Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of EXPAREL, EXPAREL Admixed With Bupivacaine HCl vs. Bupivacaine HCl Administered as Combined Sciatic and Saphenous Nerve Blocks for Postsurgical Analgesia in Subjects Undergoing Lower Extremity Surgeries

Study Overview
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Brief Summary
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This is a Phase 3, multicenter, randomized, double blinded, active controlled study in approximately 120 subjects undergoing lower extremity surgeries.

Official Title
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A Phase 3, Randomized, Double Blinded, Active Controlled, Multicenter Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of EXPAREL, EXPAREL Admixed With Bupivacaine HCl vs. Bupivacaine HCl Administered as Combined Sciatic (in Popliteal Fossa) and Saphenous (in Adductor Canal) Nerve Blocks for Postsurgical Analgesia in Subjects Undergoing Lower Extremity Surgeries

Conditions
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Lower Extremity Surgery, Bunion, Metatarsophalangeal Fushion, Midfoot Fusion, Hindfoot Fushion, Total Ankle Arthroplasty

Intervention / Treatment
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* Drug: Exparel
* Drug: Bupivacaine Hydrochloride


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy adult male or female volunteers ages 18 or older American Society of Anesthesiologists (ASA) physical status 1, 2, or 3 Able to provide informed consent, adhere to the study schedule, and complete all study assessments Body Mass Index (BMI) ≥18 and ≤40 kg/m2 Exclusion Criteria: 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, nonsteroidal anti-inflammatory drugs [NSAIDs]) Concurrent painful physical condition that may require analgesic treatment (such as long-term, consistent use of opioids) in the post dosing period for pain and which, in the investigator's opinion, may confound the post dosing assessments History of, suspected, or known addiction to or abuse of illicit drug(s), prescription medicine(s), or alcohol within the past 2 years 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 Previous participation in an EXPAREL study Uncontrolled anxiety, schizophrenia, or other psychiatric disorder that, in the opinion of the investigator, could interfere with study assessments or compliance Currently pregnant, nursing, or planning to become pregnant during the study 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. Currently on a neuromodulating agent neuroleptic agent (e.g., gabapentin, pregabalin [Lyrica], duloxetine [Cymbalta], etc.) Inadequate sensory function on the foot (monofilament test) Chronic opioid use within 30 days prior to randomization (average ≥30 oral morphine equivalents/day)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: EXPAREL arm<br>Subjects randomized to this treatment arm will receive 20 mL (266 mg)EXPAREL mixed with 20 mL saline | Drug: Exparel<br>* EXPAREL (bupivacaine liposome injectable suspension)<br>|
| Experimental: EXPAREL admix arm<br>subjects randomized to this treatment arm will receive 20 mL (266 mg)EXPAREL admixed with 20 mL (50 mg) 0.25% bupivacaine HCl. | Drug: Exparel<br>* EXPAREL (bupivacaine liposome injectable suspension)<br>Drug: Bupivacaine Hydrochloride<br>* 0.25% bupivacaine<br>|
| Active Comparator: Bupivacaine HCl Arm<br>subjects randomized to this treatment arm will receive 40 mL (100 mg)0.25% bupivacaine HCl. | Drug: Bupivacaine Hydrochloride<br>* 0.25% bupivacaine<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Magnitude of the Analgesic Effect (NRS Pain Intensity) (AUC) | To compare the magnitude of the analgesic effect (NRS pain intensity scores) following a single dose injection of EXPAREL vs. bupivacaine hydrochloride (HCl) when administered as combined sciatic (in the popliteal fossa) and saphenous (in the adductor canal) nerve blocks in subjects undergoing lower extremity surgeries. Numerical Rating Scale: an 11 point scale 0=no pain, 10= the worst pain imaginable. The area under the curve (AUC) of the NRS pain intensity scores from 0 to 96 hours post-surgery comparing EXPAREL to 0.25% bupivacaine HCl | Post surgery - 96 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Opioid Consumption | Total Opioid Consumption in oral morphine equivalents | 0 hours to 96 hours | 
| Time to First Opioid | Time to First Opioid following a single dose of EXPAREL vs. Bupivacain HCl | Post Surgery through Day 14 |