Phase 3, Sciatic Nerve Block With EXPAREL for Subjects Undergoing Bunionectomy

A Phase 3, Randomized, Double-Blind, Active-Controlled, Multicenter Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of EXPAREL vs. Bupivacaine Hydrochloric Acid (HCl) Administered as a Sciatic (in the Popliteal Fossa) Nerve Block for Postsurgical Analgesia in Subjects Undergoing Bunionectomy

The study is conducted sequentially in two parts.

Part A: The purpose is to obtain information on pharmacokinetic (PK) profile, pharmacodynamics (PD), efficacy, safety, and to assess the performance of 266 mg EXPAREL vs 133 mg EXPAREL.

Part B: The purpose is to evaluate the efficacy and safety of the preferred dosage of EXPAREL from Part A compared with bupivacaine HCl.

This is a Phase 3, multicenter, randomized, double-blind, active controlled study in approximately 180 subjects undergoing bunionectomy. The study will be conducted in two parts (Part A and Part B). Part A will be completed and analyzed before enrollment in Part B is initiated.

Subjects may be screened up to 45 days prior to the day of surgery but eligibility must be re-confirmed on the day of surgery prior to randomization.

The following screening procedures will be performed after the informed consent form (ICF) is signed (if not standard of care): assess eligibility, record medical/surgical history, record prior and concomitant medications, record demographics and baseline characteristics, record subject height and weight for body mass index (BMI) calculation, assess chronic opioid use in the past 30 days, conduct urine pregnancy test for women of childbearing potential, perform 12-lead EKG, record serious adverse events (SAEs) starting when the ICF is signed, and record medications for treatment of SAEs.

On Day 1, prior to sciatic nerve block, study staff will review Pain Rating Guide with the subject and record their responses to:

• Numeric rating scale (NRS) score on the worst pain of their operative foot in the last 30 days.
• NRS score on the average pain of their operative foot in the last 30 days.

Part A will enroll approximately 60 subjects undergoing bunionectomy into 1 of 3 arms. They will be randomized 1:1:1 to either EXPAREL 266 mg, EXPAREL 133 mg, or 0.25% bupivacaine HCl (50mg). Part A subjects will be asked to perform sensory function assessments, perform motor function assessments and obtain PK samples. Based on the findings of the interim analysis after completion of Part A, the study may stop for futility or proceed to Part B. Part B is a 2-arm study with 120 subjects being randomized 1:1 to either the better performing dosage of EXPAREL from Part A (266mg or 133mg) or 0.25% bupivacaine HCl (50mg).

All eligible subjects will receive Celecoxib 200 mg, orally (PO) pre-operatively within four hours prior to surgery.

Part A: On Day 1, Subjects will be randomized (1:1:1) to receive a sciatic (in the popliteal fossa) nerve block with a single dose of either: EXPAREL 266 mg, EXPAREL 133 mg, or 0.25% bupivacaine HCl (50 mg).

Part B: will continue enrolling with one of the EXPAREL arms (EXPAREL 266 mg arm or EXPAREL 133 mg arm) and the bupivacaine HCl arm. Therefore, the EXPAREL study arm that fails to show efficacy (conditional power less than 30% in the Part A analysis) will be dropped and the study will continue with two study arms. The final analysis will include subjects from both Part A and Part B.

1. If the conditional power of one EXPAREL arm is less than 30% and the other EXPAREL arm is greater than or equal to 30%:

   • The EXPAREL arm with conditional power less than 30% will be dropped in Part B.

2. If both EXPAREL arms have a conditional power greater than or equal to 30%:

   • If the conditional power of the 266 mg EXPAREL arm is more than 10% greater than the conditional power of the 133 mg EXPAREL arm, then the 266 mg EXPAREL arm will be kept and the 133 mg EXPAREL arm will be dropped. Otherwise, the 133 mg EXPAREL arm will be kept and the 266 mg EXPAREL arm will be dropped in Part B.

3. If the conditional power of both treatment arms is less than 30%:

   • The study will stop for futility

All subjects will receive a dose of 1000 mg of intravenous (IV) acetaminophen at the time of surgical incision. All subjects will receive one post-operative dose of 1000 mg IV acetaminophen, administered approximately 8 hours after the first dose (approximately 8 hours after incision). The maximum total dose will not exceed 2000 mg. No additional acetaminophen is permitted after the second IV acetaminophen dose.

Medications will be administered on an as needed (PRN) basis; opioids should not be given on a predetermined schedule.

After 96 hours, the analgesic regimen may be adjusted for each subject individually as deemed appropriate by the physician responsible for postsurgical care.

NRS Pain intensity scores (for pain experiencing in operative foot right now, for the worst pain experienced in the operative foot in the last 24 hours, and for the average pain in the operative foot in the last 24 hours) will be asked from the end of surgery to 96 hours post-surgery at designated timepoints.

Subjects in Part A and Part B will be discharged after the completion of the 168h and 96h assessments, respectively.

For the assessment of adverse events (AEs), SAEs, and concomitant medication use, a follow-up phone call will be made on Post Surgery Day (POD) 14 (±3 days).

Inclusion Criteria:

1. Male or female, ages 18 or older at screening
2. American Society of Anesthesiologists (ASA) physical status 1, 2, or 3
3. Able to provide informed consent, adhere to the study schedule, and complete all study assessments
4. Primary surgical indication is related to a bunion deformity (i.e., hallux valgus) and subject is scheduled to undergo a distal metaphyseal osteotomy procedure (e.g., Austin procedure as opposed to Lapiplasty, Lapidus bunionectomies or base wedge bunionectomies)
5. Indicated to undergo elective (i.e., not emergency) bunionectomy
6. Body Mass Index (BMI) ≥18 and <40 kg/m2

Exclusion Criteria:

1. Allergy, hypersensitivity, intolerance, or contraindication to any of the study medications for which an alternative is not named in the protocol (e.g., amide-type local anesthetics, opioids, bupivacaine HCl, NSAIDs)
2. Concurrent painful physical condition (e.g. arthritis, fibromyalgia, cancer) that may require analgesic treatment with NSAIDs or opioids in the post dosing period for pain that is not strictly related to the foot surgery and which, in the Investigator's opinion, may confound the post dosing assessments
3. Inadequate sensory function of the foot/ankle as assessed by the Investigator
4. History of, suspected, or known addiction to or abuse of illicit drug(s), prescription medicine(s), or alcohol within the past 2 years
5. 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
6. Previous participation in an EXPAREL study
7. Uncontrolled anxiety, schizophrenia, or other psychiatric disorder that, in the opinion of the Investigator, could interfere with study assessments or compliance
8. Currently pregnant, nursing, or planning to become pregnant during the study
9. Clinically significant medical disease that, in the opinion of the Investigator, would make participation in a clinical study inappropriate. This includes diabetic neuropathy, coagulation or bleeding disorders, severe peripheral vascular disease, renal insufficiency, hepatic dysfunction or other conditions that would constitute a contraindication to participation in the study
10. Currently on a neuromodulating agent (e.g., gabapentin, pregabalin [Lyrica], duloxetine [Cymbalta], etc.)
11. Current use of systemic glucocorticoids within 30 days of randomization in this study
12. Use of dexmedetomidine HCl (Precedex®) or clonidine within 3 days of study drug administration
13. Any use of marijuana (including tetrahydrocannabinol (THC) and cannabidiol (CBD)) within 30 days prior to randomization, or planned use during the course of the study
14. Chronic opioid use within 30 days prior to randomization (average ≥30 oral morphine equivalents/day)