 


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10. LAYOUT OF LISTINGS  
Listings will have 10-point font size. The listing will have Times New Roman, Courier New, or SAS 
Monospace type face. All final listings will be provided in both PDF and Word (or RTF) file formats. 
Titles on the Listings should appear as following: 
Listing 16.2-1.1.1 
Subject Disposition– All Subjects  
Cohort: Cohort 1; Treatment: EXPAREL 
 
The text “Cohort: Cohort 1; Treatment: EXPAREL” refers to the cohort and treatment group. There 
should be a page break between the cohort and treatment group and should be presented in the order of:  
Cohort: Cohort 1; Treatment: SOC 
Cohort: Cohort 1; Treatment: EXPAREL 
Cohort: Cohort 1; Treatment: NOT TREATED 
Cohort: Cohort 2; Treatment: SOC 
Cohort: Cohort 2; Treatment: EXPAREL 
Cohort: Cohort 2; Treatment: NOT TREATED 
Cohort: Cohort 3; Treatment: SOC 
Cohort: Cohort 3; Treatment: EXPAREL 
Cohort: Cohort 3; Treatment: NOT TREATED 
 
 
Listings should be generally ordered by Cohort, Treatment, Site, Subject and Date where applicable. If 
data is missing in a column, the column may be populated with “-“ for reading ease. 


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11. TABLE OF CONTENTS FOR LISTING MOCK-UPS 
Listing 16.2-1.1: Subject Disposition– All Subjects ................................................................................... 21 
Listing 16.2-2: Enrollment– All Subjects ................................................................................................... 22 
Listing 16.2-3: Inclusion/ Exclusion Criteria- Failures Subjects ................................................................ 23 
Cohort: -; Treatment: SCREEN FAILURES .............................................................................................. 23 
Listing 16.2-4.1: Demographics – All Subjects .......................................................................................... 24 
Listing 16.2-4.2: Demographics – Screen Failures ..................................................................................... 25 
Listing 16.2-4.3: Demographics – Subject Enrolled but No Surgery ......................................................... 26 
Listing 16.2-5.1: Baseline Characteristics (Survey of Pain Attitudes (SOPA))– All Subjects ................... 27 
Listing 16.2-5.2: Baseline Characteristics (Hospital Anxiety and Depression Score (HADS))– All 
Subjects ............................................................................................................................................ 28 
Listing 16.2-5.3: Baseline Characteristics (5-Item Opioid Compliance Checklist (OCC) – All Subjects .. 29 
Listing 16.2-6.1: Pregnancy test- All Female Subects ................................................................................ 30 
Listing 16.2-6.2: Pregnancy test- Female Screen Fails ............................................................................... 31 
Listing 16.2-7.1: Admission and Discharge- Post-Anesthesia Care Unit (PACU) – All Subjects ............. 32 
Listing 16.2-7.2: Admission and Discharge – Surgical Facility – All Subjects .......................................... 33 
Listing 16.2-8.1: Surgery Characteristics- Procedure – All Subjects ......................................................... 34 
Listing 16.2-8.2: Surgery Characteristics- Anesthesia– All Subjects ......................................................... 35 
Listing 16.2-8.3: Surgery Characteristics- Autograft– All Subjects ........................................................... 36 
Listing 16.2-8.4: Surgery Characteristics-Prior Staged Procedure – All Subjects ...................................... 37 
Listing 16.2-9: Medical/Surgical History – All Subjects ............................................................................ 38 
Listing 16.2-10: Study Drug Administration – All EXPAREL Subjects .................................................... 39 
Listing 16.2-11.1: All Adverse Events – All Subjects ................................................................................ 40 
Listing 16.2-11.2.1: All Treatment Emergent Adverse Events – All Subjects ........................................... 41 
Listing 16.2-11.2.2: All Treatment Emergent Adverse Events Related to Study Drug – All Subjects ...... 42 
Listing 16.2-11.3.1: All Serious Adverse Events – All Subjects ................................................................ 43 
Listing 16.2-11.3.2: All Non-serious Adverse Events – All Subjects ........................................................ 44 
Listing 16.2-11.4.1: All Treament Emergent Serious Adverse Events – All Subjects ............................... 45 
Listing 16.2-11.4.2: All Treatment Emergent Non-serious Adverse Events – All Subjects ....................... 46 
Listing 16.2-11.5: All Treament Emergent Study Drug Related Serious Adverse Events – All Subjects .. 47 
Listing 16.2-12: Vital Signs – All Subjects ................................................................................................ 48 
Listing 16.2-13: Numeric Rating Scale (NRS) Pain Intensity Score – All Subjects................................... 49 
Listing 16.2-14: Opioid Related Symptoms Distress Scale (ORSDS) – All Subjects ................................ 50 
Listing 16.2-15: BPI-sf – All Subjects ........................................................................................................ 51 
Listing 16.2-16: Health Outcomes Assessments – MPADSS - All Subjects .............................................. 52 
Listing 16.2-17: Health Outcomes Assessments- Discharge Disposition – All Subjects ........................... 53 
Listing 16.2-18.1: Phone Call / In Person Visit Day 14 (Pain Visits) - All Subjects .................................. 54 
Listing 16.2-18.2: Phone Call / In Person Visit Day 14 (Medication)- All Subjects .................................. 55 
Listing 16.2-19.1: Phone Call / In Person Visit Day 30 (Pain Visits) - All Subjects .................................. 56 
Listing 16.2-19.2: Phone Call / In Person Visit Day 30 (Medications) - All Subjects ............................... 57 
Listing 16.2-20.1: Multimodal Pain Medication – Pre-Operative – All Subjects ....................................... 58 


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Listing 16.2-20.2: Multimodal Pain Medication – Post-Operative – All Subjects ..................................... 59 
Listing 16.2-20.3: Intraoperative Medications – All Subjects .................................................................... 60 
Listing 16.2-20.4: Prescription Daily Pain Medications – All Subjects ..................................................... 61 
Listing 16.2-20.5: Rescue Medication – All Subjects................................................................................. 62 
Listing 16.2-20.6: Prior Medications – All Subjects................................................................................... 63 
Listing 16.2-20.7: Concomitant Medications – All Subjects ...................................................................... 64 
Listing 16.2-21: Protocol Deviations – All Subjects .................................................................................. 65 
Listing 16.2-22: Unique Adverse Events Terms and Associated Coded Terms ......................................... 66 
Listing 16.2-23: Unique Medication Terms and Associated Coded Terms ................................................ 67 


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Listing 16.2-1.1: Subject Disposition– All Subjects  
Cohort: cohort; TREATMENT: treatment-name 
 
Site Subject 
Date of 
the Start 
of the  
Last Visit 
Date of 
Last Contact 
End of 
Study 
Status 
Primary Reason 
for Early 
Termination  
If Other, 
Specify 
Additional Early 
Termination 
Details 
 
 
 
 
 
 
 
XXX 
XX-YYYY 
DDMONYYYY 
DDMONYYYY 
XXXXXXXX 
XXXXXX 
XXXXX 
XXXXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
Program: program_name 
 
 
 


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Listing 16.2-2: Enrollment– All Subjects  
Cohort: cohort; TREATMENT: treatment-name 
 
Site Subject 
Informed Consent 
Date (Day) 
Is the Subject 
Enrolled? 
Enrollment Date/Time 
(Day) 
Enrollment Cohort 
 
 
 
 
 
 
XXX 
XX-YYYY 
DDMONYYYY (XX) 
XXX 
DDMONYYYYTHH:MM (XX) 
XXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
Program: program_name 
 
 
 


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Listing 16.2-3: Inclusion/ Exclusion Criteria- Failures Subjects 
Cohort: -; Treatment: SCREEN FAILURES 
 
Site 
Subject 
Informed Consent Date 
Protocol Version 
Enrolled Under 
Criteria ID Failed 
 
 
 
 
 
 
 
 
XXX 
XX-YYYY 
DDMONYYYY 
Version 1 
 
XXXXXXXXX, XXXXXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y  
 
Program: program_name 
 
Programmer Note: column “Criteria ID Failed” should read “Inclusion 09”  for example.  
 
progra
 
 
 
 
 


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Listing 16.2-4.1: Demographics – All Subjects 
Cohort: cohort; TREATMENT: treatment-name; 
 
Site  
Subject 
Initials 
DOB 
Age (yrs)  
Sex 
Ethnicity 
Race 
  
XXX 
XX-YYYY 
AMZ 
DDMONYYYY 
XX 
X 
XXXXXXXXX 
XXXXXXXXX 
XXX 
XX-YYYY 
AMZ 
DDMONYYYY 
XX 
X 
XXXXXXXXX 
XXXXXXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
  
  
  
  
  
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
Program: program_name 
 
 
 
 
 
Note to programmer: List all races checked. If race is ‘other’ then race should be ‘Other: other-specify-
text’.  
 
 


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Listing 16.2-4.2: Demographics – Screen Failures 
Cohort: cohort; TREATMENT: Screen Failures; 
 
Site  
Subject 
Initials 
DOB 
Age  
(yrs)  
Sex 
Ethnicity 
Race 
  
XXX 
XX-YYYY 
AMZ 
DDMONYYYY 
XX 
X 
XXXXXXXXX 
XXXXXXXXX 
XXX 
XX-YYYY 
AMZ 
DDMONYYYY 
XX 
X 
XXXXXXXXX 
XXXXXXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
  
  
  
  
  
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
Program: program_name 
 
 
Note to programmer: List all races checked. If race is ‘other’ then race should be ‘Other: other-specify-
text’.  
 
 
 


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Listing 16.2-4.3: Demographics – Subject Enrolled but No Surgery 
Cohort: cohort; TREATMENT: Screen Failures; 
 
Site  
Subject 
Initials 
DOB 
Age  
(yrs)  
Sex 
Ethnicity 
Race 
  
XXX 
XX-YYYY 
AMZ 
DDMONYYYY 
XX 
X 
XXXXXXXXX 
XXXXXXXXX 
XXX 
XX-YYYY 
AMZ 
DDMONYYYY 
XX 
X 
XXXXXXXXX 
XXXXXXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
  
  
  
  
  
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
Program: program_name 
 
 
Note to programmer: List all races checked. If race is ‘other’ then race should be ‘Other: other-specify-
text’.  
 
 
 
 
 
 
 
 


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Listing 16.2-5.1: Baseline Characteristics (Survey of Pain Attitudes (SOPA))– All Subjects 
Cohort: cohort; TREATMENT: treatment-name 
 
Site  Subject 
Date (Day) 
Data Type 
Data 
XXX 
XX-YYYY 
DDMONYYYY (XX) 
Q1: There is little I can do to ease my 
pain 
0 = This is very untrue for 
me 
 
 
 
Q2: My pain does not stop me from 
leading a physically active life 
0 = This is very untrue for 
me 
 
 
 
Q3: The pain I feel is a sign that 
damage is being done 
0 = This is very untrue for 
me 
 
 
 
Q4: There is a connection between my 
emotions and my pain level 
0 = This is very untrue for 
me 
 
 
 
Q5: I will probably always have to take 
pain medications 
0 = This is very untrue for 
me 
 
 
 
Q6: When I am hurting, I deserve to be 
treated with care and concern 
0 = This is very untrue for 
me 
 
 
 
Q7: I trust that doctors can cure my 
pain 
0 = This is very untrue for 
me 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
Program: program_name 
 
Programmer Note: For column “Data Type” please display as verbatim in the shell not as what is presented in 
QS.QSTEST 
 
 


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Listing 16.2-5.2: Baseline Characteristics (Hospital Anxiety and Depression Score (HADS))– All Subjects 
Cohort: cohort; TREATMENT: treatment-name 
 
Site Subject Date (Day) 
Data Type 
Data 
XXX 
XX-XXX 
DDMONYYYY (XX) 
(A) I feel tense or ‘wound up’ 
Very often 
(D) I still enjoy the things I used to enjoy 
Very often 
(A) I get a sort of frightened feeling as if 
something awful is about to happen 
Very often 
(D) I can laugh and see the funny side of 
things 
Very often 
(A) Worrying thoughts go through my mind 
Very often 
(D) I feel cheerful 
Very often 
(A) I can sit at ease and feel relaxed 
Very often 
(D) I feel as if I am slowed down 
Very often 
(A) I get a sort of frightened feeling like 
“butterflies” in the stomach 
Very often 
(D) I have lost interest in my appearance 
Very often 
(A) I feel restless as if I have to be on the 
move 
Very often 
(D) I look forward with enjoyment of things 
Very often 
(A) I get sudden feelings of panic 
Very often 
(D) I can enjoy a good book or radio or TV 
Program 
Very often 
Total Score Anxiety 
9 
  
  
  
Total Score Depression  
9 
 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
Program:program_name 
 
Programmer Note: For column “Data Type” please display as verbatim in the shell not as what is presented in 
QS.QSTEST 
 
 
 


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Listing 16.2-5.3: Baseline Characteristics (5-Item Opioid Compliance Checklist (OCC) – All Subjects 
Cohort: cohort; TREATMENT: treatment-name 
 
Site  
Subject 
Date (Day) 
Data Type 
Data 
XXX 
XX-XXX 
DDMONYYYY (XX) Over the past month have you: 
 
1. Lost or misplaced your opioid medications? 
Yes 
2. Run out of your pain medication early? 
Yes 
3. Missed any scheduled medical appointments? 
Yes 
4. Used any illegal or unauthorized substances? 
Yes 
5. Been completely honest about your personal drug 
use? 
Yes 
  
  
  
  
  
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y  
 
Program:program_name 
 
Programmer Note: For column “Data Type” please display as verbatim in the shell not as what is presented in 
QS.QSTEST 
 
 


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Listing 16.2-6.1: Pregnancy test- All Female Subects  
Cohort: cohort; TREATMENT: treatment-name 
 
Site  
Subject 
Is subject of child bearing 
potential? 
If Yes, Was Urine 
Pregnancy Test done? 
Test Result 
XXX 
XX-YYYY 
X 
X 
XXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
  
  
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y  
 
Program: program_name 
 
 


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Listing 16.2-6.2: Pregnancy test- Female Screen Fails  
 
Site  
Subject 
Is subject of child bearing 
potential? 
If Yes, Was Urine 
Pregnancy Test done? 
Test Result 
XXX 
XX-YYYY 
X 
X 
XXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
  
  
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y  
 
Program: program_name 
 
 


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Listing 16.2-7.1: Admission and Discharge- Post-Anesthesia Care Unit (PACU) – All Subjects 
Cohort: cohort; TREATMENT: treatment-name 
 
Site 
Subject 
Admission 
Date/Time (Day) 
Discharge 
Date/Time (Day) 
Total length of 
stay (hours) 
XXX 
XX-YYYY 
DDMONYYYYTHH:MM (XX) 
DDMONYYYYTHH:MM (XX) 
XXX.X 
  
  
  
  
  
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y  
 
Program: program_name 
 
Programmer Note: For column “Total length of stay (hours)” please populate with the numeric number not as 
P0DT1H24M as displayed in SDTM.HO.HODUR 
 
 


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Listing 16.2-7.2: Admission and Discharge – Surgical Facility – All Subjects 
Cohort: cohort; TREATMENT: treatment-name 
 
Site Subject 
Admission 
Date/ Time (Day) 
Discharge 
Date/ Time (Day) 
Total length of stay 
in step-down  
(hours) 
Total length of 
stay in 
hospital/facility  
(hours) 
XXX 
XX-YYYY 
DDMONYYYYTHH:MM (XX) 
DDMONYYYYTHH:MM (XX) 
XX 
XX 
  
  
  
  
  
  
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y  
 
Program: program_name 
 
 
Programmer Note: For column “Total length of stay in hospital/facility (hours)” please populate with the 
numeric number not as P0DT1H24M as displayed in SDTM.HO.HODUR 
 
 
 
 
 


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Listing 16.2-8.1: Surgery Characteristics- Procedure – All Subjects 
Cohort: cohort; TREATMENT: treatment-name 
 
Site  
Subject 
Start Date/ Time (Day)/ 
End Date/Time (Day)/ 
Duration [1] 
Procedure Name 
Surgery 
Performed by 
Incision 
Length (cm) 
XXX 
XX-YYYY 
DDMONYYYYTHH:MM (XX)/ 
DDMONYYYYTHH:MM (XX)/ 
XXXX 
XXXXXX/ Subtypes 
XXX 
3 
  
  
  
  
  
  
[1] Duration of surgery is calculated as the difference between the end of surgery and start of surgery 
times and reported in hours 
 
 
 
 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
Program: program_name 
 
 


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Listing 16.2-8.2: Surgery Characteristics- Anesthesia– All Subjects 
Cohort: cohort; TREATMENT: treatment-name 
 
Site 
Subject 
Surgery Start  
Date (Day) 
Anesthsia 
Start Time 
Anesthsia 
End Time 
Type of 
Anesthesia 
XXX 
XX-YYYY 
DDMONYYYY (XX) 
HH:MM 
HH:MM 
XXXXX 
  
  
  
  
  
  
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
Program: program_name 
 
 
Note to programmer: If anesthesia type is ‘other’ then text should read ‘other: specify-text’.  
 
 
 
 
 
 


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Listing 16.2-8.3: Surgery Characteristics- Autograft– All Subjects 
Cohort: cohort; TREATMENT: treatment-name 
 
Site  
Subject 
Surgery Start Date (Day) 
Was an Autograft Taken? 
If Yes, Harvest Site 
XXX 
XX-YYYY 
DDMONYYYY (XX) 
Yes 
Other: XXXXXX 
  
  
  
  
  
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y  
 
Program: program_name 
 
 
 
 
 


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Listing 16.2-8.4: Surgery Characteristics-Prior Staged Procedure – All Subjects 
Cohort: cohort; TREATMENT: treatment-name 
 
Site Subject 
Surgery part 
of a staged 
procedure? 
Staged Procedure Type 
Start Date/Time (Day) 
Stop Date/Time (Day) 
 
 
 
 
 
 
 
XXX 
XX-YYYY 
XXX 
XXXXXXXX 
DDMONYYYYTHH:MM (XX) 
DDMONYYYYTHH:MM (XX) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
Program: program_name 
 
 
 


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Listing 16.2-9: Medical/Surgical History – All Subjects 
Cohort: cohort; Treatment: treatment-name 
 
Site 
Subject 
Medical History 
Number  
Data Type 
Data 
XXX 
XX-YYYY 
XX 
Start Date 
DDMONYYYY 
 
 
 
Stop Date 
DDMONYYYY 
 
 
 
System Organ Class 
XXXXXXXXXXXXXXXXXX 
 
 
 
  Preferred 
XXXXXXXXXXXXXXXXXXXX 
 
 
 
    Verbatim 
XXXXXXXXXXXXXXXXXXXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Only subjects with relevant medicial history or surgery are included in this listing.  
 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
Program:program_name 
 
Note to programmer: If condition is ongoing, put ONGOING in stop row.  Do not split a condition across 
pages. Insert a page break between subjects. The column “Medicial History Number” should correspond to 
MHSEQ 
 


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Listing 16.2-10: Study Drug Administration – All EXPAREL Subjects 
Cohort: cohort; TREATMENT: EXPAREL 
 
Site  
Subject 
Case Obs 
Correctly? 
Start Date/Time (Day)/ 
End Date/Time (Day  
Total 
Volume (mL)  
Study Drug 
Administered by 
XXX 
XX-YYYY 
XXX 
DDMONYYYYTHH:MM (XX)/ 
DDMONYYYYTHH:MM (XX) 
XXX 
XXX 
  
  
  
  
  
  
Note: Only subjects in Cohort 3 were administered EXPAREL. 
 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
Program: program_name 
 
Note to programmer: If Not Done is checked then text should read ‘Not Done: reason-text’.  
 
 
 


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Listing 16.2-11.1: All Adverse Events – All Subjects 
Cohort: cohort; Treatment: treatment-name 
 
Site 
Subject 
TEAE Data Type 
Data 
XXX 
XX-YYYY 
N 
Start Date/ Time (Day) 
DDMONYYYYTHH:MM (XX) 
 
 
 
Stop Date/ Time (Day) 
DDMONYYYYTHH:MM (XX) 
 
 
 
AE Number 
X 
 
 
 
System Organ Class 
XXXXXXXXXXXXXXXXXX 
 
 
 
  Preferred 
  XXXXXXXXXXXXXXXXXXXX 
 
 
 
    Verbatim 
    XXXXXXXXXXXXXXXXXXXXXX 
 
 
 
Severity 
XXXXXXXX 
 
 
 
Relationship to Study 
Drug 
XXXXXXXX 
 
 
 
Action Taken with Subject 
XXXXXXXXXXXXXXXXXXXXX 
 
 
 
Outcome 
XXXXXXXXXXXXXX 
 
 
 
Serious 
XXX 
 
 
 
  Serious Cause(s) 
  XXXXXXXXXXXXX 
 
 
 
 
  XXXXXXXXXXXXXXXXXXXXXX 
 
 
 
 
 
 
 
 
 
 
TEAE: Treatment-emergent AE (Y=TEAE/N=Not TEAE) 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
Program: program_name 
 
Note to programmer: If AE is ongoing, put ONGOING in stop row. Do not split an AE across pages. Insert a 
page break between subjects.  
 
 


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Listing 16.2-11.2.1: All Treatment Emergent Adverse Events – All Subjects 
Cohort: cohort; Treatment: treatment-name 
 
Site 
Subject 
Data Type 
Data 
XXX 
XX-YYYY 
Start Date/ Time (Day) 
DDMONYYYYTHH:MM (XX) 
 
 
Stop Date/ Time (Day) 
DDMONYYYYTHH:MM (XX) 
 
 
AE Number 
X 
 
 
System Organ Class 
XXXXXXXXXXXXXXXXXX 
 
 
  Preferred 
  XXXXXXXXXXXXXXXXXXXX 
 
 
    Verbatim 
    XXXXXXXXXXXXXXXXXXXXXX 
 
 
Severity 
XXXXXXXX 
 
 
Relationship to Study 
Drug 
XXXXXXXX 
 
 
Action Taken with Subject 
XXXXXXXXXXXXXXXXXXXXX 
 
 
Outcome 
XXXXXXXXXXXXXX 
 
 
Serious 
XXX 
 
 
  Serious Cause(s) 
  XXXXXXXXXXXXX 
 
 
 
  XXXXXXXXXXXXXXXXXXXXXX 
 
 
 
 
 
 
 
 
TEAE: Treatment-emergent AE (Y=TEAE/N=Not TEAE) 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: If AE is ongoing, put ONGOING in stop row. Do not split an AE across pages. Insert a 
page break between subjects.  
 
 


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Listing 16.2-11.2.2: All Treatment Emergent Adverse Events Related to Study Drug – All Subjects 
Cohort: cohort; Treatment: treatment-name 
 
Site 
Subject 
Data Type 
Data 
XXX 
XX-YYYY 
Start Date/ Time (Day) 
DDMONYYYYTHH:MM (XX) 
 
 
Stop Date/ Time (Day) 
DDMONYYYYTHH:MM (XX) 
 
 
AE Number 
X 
 
 
System Organ Class 
XXXXXXXXXXXXXXXXXX 
 
 
  Preferred 
  XXXXXXXXXXXXXXXXXXXX 
 
 
    Verbatim 
    XXXXXXXXXXXXXXXXXXXXXX 
 
 
Severity 
XXXXXXXX 
 
 
Relationship to Study 
Drug 
XXXXXXXX 
 
 
Action Taken with Subject 
XXXXXXXXXXXXXXXXXXXXX 
 
 
Outcome 
XXXXXXXXXXXXXX 
 
 
Serious 
XXX 
 
 
  Serious Cause(s) 
  XXXXXXXXXXXXX 
 
 
 
  XXXXXXXXXXXXXXXXXXXXXX 
 
 
 
 
 
 
 
 
TEAE: Treatment-emergent AE (Y=TEAE/N=Not TEAE) 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: If AE is ongoing, put ONGOING in stop row. Do not split an AE across pages. Insert a 
page break between subjects.  
 
 
 


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Listing 16.2-11.3.1: All Serious Adverse Events – All Subjects 
Cohort: cohort; Treatment: treatment-name 
 
Site 
Subject 
TEAE Data Type 
Data 
XXX 
XX-YYYY 
N 
Start Date/ Time (XX) 
DDMONYYYYTHH:MM (XX) 
 
 
 
Stop Date/ Time (XX) 
DDMONYYYYTHH:MM (XX) 
 
 
 
AE Number 
X 
 
 
 
System Organ Class 
XXXXXXXXXXXXXXXXXX 
 
 
 
  Preferred 
  XXXXXXXXXXXXXXXXXXXX 
 
 
 
    Verbatim 
    XXXXXXXXXXXXXXXXXXXXXX 
 
 
 
Severity 
XXXXXXXX 
 
 
 
Relationship to Study 
Drug 
XXXXXXXX 
 
 
 
Action Taken 
XXXXXXXXXXXXXXXXXXXXX 
 
 
 
Outcome 
XXXXXXXXXXXXXX 
 
 
 
Serious 
XXX 
 
 
 
  Serious Cause(s) 
  XXXXXXXXXXXXX 
 
 
 
 
  XXXXXXXXXXXXXXXXXXXXXX 
 
 
 
 
 
 
 
 
 
 
TEAE: Treatment-emergent AE (Y=TEAE/N=Not TEAE) 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: If AE is ongoing, put ONGOING in stop row. Do not split an AE across pages. Insert a 
page break between subjects.  
 
 


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Listing 16.2-11.3.2: All Non-serious Adverse Events – All Subjects 
Cohort: cohort; Treatment: treatment-name 
 
Site 
Subject 
TEAE Data Type 
Data 
XXX 
XX-YYYY 
N 
Start Date/ Time (XX) 
DDMONYYYYTHH:MM (XX) 
 
 
 
Stop Date/ Time (XX) 
DDMONYYYYTHH:MM (XX) 
 
 
 
AE Number 
X 
 
 
 
System Organ Class 
XXXXXXXXXXXXXXXXXX 
 
 
 
  Preferred 
  XXXXXXXXXXXXXXXXXXXX 
 
 
 
    Verbatim 
    XXXXXXXXXXXXXXXXXXXXXX 
 
 
 
Severity 
XXXXXXXX 
 
 
 
Relationship to Study 
Drug 
XXXXXXXX 
 
 
 
Action Taken 
XXXXXXXXXXXXXXXXXXXXX 
 
 
 
Outcome 
XXXXXXXXXXXXXX 
 
 
 
Serious 
XXX 
 
 
 
  Serious Cause(s) 
  XXXXXXXXXXXXX 
 
 
 
 
  XXXXXXXXXXXXXXXXXXXXXX 
 
 
 
 
 
 
 
 
 
 
TEAE: Treatment-emergent AE (Y=TEAE/N=Not TEAE) 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: If AE is ongoing, put ONGOING in stop row. Do not split an AE across pages. Insert a 
page break between subjects.  
 
 


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Listing 16.2-11.4.1: All Treament Emergent Serious Adverse Events – All Subjects 
Cohort: cohort; Treatment: treatment-name 
 
Site 
Subject 
Data Type 
Data 
XXX 
XX-YYYY 
Start Date/ Time (XX) 
DDMONYYYYTHH:MM (XX) 
 
 
Stop Date/ Time (XX) 
DDMONYYYYTHH:MM (XX) 
 
 
AE Number 
X 
 
 
System Organ Class 
XXXXXXXXXXXXXXXXXX 
 
 
  Preferred 
  XXXXXXXXXXXXXXXXXXXX 
 
 
    Verbatim 
    XXXXXXXXXXXXXXXXXXXXXX 
 
 
Severity 
XXXXXXXX 
 
 
Relationship to Study 
Drug 
XXXXXXXX 
 
 
Action Taken 
XXXXXXXXXXXXXXXXXXXXX 
 
 
Outcome 
XXXXXXXXXXXXXX 
 
 
Serious 
XXX 
 
 
  Serious Cause(s) 
  XXXXXXXXXXXXX 
 
 
 
  XXXXXXXXXXXXXXXXXXXXXX 
 
 
 
 
 
 
 
 
TEAE: Treatment-emergent AE (Y=TEAE/N=Not TEAE) 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: If AE is ongoing, put ONGOING in stop row. Do not split an AE across pages. Insert a 
page break between subjects.  
 
 


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Listing 16.2-11.4.2: All Treatment Emergent Non-serious Adverse Events – All Subjects 
Cohort: cohort; Treatment: treatment-name 
 
Site 
Subject 
Data Type 
Data 
XXX 
XX-YYYY 
Start Date/ Time (XX) 
DDMONYYYYTHH:MM (XX) 
 
 
Stop Date/ Time (XX) 
DDMONYYYYTHH:MM (XX) 
 
 
AE Number 
X 
 
 
System Organ Class 
XXXXXXXXXXXXXXXXXX 
 
 
  Preferred 
  XXXXXXXXXXXXXXXXXXXX 
 
 
    Verbatim 
    XXXXXXXXXXXXXXXXXXXXXX 
 
 
Severity 
XXXXXXXX 
 
 
Relationship to Study 
Drug 
XXXXXXXX 
 
 
Action Taken 
XXXXXXXXXXXXXXXXXXXXX 
 
 
Outcome 
XXXXXXXXXXXXXX 
 
 
Serious 
XXX 
 
 
  Serious Cause(s) 
  XXXXXXXXXXXXX 
 
 
 
  XXXXXXXXXXXXXXXXXXXXXX 
 
 
 
 
 
 
 
 
TEAE: Treatment-emergent AE (Y=TEAE/N=Not TEAE) 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: If AE is ongoing, put ONGOING in stop row. Do not split an AE across pages. Insert a 
page break between subjects.  
 
 


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Listing 16.2-11.5: All Treament Emergent Study Drug Related Serious Adverse Events – All Subjects 
Cohort: cohort; Treatment: treatment-name 
 
Site 
Subject 
Data Type 
Data 
XXX 
XX-YYYY 
Start Date/ Time (XX) 
DDMONYYYYTHH:MM (XX) 
 
 
Stop Date/ Time (XX) 
DDMONYYYYTHH:MM (XX) 
 
 
AE Number 
X 
 
 
System Organ Class 
XXXXXXXXXXXXXXXXXX 
 
 
  Preferred 
  XXXXXXXXXXXXXXXXXXXX 
 
 
    Verbatim 
    XXXXXXXXXXXXXXXXXXXXXX 
 
 
Severity 
XXXXXXXX 
 
 
Relationship to Study 
Drug 
XXXXXXXX 
 
 
Action Taken 
XXXXXXXXXXXXXXXXXXXXX 
 
 
Outcome 
XXXXXXXXXXXXXX 
 
 
Serious 
XXX 
 
 
  Serious Cause(s) 
  XXXXXXXXXXXXX 
 
 
 
  XXXXXXXXXXXXXXXXXXXXXX 
 
 
 
 
 
 
 
 
TEAE: Treatment-emergent AE (Y=TEAE/N=Not TEAE) 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: If AE is ongoing, put ONGOING in stop row. Do not split an AE across pages. Insert a 
page break between subjects.  
 
 


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Listing 16.2-12: Vital Signs – All Subjects 
Cohort: cohort; TREATMENT: treatment-name 
 
Site  
Subject 
Done?  
Date/Time (Day) 
Height  
(cm) 
Weight  
(kg) 
BMI 
XXX 
XX-YYYY 
Yes 
DDMONYYYYTHH:MM (XX) 
XX 
XX 
XX 
XXX 
XX-YYYY 
Yes 
DDMONYYYYTHH:MM (XX) 
XX 
XX 
XX 
XXX 
XX-YYYY 
Yes 
DDMONYYYYTHH:MM (XX) 
XX 
XX 
XX 
XXX 
XX-YYYY 
No, XXXXXX 
DDMONYYYYTHH:MM (XX) 
- 
- 
- 
  
  
  
  
  
  
  
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
Program:program_name 
Note to programmer: If Not Done is checked then text should read ‘Not Done: reason-text’. If data is 
missing populate with “-“. 
 
 
 


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Listing 16.2-13: Numeric Rating Scale (NRS) Pain Intensity Score – All Subjects 
Cohort: cohort; TREATMENT: treatment-name 
 
Site 
Subject 
Time Point / Asleep 
During Time Point [1] 
Date/Time (Day) 
NRS Pain 
Intensity Score 
 
 
 
 
 
XXX 
XX-YYYY 
Screening 
DDMONYYYYTHH:MM (XX) 
- 
 
 
48 hours / No 
DDMONYYYYTHH:MM (XX) 
XXX 
 
 
Discharge 
DDMONYYYYTHH:MM (XX) 
XXX 
 
 
14 days 
DDMONYYYYTHH:MM (XX) 
XXX 
 
 
 
 
 
[1] Asleep During Time Point only used for schelduled 6 – 72 hours. 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
Program: program_name 
 
Note to programmer: Include all NRS scores. For colum “Time Point / Asleep During Time Point [1]” a 
subject is considered to be asleep during an assessment if SDTM.QS.qscat=” NRS-R Pain Intensity” 
and QSREASND=”ASLEEP” 
 
 


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Listing 16.2-14: Opioid Related Symptoms Distress Scale (ORSDS) – All Subjects 
Cohort: cohort; TREATMENT: treatment-name 
 
Site  Subject Time 
Point  Date/Time (Day) 
Symptom 
Did 
Have 
# 
Episodes 
Often 
Severe 
Distress 
or 
Bother  
XXX 
XX-YYYY 24 hrs DDMONYYYYTHH:MM 
(XX) 
Fatigue 
N 
 
- 
 
 
Drowsiness 
- 
 
Occasionally Slight A little 
bit 
Concentrate 
N 
Nausea 
N 
Dizziness 
N 
Constipation 
N 
Itching 
N 
Urination 
N 
 
 
 
 
Confusion 
N 
  
  
  
  
Retching/vomiting N 
  
  
  
  
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
Program: program_name 
 
Note to programmer: Add in all applicable visits. 
 
 
 
 
 
 
 


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Listing 16.2-15: BPI-sf – All Subjects 
Cohort: cohort; TREATMENT: treatment-name 
 
Site  Subject Timepoint Date of 
Assessment 
Data Type 
Data 
XXX 
XX-YYYY Screening DDMONYYYYTHH:MM Have you had pain, other than everyday pain 
kinds of pain today?  
Yes 
 
 
 
 
Area where you feel pain 
Front leg, 
Back Leg  
 
 
 
 
Area where it hurts the most  
Front Leg  
 
 
 
 
Rate your pain that describes your pain at 
its worst in the last 24 hours 
1 
 
 
 
 
Rate your pain that describes your pain at 
its least in the last 24 hours 
2 
 
 
 
 
Rate your pain that describes your pain  on 
average 
3 
 
 
 
 
Rate your pain that describes your pain  
right now 
2 
 
 
 
 
In the last 24 hours, how much relief have 
pain medications provided? ( Percentage) 
1 
 
 
 
 
During the past 24 hours pain has 
interfered with: General Activity  
2 
 
 
 
 
During the past 24 hours pain has 
interfered with: Mood 
3 
 
 
 
 
During the past 24 hours pain has 
interfered with: Walking Abililty  
4 
 
 
 
 
During the past 24 hours pain has 
interfered with: Normal Work 
2 
 
 
 
 
During the past 24 hours pain has 
interfered with: Relationships 
1 
 
 
 
 
During the past 24 hours pain has 
interfered with: Sleep 
1 
  
  
  
  
During the past 24 hours pain has 
interfered with: Enjoyment of life  
3 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
 


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Listing 16.2-16: Health Outcomes Assessments – MPADSS - All Subjects 
Cohort: cohort; TREATMENT: treatment-name 
 
Site  Subject Timepoint 
Done?  
Date/ Time (Day) 
Data Type 
Data 
XXX 
XX-YYYY 24 Hours  
Yes  
DDMONYYYYTHH:MM (XX) 
Vital Signs 
2 = <=20% of 
preoperative value 
 
 
 
 
 
Ambulation 
2 = Steady gait/no 
dizziness 
 
 
 
 
 
Nausea/Vomiting 
2 = Minimal 
 
 
 
 
 
Pain 
2 = Minimal 
 
 
 
 
 
Surgical Bleeding 
2 = Minimal 
 
 
 
 
 
Score  
10 
 
 
 
 
 
 
 
XXX 
XX-YYYY 48 Hours  
No, XX 
DDMONYYYYTHH:MM (XX) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
  
  
  
  
MPADSS= Modified Post-Anesthesia Discharge Scoring System; 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
Note to programmer: If Not Done is checked then text should read ‘Not Done: reason-text’.  
 
 
 


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Listing 16.2-17: Health Outcomes Assessments- Discharge Disposition – All Subjects 
Cohort: cohort; TREATMENT: treatment-name 
 
Site 
Subject 
Where will the Subject be Discharged? 
XXX 
XX-YYYY 
Home 
XXX 
XX-YYYY 
Home 
XXX 
XX-YYYY 
Home 
XXX 
XX-YYYY 
Home 
  
  
  
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
Program: program_name 
 
Programmer Note: if column “Where will the Subject be Discharged?” is Other, it should read “Other:text”. 
 
 
 
 
 
 
 
 
 


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Listing 16.2-18.1: Phone Call / In Person Visit Day 14 (Pain Visits) - All Subjects 
Cohort: cohort; TREATMENT: treatment-name 
 
Site  Subject  
Completed? 
Phone Call 
or In Person 
Visit? 
Date of Visit 
(Day) 
How Many Times 
Called 
Physician About 
Pain Related to 
Your Surgery? 
Any Unscheduled 
Pain-Related 
Visits Since 
Discharge? 
If Yes, 
Number 
of 
Pain-
related 
Visits 
XXX 
XX-YYYY 
XXX 
XXX 
DDMONYYYY(XX) 
XXX 
XXX 
XXX 
XXX 
XX-YYYY 
XXX 
XXX 
DDMONYYYY(XX) 
XXX 
XXX 
XXX 
XXX 
XX-YYYY 
XXX 
XXX 
DDMONYYYY(XX) 
XXX 
XXX 
XXX 
XXX 
XX-YYYY 
XXX 
XXX 
DDMONYYYY(XX) 
XXX 
XXX 
XXX 
XXX 
XX-YYYY 
XXX 
XXX 
DDMONYYYY(XX) 
XXX 
XXX 
XXX 
 
 
 
 
 
 
 
 
  
  
  
  
  
  
  
  
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
Program: program_name 
Note to programmer: If Was Day 14 Visit Completed? is ‘No’ then text should read ‘No: reason-text’.  
 
 
 
 
 


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Listing 16.2-18.2: Phone Call / In Person Visit Day 14 (Medication)- All Subjects 
Cohort: cohort; TREATMENT: treatment-name 
 
Site  Subject  
Completed? Phone Call or In 
Person Visit? 
Date of Visit 
(Day) 
Any Requests for 
Refills for Opioid 
Medication? 
If Yes, Number of 
Refill Requests 
XXX 
XX-YYYY 
XXX 
XXX 
DDMONYYYY(XX) 
XXX 
XXX 
XXX 
XX-YYYY 
XXX 
XXX 
DDMONYYYY(XX) 
XXX 
XXX 
XXX 
XX-YYYY 
XXX 
XXX 
DDMONYYYY(XX) 
XXX 
XXX 
XXX 
XX-YYYY 
XXX 
XXX 
DDMONYYYY(XX) 
XXX 
XXX 
XXX 
XX-YYYY 
XXX 
XXX 
DDMONYYYY(XX) 
XXX 
XXX 
  
  
  
  
  
  
  
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
Note to programmer: If Was Day 14 Visit Completed? is ‘No’ then text should read ‘No: reason-text’.  
 
 
 
 


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Listing 16.2-19.1: Phone Call / In Person Visit Day 30 (Pain Visits) - All Subjects 
Cohort: cohort; TREATMENT: treatment-name 
 
Site  
Subject  
Was Phone 
Call Made to 
the Subject? 
Date of Phone 
Contact (Day) 
Any Hospital/ 
Facility 
Readmissions 
Since 
Discharge? 
(Number) 
If Yes, Of the 
Total 
Readmissions, How 
Many Were Related 
to Pain 
Any ED Visits 
Since Subject 
Discharge? 
(Number)  
  
  
  
  
XXX 
XX-YYYY 
XXX 
DDMONYYYY (XX) 
XXX (xx) 
XXX 
XXX (xx) 
XXX 
XX-YYYY 
XXX 
DDMONYYYY (XX) 
XXX (xx) 
XXX 
XXX (xx) 
XXX 
XX-YYYY 
XXX 
DDMONYYYY (XX) 
XXX (xx) 
XXX 
XXX (xx) 
XXX 
XX-YYYY 
XXX 
DDMONYYYY (XX) 
XXX (xx) 
XXX 
XXX (xx) 
XXX 
XX-YYYY 
XXX 
DDMONYYYY (XX) 
XXX (xx) 
XXX 
XXX (xx) 
  
  
  
  
  
  
  
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
Program: program_name 
Note to programmer: If Was Day 30 Visit Completed? is ‘No’ then text should read ‘No: reason-text’.  
 
 
 
 


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Listing 16.2-19.2: Phone Call / In Person Visit Day 30 (Medications) - All Subjects 
Cohort: cohort; TREATMENT: treatment-name 
 
Site  
Subject  
Was Phone Call Made to the 
Subject? 
Date of Phone Contact (Day) 
Currently Taking 
Opioid 
Medications? 
  
  
XXX 
XX-YYYY 
XXX 
DDMONYYYY (XX) 
XXX 
XXX 
XX-YYYY 
XXX 
DDMONYYYY (XX) 
XXX 
XXX 
XX-YYYY 
XXX 
DDMONYYYY (XX) 
XXX 
XXX 
XX-YYYY 
XXX 
DDMONYYYY (XX) 
XXX 
XXX 
XX-YYYY 
XXX 
DDMONYYYY (XX) 
XXX 
  
  
  
  
  
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
Program: program_name 
Note to programmer: If Was Day 30 Visit Completed? is ‘No’ then text should read ‘No: reason-text’.  
 
 
 
 


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Listing 16.2-20.1: Multimodal Pain Medication – Pre-Operative – All Subjects 
Cohort: cohort; TREATMENT: treatment-name 
 
Site 
Subject 
Medication 
Was Medication 
Taken? 
Date/ Time (Day) 
Dose (units) 
Route 
XXX 
XX-YYYY 
Tylenol (PO) 
XXX 
DDMONYYYYTHH:MM (XX) 
XX(XXXX) 
XX 
Gabapentin (PO) 
XXX 
DDMONYYYYTHH:MM (XX) 
XX(XXXX) 
XX 
Robaxin (PO) 
XXX 
DDMONYYYYTHH:MM (XX) 
XX(XXXX) 
XX 
Pregabalin (PO) 
XXX 
DDMONYYYYTHH:MM (XX) 
XX(XXXX) 
XX 
  
  
  
  
  
  
  
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
Program: program_name 
 
Note to programmer: If Mediciation is not taken then text should read ‘No: reason-text’.  
 
 


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Listing 16.2-20.2: Multimodal Pain Medication – Post-Operative – All Subjects 
Cohort: cohort; TREATMENT: treatment-name 
 
Site 
Subject 
Medication 
Was Medication 
Taken? 
Date/ Time (Day) 
Dose (units) 
Route 
XXX 
XX-YYYY 
Tylenol (PO) 
XXX 
DDMONYYYYTHH:MM (XX) 
XX(XXXX) 
XX 
Gabapentin (PO) 
XXX 
DDMONYYYYTHH:MM (XX) 
XX(XXXX) 
XX 
Robaxin (PO) 
XXX 
DDMONYYYYTHH:MM (XX) 
XX(XXXX) 
XX 
Pregabalin (PO) 
XXX 
DDMONYYYYTHH:MM (XX) 
XX(XXXX) 
XX 
  
  
  
  
  
  
  
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
Program: program_name 
 
Note to programmer: If Mediciation is not taken then text should read ‘No: reason-text’.  
 
 
 
 
 
 
 
 


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Listing 16.2-20.3: Intraoperative Medications – All Subjects 
Cohort: cohort; Treatment: treatment-name 
 
Site  
Subject 
 
Data Type 
Data 
XXX 
XX-YYYY 
 
Start Date/ Time 
DDMONYYYYTHH:MM 
 
 
 
End Date/ Time 
DDMONYYYYTHH:MM 
 
 
 
Medication Number 
X 
 
 
 
ATC Level 1 
XXXXXXXXXXXXXXXXXX 
 
 
 
  ATC Level 2 
  XXXXXXXXXXXXXXXXXXXX 
 
 
 
    ATC Level 3 
    XXXXXXXXXXXXXXXXXXXXXX 
 
 
 
      ATC Level 4 
      XXXXXXXXXXXXXXXXXXXX 
 
 
 
  Preferred Name 
XXXXXXXXXXXXXXXXXXXXX 
 
 
 
    Verbatim 
  XXXXXXXXXXXXXXXXXXXX 
 
 
 
Dose 
XXXXXXXX 
 
 
 
Unit 
XXXXXXXX 
 
 
 
Route 
XXXXXXXX 
 
 
 
Associated AE # 
XXX AE # XX, XX 
 
 
 
 
 
 
ATC=Anatomical therapeutic class 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
Program: program_name 
 
Note to programmer: If medication has unknown end time, put ‘Unknown’ after date in End row. Do not split a 
medication across pages. The AE number should correspond SDTM.AE.AESEQ  
 
 


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Listing 16.2-20.4: Prescription Daily Pain Medications – All Subjects 
Cohort: cohort; Treatment: treatment-name 
 
Site  
Subject 
 
Data Type 
Data 
XXX 
XX-YYYY 
 
Start Date/ Time 
DDMONYYYYTHH:MM 
 
 
 
Medication Number 
X 
 
 
 
ATC Level 1 
XXXXXXXXXXXXXXXXXX 
 
 
 
  ATC Level 2 
  XXXXXXXXXXXXXXXXXXXX 
 
 
 
    ATC Level 3 
    XXXXXXXXXXXXXXXXXXXXXX 
 
 
 
      ATC Level 4 
      XXXXXXXXXXXXXXXXXXXX 
 
 
 
  Preferred Name 
XXXXXXXXXXXXXXXXXXXXX 
 
 
 
    Verbatim 
  XXXXXXXXXXXXXXXXXXXX 
 
 
 
Dose 
XXXXXXXX 
 
 
 
Unit 
XXXXXXXX 
 
 
 
Route 
XXXXXXXX 
 
 
 
 
 
 
 
 
 
 
ATC=Anatomical therapeutic class 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
Program: program_name 
 
Note to programmer: If medication has unknown end time, put ‘Unknown’ after date in End row. Do not split a 
medication across pages. If Unit or Route is ‘Other’, text should read ‘Other: specify-text’. Insert a page 
break between subjects.  
 
 


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Listing 16.2-20.5: Rescue Medication – All Subjects 
Cohort: cohort; TREATMENT: treatment-name 
 
Site 
Subject 
Medication 
Date/ Time (Day) 
Dose (unit) 
Route 
XXX 
XX-YYYY 
XXXXXXXXXXXX 
DDMONYYYYTHH:MM (XX) 
XX(mg) 
XXXXXXX 
XXXXXXXXXXXX 
DDMONYYYYTHH:MM (XX) 
XX(mg) 
XXXXXXX 
XXXXXXXXXXXX 
DDMONYYYYTHH:MM (XX) 
XX(mg) 
XXXXXXX 
XXXXXXXXXXXX 
DDMONYYYYTHH:MM (XX) 
XX(mg) 
XXXXXXX 
  
  
  
  
  
  
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
Program: program_name 
 
 
 


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Listing 16.2-20.6: Prior Medications – All Subjects 
Cohort: cohort; Treatment: treatment-name 
 
Site 
Subject 
Reason for 
Use 
Data Type 
Data 
XXX 
XX-YYYY 
XXXXXXXX 
Start Date and Time 
DDMONYYYYTHH:MM 
 
 
 
End Date and Time 
DDMONYYYYTHH:MM 
 
 
 
Medication Number 
X 
 
 
 
ATC Level 1 
XXXXXXXXXXXXXXXXXX 
 
 
 
  ATC Level 2 
  XXXXXXXXXXXXXXXXXXXX 
 
 
 
    ATC Level 3 
    XXXXXXXXXXXXXXXXXXXXXX 
 
 
 
      ATC Level 4 
      XXXXXXXXXXXXXXXXXXXX 
 
 
 
  Preferred Name 
XXXXXXXXXXXXXXXXXXXXX 
 
 
 
    Verbatim 
  XXXXXXXXXXXXXXXXXXXX 
 
 
 
Dose (Unit) 
XXXXXXXX (XXXXXXXX) 
 
 
 
Route 
XXXXXXXX 
 
 
 
Frequency 
XXXXXXXX 
 
 
 
Given for AE or MH? 
XXXXXXXXXXXXXXXX AE # XX (or MH # XX) 
ATC=Anatomical therapeutic class 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
Program: program_name 
 
Programmer Note: AE and MH number should correspond to AESEQ and MHSEQ 
 
 
 
 


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Listing 16.2-20.7: Concomitant Medications – All Subjects 
Cohort: cohort; Treatment: treatment-name 
 
Site 
Subject 
Reason for 
Use 
Data Type 
Data 
XXX 
XX-YYYY 
XXXXXXXX 
Start Date and Time 
DDMONYYYYTHH:MM 
 
 
 
End Date and Time 
DDMONYYYYTHH:MM 
 
 
 
Medication Number 
X 
 
 
 
ATC Level 1 
XXXXXXXXXXXXXXXXXX 
 
 
 
  ATC Level 2 
  XXXXXXXXXXXXXXXXXXXX 
 
 
 
    ATC Level 3 
    XXXXXXXXXXXXXXXXXXXXXX 
 
 
 
      ATC Level 4 
      XXXXXXXXXXXXXXXXXXXX 
 
 
 
  Preferred Name 
XXXXXXXXXXXXXXXXXXXXX 
 
 
 
    Verbatim 
  XXXXXXXXXXXXXXXXXXXX 
 
 
 
Dose (Unit) 
XXXXXXXX (XXXXXXXX) 
 
 
 
Route 
XXXXXXXX 
 
 
 
Frequency 
XXXXXXXX 
 
 
 
Given for AE or MH? 
XXXXXXXXXXXXXXXX AE # XX (or MH # XX) 
ATC=Anatomical therapeutic class 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
Program: program_name 
 
 


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Listing 16.2-21: Protocol Deviations – All Subjects 
Cohort: cohort; Treatment: treatment-name 
 
 
Site  
Subject 
Category 
Date and Time 
Description 
 
 
 
 
 
XXX 
XX-YYYY 
XXX 
DDMONYYYYTHH:MM 
XXXXXXXXXXXXXXXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM  
SAS X.Y 
 
Program: program_name 
 
Note to programmer: Subjects may have multiple deviations. Sort deviations by cohort, treatment, center, 
subject. 
 
 


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Listing 16.2-22: 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 version 22.0 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM  
SAS X.Y 
 
Program: program_name 
 
Note to programmer: Sort by SOC and preferred term in alphabetical order.  
 
 
 
 


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Listing 16.2-23: 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 Version March 2019 B3 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM  
SAS X.Y 
 
Program: program_name 
 
Note to programmer: Sort by ATC1, ATC2, ATC3, ATC4 and preferred name in alphabetical order


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