Femoral Nerve Block With Liposome Bupivacaine for Postsurgical Analgesia Following Total Knee Arthroplasty

A Multicenter, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled, Dose Ranging Study to Evaluate the Safety, Efficacy, and Pharmacokinetics of Single Injection Femoral Nerve Block With Liposome Bupivacaine for Postsurgical Analgesia in Subjects Undergoing Total Knee Arthroplasty

The primary objectives of Part 1 are to (1) evaluate three dose levels of liposome bupivacaine versus placebo with respect to the magnitude and duration of the analgesic effect achieved following single dose injection femoral nerve block with liposome bupivacaine, and (2) select a single therapeutic dose of liposome bupivacaine from the three dose levels to be tested in Part 2.

Part 2: The primary objective of Part 2 is to compare the magnitude and duration of the analgesic effect of single injection femoral nerve block of a single dose level of liposome bupivacaine (selected from Part 1) with placebo (preservative-free normal saline).

Study Overview

• Status: Completed
• Conditions: Postoperative Pain
• Intervention / Treatment: Drug: EXPAREL 67 mg; Drug: EXPAREL 133 mg; Drug: EXPAREL 266 mg; Drug: Placebo

Detailed Description

This is a Phase 2/3, multicenter, randomized, double-blind, parallel-group, placebo-controlled, dose-ranging study in subjects undergoing primary unilateral total knee arthroplasty (TKA) under general or spinal anesthesia. Note: Bupivacaine cannot be used as the spinal anesthetic.

Part 1 During Part 1 of the study, approximately 100 subjects (25 per treatment arm) will be randomized to receive a single dose injection femoral nerve block with either one of three doses of liposome bupivacaine (67, 133, or 266 mg) or placebo in 20 mL under ultrasound guidance. Preservative-free normal saline will be added to the 67 mg and 133 mg doses of study drug to achieve a volume of 20 mL.

Part 2 In Part 2 of the study, approximately 180 subjects (randomized 1:1, resulting in approximately 90 liposome bupivacaine subjects and 90 placebo subjects) will receive a single dose injection femoral nerve block with the selected dose level of liposome bupivacaine (i.e., 67, 133, or 266 mg) or placebo in 20 mL under ultrasound guidance.

• Study Type: Interventional
• Enrollment (Actual): 297
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35216
      • ACHIEVE CLINICAL RESEARCH LLC 2017 Canyon Road Suite 41
    • Mobile, Alabama, United States, 36608
      • HORIZON RESEARCH GROUP INC 3610 Springhill Memorial Dr. N
    • Mobile, Alabama, United States, 36660
      • Veritas Research, LLC
    • Sheffield, Alabama, United States, 35660
      • SHOALS MEDICAL TRIALS INC. 1300 S Montgomery Ave
  • Arizona
    • Phoenix, Arizona, United States, 85023
      • PHOENIX ORTHOPAEDIC SURGEONS 2525 W. Greenway Road Suite 114
  • California
    • Laguna Hills, California, United States, 92653
      • ALLIANCE RESEARCH CENTERS 24411 Health Center Drive Suite 350
    • San Bernardino, California, United States, 92508
      • ORTHOPADIC SURGERY Loma Linda University Health Care Dept. Pf Orthopaedic Surgery 250 East Caroline Street Suite A
    • San Diego, California, United States, 92103
      • University of California, San Diego
    • San Diego, California, United States, 92130
      • Ilfeld, Brian (Thornton) UNIVERSITY OF CALIFORNIA, SAN DIEGO 10610 Hunters Glen Drive
  • Florida
    • DeLand, Florida, United States, 32720
      • FLORIDA RESEARCH ASSOCIATES, LLC / FLORIDA ORTHOPAEDIC ASSOCIATES 740 W. Plymouth Ave
    • Miami, Florida, United States, 33136
      • JACKSON MEMORIAL HOSPITAL UNVERSITY OF MIAMI 1611 Nw. 12th Ave C300
    • Pensacola, Florida, United States, 32504
      • PENSACOLA RESEARCH CONSULTANTS,INC 5149 N.9th Avenue Suite 241
    • Sunrise, Florida, United States, 33323
      • SHERIDAN CLINICAL RESEARCH, INC. 1613 N. Harrison Parkway Building C Suite 200
    • Tamarac, Florida, United States, 33321
      • PHOENIX CLINICAL RESEARCH,LLC 7171 N. University Drive Suite 100
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • UNIVERSITY OF KANSAS HOSPITAL & MEDICAL CENTER Dept. Of Anesthesiology 3901 Rainbow Blvd. Ms 1034
  • Michigan
    • Troy, Michigan, United States, 48085
      • BEAUMONT HEALTH SYSTEM 44201 Dequindre Road Suite Pob 120
  • New Jersey
    • Camden, New Jersey, United States, 08103
      • COOPER UNIVERSITY HOSPITAL 1 Cooper Plaza 202 Dorrance Building
    • Newark, New Jersey, United States, 07101
      • UNIVERSITY OF MEDICINE AND DENSITRY OF NEW JERSEY/NEW JERSEY MEDICAL SCHOOL 185 South Orange Ave. Department of Anesthesiology - MSB E538
  • New York
    • Mount Kisco, New York, United States, 10549
      • NORTHERN WESTCHESTER HOSPTIAL Department Of Clinical Trials 400 East Main St.
    • New York, New York, United States, 10025
      • ST. LUKE-ROOSEVELT HOSPITAL CENTER Dept. Of Anesthesiology 1111 Amsterdam Ave. Travis Bld. 7
    • New York, New York, United States, 10065
      • INSALL-SCOTT-KELLY INSTITUTE 210 East 64th Street
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL Department Of Anesthesiology 101 Manning Drive N0021, Cb 7010
  • Ohio
    • Cleveland, Ohio, United States, 44111
      • CLEVELAND CLINIC FAIRVIEW HOSPTIAL 1801 Lorain Avenue
    • Cleveland, Ohio, United States, 44195
      • CLEVELAND CLINIC 9500 Euclid Ave P-77
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • PENN STATE MILTON S. HERSHEY MEDICAL CENTER H187,500 University Drive
    • Philadelphia, Pennsylvania, United States, 19107
      • THOMAS JEFFERSON UNIVERSITY Dept. Of Anesthesiology 111 S. 11th Street Suite G 8490
    • Pittsburgh, Pennsylvania, United States, 15232
      • UPMC PRESBYTERIAN SHADYSIDE/ DEPT. OF ANESTHESIOLOGY POSNER PAIN CENTER 532 South Aiken Avenue Suite 407
  • Texas
    • Galveston, Texas, United States, 77551
      • UNIVERSITY OF TEXAS MEDICAL BRANCH Dept. Chairman, Orthopedic Surgery & Rehabilitation 2.316 Rebecca Sealy Hospital 301 University Blvd.
    • Houston, Texas, United States, 77024
      • RESEARCH CONCEPTS,GP LLC 921 Gessner Rd. Anesthesia Dept., Classroom F
    • Nassau Bay, Texas, United States, 77058
      • CHRISTUS ST. JOHN HOSPITAL 18300 St. John Dr., 2nd Floor, Surgery

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Male or female, >=18 years of age.
2. Scheduled to undergo primary unilateral TKA under general or spinal anesthesia.
3. American Society of Anesthesiologists (ASA) Physical Status 1, 2, or 3.
4. Able to demonstrate motor function by performing a 20-meter walk, unassisted with the optional use of a 4-legged walker, and sensory function by exhibiting sensitivity to cold.
5. Able to provide informed consent, adhere to the study visit schedule, and complete all study assessments.

Exclusion Criteria:

1. Currently pregnant, nursing, or planning to become pregnant during the study or within 1 month after study drug administration. Female subjects must be surgically sterile, at least 2 years menopausal, or using an acceptable method of birth control.

   If of childbearing potential, must have a documented negative pregnancy test within 24 hours before surgery.

2. Planned concurrent surgical procedure (e.g., bilateral TKA).

3. Use of any of the following medications within the times specified before surgery:

   long-acting opioid medication, NSAIDs, aspirin (except for low-dose aspirin used for cardioprotection) or acetaminophen within 3 days, or and any opioid medication within 24 hours.

4. Concurrent painful physical condition or concurrent surgery that may require analgesic treatment (such as an NSAID or opioid) in the postsurgical period for pain that is not strictly related to the surgical site administered study treatment, and which may confound the postsurgical assessments (e.g., significant pain from other joints including the non-index knee joint, chronic neuropathic pain, prior contralateral TKA, concurrent foot surgery).
5. 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 norepinepherine reuptake inhibitors (SNRIs), gabapentin, pregabalin (Lyrica®), or duloxetine (Cymbalta®).
6. Current use of systemic glucocorticosteroids within 1 month of enrollment in this study.
7. Body weight < 50 kilograms (110 pounds) or a body mass index ≥ 40 kg/m2.
8. Contraindication to hydromorphone, oxycodone, or bupivacaine.
9. 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.
10. Previous participation in a liposome bupivacaine study.
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. Failure to pass the urine drug screen.
13. Uncontrolled anxiety, schizophrenia, or other psychiatric disorder that, in the opinion of the Investigator, could interfere with study assessments or compliance.
14. Malignancy in the last 2 years, with the exception of non-metastatic basal cell or squamous cell carcinoma of the skin or localized carcinoma in situ of the cervix.
15. Current or historical evidence of any clinically significant disease or condition, especially cardiovascular or neurological conditions that, in the opinion of the Investigator, may increase the risk of surgery or complicate the subject's postsurgical course.
16. Significant medical conditions or laboratory results that, in the opinion of the Investigator, indicate an increased vulnerability to study drugs and procedures.
17. Subjects who are planned to receive Entereg® (alvimopan).
18. Subjects who will receive prophylactic antiemetics or planned postsurgical antiemetics given without regard to the subject's emesis needs.
19. Use of dexmedetomidine HCl (Precedex®) within 3 days of surgery.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: (Part 1) EXPAREL 67 mg; 5 mL EXPAREL (bupivacaine liposome injectable suspension) expanded with 15 mL normal saline as single-injection femoral nerve block ≤2 h preoperatively	Drug: EXPAREL 67 mg; 5 mL EXPAREL expanded with 15 mL normal saline as single-injection femoral nerve block prior to total knee arthroplasty; Other Names: Bupivacaine liposome injectable suspension 67 mg/5 mL
Experimental: (Part 1) EXPAREL 133 mg; 10 mL EXPAREL (bupivacaine liposome injectable suspension) expanded with 10 mL normal saline as single-injection femoral nerve block ≤2 h preoperatively	Drug: EXPAREL 133 mg; 10 mL EXPAREL expanded with 10 mL normal saline as single-injection femoral nerve block prior to total knee arthroplasty; Other Names: Bupivacaine liposome injectable suspension 133 mg/10 mL
Experimental: (Part 1) EXPAREL 266 mg; 20 mL EXPAREL (bupivacaine liposome injectable suspension) as single-injection femoral nerve block ≤2 h preoperatively	Drug: EXPAREL 266 mg; 20 mL EXPAREL as single-injection femoral nerve block prior to total knee arthroplasty; Other Names: Bupivacaine liposome injectable suspension 266 mg/20 mL
Placebo Comparator: (Part 1) Placebo; 20 mL normal saline as single-injection femoral nerve block ≤2 h preoperatively	Drug: Placebo; Normal saline 20 mL as single-injection femoral nerve block prior to total knee arthroplasty; Other Names: Preservative-free normal saline.
Experimental: (Part 2) EXPAREL 266 mg; 20 mL EXPAREL (bupivacaine liposome injectable suspension) as single-injection femoral nerve block ≤2 h preoperatively	Drug: EXPAREL 266 mg; 20 mL EXPAREL as single-injection femoral nerve block prior to total knee arthroplasty; Other Names: Bupivacaine liposome injectable suspension 266 mg/20 mL
Placebo Comparator: (Part 2) Placebo; 20 mL normal saline as single-injection femoral nerve block ≤2 h preoperatively	Drug: Placebo; Normal saline 20 mL as single-injection femoral nerve block prior to total knee arthroplasty; Other Names: Preservative-free normal saline.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Curve (AUC) of Numeric Rating Scale at Rest (NRS-R) Pain Intensity Scores Through 72 Hours	AUC of NRS-R pain intensity scores through 72 hours. Pain intensity scores were measured on an 11-point NRS (0=no pain and 10=worst possible pain)	0-72 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total Postsurgical Opioid Consumption Through 72 Hours	Total postsurgical opioid consumption of opioid rescue pain medication (converted to IV morphine equivalents) through 72 hours	0-72 hours
Time to First Opioid Rescue Through 72 Hours	Time to first opioid rescue medication consumed through 72 hours	0-72 hours

Collaborators and Investigators

• Sponsor: Pacira Pharmaceuticals, Inc

Study record dates

Study Major Dates

• Study Start: September 1, 2012
• Primary Completion (Actual): December 1, 2013
• Study Completion (Actual): December 1, 2013

Study Registration Dates

• First Submitted: September 7, 2012
• First Submitted That Met QC Criteria: September 7, 2012
• First Posted (Estimate): September 11, 2012

Study Record Updates

• Last Update Posted (Actual): December 9, 2020
• Last Update Submitted That Met QC Criteria: November 15, 2020
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Keywords: Analgesia; Pain management; Total knee arthroplasty
• Additional Relevant MeSH Terms: Pathologic Processes; Postoperative Complications; Pain; Neurologic Manifestations; Pain, Postoperative; Physiological Effects of Drugs; Central Nervous System Depressants; Peripheral Nervous System Agents; Sensory System Agents; Anesthetics; Anesthetics, Local; Bupivacaine
• Other Study ID Numbers: 402-C-323

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No