Local Infiltration Analgesia With and Without EXPAREL Following Total Knee Arthroplasty

Study Overview
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Brief Summary
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This is a Phase 4, multicenter, randomized, double-blind, controlled trial in approximately 140 adult subjects undergoing primary unilateral TKA under spinal anesthesia with bupivacaine HCl (10-15 mg).

Detailed Description
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On Day 0, eligible subjects will be randomized 1:1 to two treatment groups. Subjects in Group 1 will receive local infiltration analgesia (LIA) with EXPAREL 266 mg in 20 mL admixed with bupivacaine hydrochloride (HCl) 0.5% in 20 mL and expanded in volume with 80 mL normal saline (total volume of 120 mL). Subjects in Group 2 will receive LIA with bupivacaine HCl 0.5% in 20 mL expanded in volume with 100 mL normal saline (total volume of 120 mL). Investigators will use their usual surgical technique to perform the TKA. Study drug will be administered using six 20 cc syringes with 22-gauge needles prior to wound closure. Each stick should deliver approximately 1-1.5 cc to the intended area. The tissue should visibly expand with minimal leakage. Study drug should be injected in the prescribed locations based on the areas of highest nerve density. Infiltration Technique Prior to cementation Syringe #1: Posterior capsule (8-10 sticks medial and 8-10 sticks lateral). Syringe #2: Femur medial and lateral periosteum, posterior periosteum, suprapatellar/quadriceps tendon (20 sticks). Syringe #3: Tibia fat pad (5 sticks); pes anserinus, medial collateral ligament, and gutter (15 sticks). Syringe #4: Circumferential periosteum (15-20 sticks). After cementation Syringe #5: Midline quadriceps tendon (10 sticks); retinaculum, medial gutter, femoral to tibia (10 sticks). Syringe #6: Lateral gutter, femoral to tibial (10 sticks); subcutaneous/closure (10 sticks). In addition to LIA, all study participants will receive a standardized approach for managing postsurgical pain that includes a scheduled multimodal pain regimen including adjunctive analgesics, non-steroidal anti-inflammatory drugs (NSAIDs), and rescue analgesics as needed. Postsurgical clinical assessments will include pain intensity scores using a 10-cm visual analog scale (VAS); overall benefit of analgesia score (OBAS) questionnaire; total postsurgical opioid consumption; physical therapy assessment; nurse's satisfaction with overall analgesia; and discharge readiness. Adverse events (AEs) will be recorded from the time the informed consent form is signed through postsurgical Day 29. Postsurgical health economic outcome assessments will include hospital length of stay (LOS), use of skilled nursing facility, outpatient physical therapy use, hospital readmissions, and use of other health services following discharge (phone calls related to postsurgical pain, unscheduled visits related to postsurgical pain, and visits to emergency department) through postsurgical Day 29. A follow-up visit will be scheduled for all subjects on postsurgical Day 14. A follow-up phone call will be made on postsurgical Day 29 to all subjects who received study drug to assess for AEs.

Official Title
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A Multicenter, Randomized, Double-Blind, Controlled Trial Comparing Local Infiltration Analgesia With EXPAREL to Local Infiltration Analgesia Without EXPAREL to Manage Postsurgical Pain Following Total Knee Arthroplasty

Conditions
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Pain

Intervention / Treatment
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* Drug: EXPAREL
* Drug: Bupivacaine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, at least 18 years of age at screening. Scheduled to undergo primary, unilateral, tricompartmental TKA under spinal anesthesia. Primary indication for TKA is degenerative osteoarthritis of the knee. American Society of Anesthesiologists (ASA) physical status 1, 2, or 3. Female subjects must be surgically sterile; or at least 2 years postmenopausal; or have a monogamous partner who is surgically sterile; or practicing double-barrier contraception; or practicing abstinence (must agree to use double-barrier contraception in the event of sexual activity); or using an insertable, injectable, transdermal, or combination oral contraceptive approved by the FDA for greater than 2 months prior to screening and commit to the use of an acceptable form of birth control for the duration of the study and for 30 days after completion of the study. Able to provide informed consent, adhere to the study visit schedule, and complete all study assessments. Exclusion Criteria: Currently pregnant, nursing, or planning to become pregnant during the study or within 1 month after study drug administration. History of previous prior contralateral TKA or open knee surgery on the knee being considered for TKA. Prior arthroscopy is permitted. Planned concurrent surgical procedure (e.g., bilateral TKA). Undergoing unicompartmental TKA or revision TKA. Concurrent painful physical condition that may require analgesic treatment (such as an NSAID or opioid) in the postsurgical period for pain that is not strictly related to the knee surgery and which may confound the postsurgical assessments (e.g., significant pain from other joints including the non-index knee joint, chronic neuropathic pain, concurrent or prior contralateral TKA, concurrent foot surgery). Comorbidity impacting current physical function of Investigator opinion that it may impact postsurgical rehabilitation. Allergy, hypersensitivity, or contraindication to any of the study medications (i.e., bupivacaine, pregabalin, acetaminophen/paracetamol, celecoxib, oxycodone, morphine, hydromorphone, or tranexamic acid). Use of any of the following medications within the times specified before surgery: long-acting opioid medication or NSAIDs (except for low-dose aspirin used for cardioprotection) within 3 days, or any opioid medication within 24 hours. Initiation of treatment with any of the following medications within 1 month of study drug administration or if the medication(s) are being given to control pain: selective serotonin reuptake inhibitors (SSRIs), selective norepinephrine reuptake inhibitors (SNRIs), gabapentin, pregabalin (Lyrica®), or duloxetine (Cymbalta®). If a subject is taking one of these medications for a reason other than pain control, he or she must be on a stable dose for at least 1 month prior to study drug administration. Current use of systemic glucocorticosteroids within 1 month of enrollment in this study. Use of dexmedetomidine HCl (Precedex®) within 3 days of study drug administration. History of coronary or vascular stent placed within the past 3 months (may be extended to 1 year if medically indicated per physician discretion). Have been treated for a deep vein thrombosis, pulmonary embolism, myocardial infarction, or ischemic stroke within the past 6 months (may be extended to 1 year if medically indicated per physician discretion). Rheumatoid or inflammatory arthritis or disease. Severely impaired renal or hepatic function (e.g., 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.) Any neurologic or psychiatric disorder that might impact postsurgical pain or interfere with study assessments. Malignancy in the last 2 years, per physician discretion. History of misuse, abuse, or dependence on opioid analgesics, other prescription drugs, illicit drugs, or alcohol. Failure to pass the alcohol breath test or urine drug screen. Body weight <50 kg (110 pounds) or a body mass index >40 kg/m2. Previous participation in an EXPAREL study. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: EXPAREL<br>Single dose of EXPAREL 266 mg in 20 mL admixed with bupivacaine HCl 0.5% in 20 mL and expanded in volume with 80 mL normal saline (total volume of 120 mL). | Drug: EXPAREL<br>* EXPAREL and bupivacaine HCl<br>* Other names: bupivacaine liposome injectable suspension;|
| Active Comparator: Bupivacaine<br>Bupivacaine HCl 0.5% in 20 mL expanded in volume with 100 mL normal saline (total volume of 120 mL). | Drug: Bupivacaine<br>* Single dose of bupivacaine HCl 0.5%<br>* Other names: bupivacaine HCl;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under The Curve (AUC) of Visual Analog Scale (VAS) Pain Intensity Scores From 12 to 48 Hours | AUC of VAS pain intensity scores from 12 to 48 hours, which represents total pain experienced from 12 to 48 hours. Visual Analog Scale (VAS) is a pain scale. The VAS was presented as a straight 10 cm line, where 0 cm is no pain and 10 cm is the worst pain possible. Patients were asked, How much pain are you experiencing right now? Please place a vertical mark on the line below to indicate the level of pain you are experiencing right now. | From 12-48 hours | 
| Total Postsurgical Opioid Consumption Through 48 Hours | Total postsurgical opioid consumption (converted to oral morphine equivalents) through 48 hours | 0-48 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Opioid-free Subjects at 48 Hours |  | 48 hours | 
| Time to First Opioid Rescue in the First 48 Hours | Time to first opioid rescue was estimated from Kaplan-Meier analysis and presented as quartiles (ie, time to rescue for the first 25% / 50% / 75% of subjects within each treatment group). | 48 hours | 
| Overall Benefit of Analgesia Score at 48 Hours | The overall benefit of analgesic score (OBAS) comprises seven questions to assess pain intensity, adverse effects, and patients' satisfaction with analgesia (eg, Please rate your current pain at rest on a scale between 0=minimal pain and 4=maximum imaginable pain). Overall scores ranged between 0- 28. OBAS measures patients' benefit from postoperative pain therapy. A lower composite score indicates greater benefit from the therapy. | 48 hours |