Evaluate the Safety and Efficacy of EXPAREL When Administered Via Infiltration Into the TAP vs. Bupivacaine Alone in Subjects Undergoing Elective C-Sections

Conditions:Chronic Pain
Therapuetic Areas:Musculoskeletal
Age Range:18 - Any
Start Date:June 1, 2017
End Date:November 30, 2018
Contact:Hassan Danesi, MD

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A Multicenter, Randomized, Double-blind, Active-controlled Study to Evaluate the Safety and Efficacy of EXPAREL When Administered Via Infiltration Into the Transversus Abdominis Plane (TAP) Versus Bupivacaine Alone in Subjects Undergoing Elective Cesarean Section

Primary objective: The primary objective of this study is to compare total opioid consumption
through 72 hours following EXPAREL+bupivacaine HCl infiltration into the transversus
abdominis plane (TAP) after spinal anesthesia to active bupivacaine HCl TAP infiltration
after spinal anesthesia in subjects undergoing an elective cesarean section (C-section).

Secondary objective: The secondary objectives are to assess efficacy and safety parameters
and patient satisfaction.

This is a Phase-4, multicenter, randomized, double-blind, active-controlled study in
approximately 152 adult subjects undergoing elective C-section. All subjects will remain in
the hospital for up to 72 hours postsurgery.


Subjects will be screened within 7 days prior to surgery; screening on the day of surgery
will be allowed but is discouraged. During the screening visit, subjects will be assessed for
any past or present medical conditions that in the opinion of the investigator would preclude
them from study participation. After the informed consent form (ICF) is signed, a medical
history, surgical history, physical examination, 12-lead electrocardiogram (ECG), vital sign
measurements, alcohol breath test and urine drug screen, and clinical laboratory tests
(hematology and chemistry) will be performed.

Day of Surgery:

Pre-operative medications: Use of pre-operative analgesics (eg, opioid medications,
acetaminophen, nonsteroidal anti-inflammatory drugs [NSAIDs]) is prohibited.

Eligible subjects will be randomized in a blinded 1:1 ratio to either:

- Group 1: EXPAREL+bupivacaine TAP infiltration following spinal anesthesia

- Group 2: Active bupivacaine HCl TAP infiltration following spinal anesthesia On Day 1,
prior to the C-section, all subjects will receive an intrathecal injection of 150 mcg
morphine (eg, Duramorph®) as standard of care in conjunction with single-shot spinal
anesthesia (1.4-1.6 mL bupivacaine HCl 0.75%) plus 15 mcg intrathecal fentanyl. A
combined spinal epidural (CSE) anesthesia technique may also be used provided the
epidural component is not used.

Intraoperative medications: The intraoperative use of the following medications is
discouraged, but may be permitted if clinically indicated based on the investigator's
discretion (all medications must be appropriately recorded [ie, drug, dose, and route of
administration]): ketamine and midazolam (Versed®). Prophylactic use of dexamethasone for
prevention of nausea and vomiting is prohibited.

After delivery of the baby and prior to the TAP infiltration, a small amount of lidocaine (<2
mL) may be administered subcutaneously to form a skin wheal over the area of the needle
insertion site. A 2-point classic TAP block will be performed under ultrasound guidance
within 1 hour (± 30 minutes) following skin incision closure of the C-section. A confirmatory
ultrasound picture or video will be taken of each side of the abdomen after the TAP needle
position has been established and following infiltration of study drug.

TAP infiltration: Subjects randomized to the EXPAREL+bupivacaine group (Group 1) will receive
a single 20-mL dose of EXPAREL 266 mg expanded in volume with 20 mL normal saline plus 20 mL
0.25% bupivacaine for a total volume of 60 mL, administered as 30 mL (10 mL EXPAREL, 10 mL
0.25% bupivacaine HCl, and 10 mL saline) on each side of the abdomen. Subjects randomized to
the active bupivacaine group (Group 2) will receive 20 mL 0.25% bupivacaine expanded in
volume with 40 mL normal saline for a total volume of 60 mL, administered as 30 mL (10 mL
0.25% bupivacaine HCl and 20 mL saline) on each side of the abdomen.

Postsurgical Analgesia: Patient-controlled analgesia is not permitted. The following
multimodal pain regimen will be initiated immediately following the delivery of the baby:

- IV ketorolac 15 mg once at the time of skin incision closure and prior to the TAP

- Intravenous (IV) acetaminophen 1000 mg at the time of skin incision closure

- Scheduled oral (PO) acetaminophen 650 mg at the end of surgery and every 6 hours (q6h)
for up to 72 hours

- Scheduled PO ibuprofen 600 mg at the end of surgery and q6h for up to 72 hours The date,
time, and dose of all standardized multimodal pain medications administered must be
recorded. Note: The scheduled PO medication will be administered on a q6h schedule only
through hospital discharge.

Rescue Medication: Subjects should only receive opioid rescue pain medication upon request
for breakthrough pain. Postsurgical rescue medication will comprise PO immediate-release
oxycodone (initiated at 5-10 mg every 4 hours [q4h] or as needed [PRN]). If a subject is
unable to tolerate PO medication or fails the PO oxycodone rescue, IV morphine (initiated at
1-2 mg) or hydromorphone (initiated at 0.3-0.5 mg) may be administered q4h or PRN. All
surgical and postsurgical opioid and other analgesics (pain medications) administered must be
documented through Day 14 postsurgery. Additionally, an unscheduled pain intensity score
using a 10-cm visual analog scale (VAS) must be completed immediately prior to any rescue
medication while in the hospital.

Permitted medications for the prevention and treatment of possible medication side effects
include the following and may be used at the discretion of the study site principal

- Ondansetron 4 mg IV immediately after delivery of the baby.

- Ondansetron 4 mg IV (should not exceed a maximum of 12 mg in a 24-hour period) for
intraoperative and postoperative nausea and vomiting

- Metoclopramide 10 mg PO PRN for nausea and vomiting

- Nalbuphine IV 2.5 mg PRN for pruritus

- Naloxone IV 50-100 mcg PRN for pruritus.

Postsurgical Assessments:

Subjects will remain in the hospital for up to 72 hours postsurgery. Postsurgical assessments
will include:

- Opioid use

- Time of first unassisted ambulation

- Pain intensity scores using a 10-cm VAS at rest

- Discharge readiness

- Subject's satisfaction with postsurgical pain control

- Overall benefit of anesthesia score (OBAS) questionnaire

- Quality of recovery 15-item questionnaire (QoR-15)

While in the hospital, subjects will be provided with a Patient Diary and will use the diary
to record all scheduled and unscheduled VAS scores. For all scheduled assessments and
unscheduled assessments in the hospital, subjects will assess, "How much pain are you
experiencing right now" and a vertical mark will be placed on the VAS line to indicate the
level of pain experienced at the time of assessment. If a subject is discharged prior to a
scheduled VAS assessment, a member of the study site staff will telephone the subject to
remind her to complete the scheduled VAS assessment at the scheduled time and to record the
assessment in the Patient Diary.

At hospital discharge, the subject will be instructed to record in the Patient Diary VAS pain
intensity score daily and all pain medications taken following hospital discharge through Day

At home, the subject will assess pain intensity at rest each day at noon (± 4 hours). This
assessment should capture her average pain at rest in the prior 24 hours by assessing "What
has been your average pain since your last pain assessment?" (ie, from noon on the previous
day to the current assessment). At the same time, the subject should record any pain
medication (medication name, date, time, and dose) taken in the prior 24 hours.

A phone call will be made to each subject on Day 14 for safety purposes and to inquire as to
whether the subject has made any unscheduled phone calls or office visits related to pain;
experienced any hospital readmission; or experienced an emergency room visit since hospital
discharge. Adverse events (AEs) and serious adverse events (SAEs) will be recorded from the
time the ICF is signed through Day 14.

Inclusion Criteria:

1. Females 18 years of age and older at screening.

2. Term pregnancies of 37 to 42 weeks gestation, scheduled to undergo elective C-section.

3. American Society of Anesthesiology (ASA) physical status 1, 2, or 3.

4. Able to provide informed consent, adhere to the study visit schedule, and complete all
study assessments.

Exclusion Criteria:

1. Subjects who, in the opinion of the study site principal investigator, have a
high-risk pregnancy (eg, multiple gestations, pregnancy resulting from in vitro
fertilization, gestational diabetes, end-term prolonged bed rest required for medical

2. Subjects with a pregnancy-induced medical condition or complication (eg, hypertension,
pre-eclampsia, chorioamnionitis).

3. Subjects with 3 or more prior C-sections.

4. Pre-pregnancy body mass index >50 kg/m2 or otherwise not anatomically appropriate to
undergo a TAP block.

5. Allergy, hypersensitivity, intolerance, or contraindication to any of the study
medications for which an alternative is not named in the protocol (eg, amide-type
local anesthetics, opioids, bupivacaine, NSAIDs, spinal anesthesia).

6. Planned concurrent surgical procedure with the exception of salpingo-oophorectomy or
tubal ligation.

7. Severely impaired renal or hepatic function (eg, serum creatinine level >2 mg/dL
[176.8 μmol/L], blood urea nitrogen level >50 mg/dL [17.9 mmol/L], serum aspartate
aminotransferase [AST] level >3 times the upper limit of normal [ULN], or serum
alanine aminotransferase [ALT] level >3 times the ULN.)

8. Subjects at an increased risk for bleeding or a coagulation disorder (defined as
platelet count less than 80,000 × 103/mm3 or international normalized ratio greater
than 1.5)

9. Concurrent painful physical condition that may require analgesic treatment (such as
long-term, consistent use of opioids) in the postsurgical period for pain that is not
strictly related to the surgery and which may confound the postsurgical assessments.

10. Clinically significant medical disease in either the mother or baby that, in the
opinion of the investigator, would make participation in a clinical study
inappropriate. This includes any psychiatric or other disease in the mother that would
constitute a contraindication to participation in the study or cause the mother to be
unable to comply with the study requirements.

11. History of, suspected, or known addiction to or abuse of illicit drug(s), prescription
medicine(s), or alcohol within the past 2 years.

12. Administration of an investigational drug within 30 days or 5 elimination half-lives
of such investigational drug, whichever is longer, prior to study drug administration,
or planned administration of another investigational product or procedure during the
subject's participation in this study

13. Previous participation in an EXPAREL study.

In addition, the subject will be ineligible to receive study drug and will be
withdrawn from the study if she meets the following criterion during surgery:

14. Any clinically significant event or condition uncovered during the surgery (eg,
excessive bleeding, acute sepsis) that might render the subject medically unstable or
complicate the subject's postsurgical course.
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