Clinical trial NCT02713178: Efficacy, Safety, and Pharmacokinetics of Femoral Nerve Block With EXPAREL in Total Knee Arthroplasty
Official title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy, Safety, and Pharmacokinetics of Femoral Nerve Block With EXPAREL for Postsurgical Analgesia in Subjects Undergoing Total Knee Arthroplasty
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Pain
Lead sponsor: Pacira Pharmaceuticals, Inc
Sponsor class: INDUSTRY
First posted: 2016-03-18
Enrollment: 232
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled study in 232 adult subjects undergoing primary unilateral TKA under general or spinal anesthesia.

Detailed description: On Day 0, eligible subjects will be randomized in a 1:1:1 ratio to receive a single dose of either EXPAREL 133 mg in 10 mL expanded in volume with 10 mL of normal saline for a total volume of 20 mL (Group 1); EXPAREL 266 mg in 20 mL (Group 2); or placebo 20 mL (Group 3). Study drug (EXPAREL or placebo) will be administered in a blinded manner via an ultrasound guided single-dose femoral nerve block at least 1 hour prior to surgery. Prior to placement of the prosthesis, 8 mL of bupivacaine hydrochloride (HCl) (0.5%) diluted with 8 mL of normal saline will be administered by the surgeon as a periarticular infiltration to the posterior capsule (8 mL medially and 8 mL laterally).

Postsurgical assessments will include pain intensity scores using a 10-cm visual analog scale (VAS); total postsurgical opioid consumption; overall benefit of analgesia score (OBAS) questionnaire; subject satisfaction with overall analgesia using a 5-point Likert scale; neurological assessment; sensory function assessment; motor function assessment; the study physical therapy assessments (ie, timed walk, timed up and go, and stair climbing tests); discharge readiness; unscheduled phone calls or office visits related to pain; 12-lead ECGs; vital sign measurements; and clinical laboratory tests. Adverse events will be recorded from the time the informed consent form (ICF) is signed through postsurgical Day 29.

Follow-up visits will be scheduled for all subjects on postsurgical Days 6 and 10. A follow-up phone call will be made on postsurgical Day 29.

Pharmacokinetic (PK) parameters will be estimated from plasma bupivacaine measurements using non-compartmental analysis based on the sampling schedule of baseline (prior to the nerve block) through postsurgical Day 10.

Eligibility criteria: Inclusion Criteria:

1. Male or female, at least 18 years of age at screening.
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. Female subject 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.
5. Able to demonstrate sensory function by exhibiting sensitivity to cold, pinprick, and light touch.
6. 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.
2. Planned concurrent surgical procedure (e.g., bilateral TKA).
3. 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).
4. Previous open knee surgery on the knee being considered for TKA. Prior arthroscopy is permitted.
5. History of hypersensitivity or idiosyncratic reaction to amide-type local anesthetics.
6. Contraindication to any one of the following: bupivacaine, oxycodone, morphine, or hydromorphone.
7. 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.
8. 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.
9. Current use of systemic glucocorticosteroids within 1 month of enrollment in this study.
10. Use of dexmedetomidine HCl (Precedex®) within 3 days of study drug administration.
11. History of impaired kidney function, poorly controlled chronic respiratory disease, rheumatoid arthritis, coagulopathy, or loss of sensation in extremities.
12. Impaired kidney function (e.g., serum creatinine level \>2 mg/dL \[176.8 µmol/L\] or blood urea nitrogen level \>50 mg/dL \[17.9 mmol/L\]) or impaired liver function (e.g., serum aspartate aminotransferase \[AST\] level \>3 times the upper limit of normal \[ULN\] or serum alanine aminotransferase \[ALT\] level \>3 times the ULN.)
13. Uncontrolled anxiety, psychiatric, or neurological disorder that might interfere with study assessments.
14. Any chronic neuromuscular deficit effecting the peripheral nerves or muscles of the surgical extremity.
15. Any chronic condition or disease that would compromise neurological or vascular assessments.
16. 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.
17. Suspected or known history of drug or alcohol abuse within the previous year.
18. Body weight \<50 kg (110 pounds) or a body mass index \>44 kg/m2.
19. Previous participation in an EXPAREL study.
20. 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.

Primary outcomes:
measure: Area Under the Curve (AUC) of Visual Analog Scale (VAS) Pain Intensity Scores Through 72 Hours
timeFrame: 0-72 hours
Secondary outcomes:
measure: Total Postsurgical Opioid Consumption Through 72 Hours
timeFrame: 0-72 hours
measure: Percentage of Opioid-free Participants Through 72 Hours
timeFrame: 0-72 hours
measure: Time to First Opioid Rescue Through 72 Hours
timeFrame: 0-72 hours
Other outcomes:
Locations:
city: Mobile
country: United States
facility: Horizon Research Group, Inc
state: Alabama
city: Englewood
country: United States
facility: Denver Metro Orthopedics
state: Colorado
city: Miami
country: United States
facility: Jackson Memorial Hospital/University of Miami
state: Florida
city: Pensacola
country: United States
facility: Pensacola Research Associates
state: Florida
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Bronx
country: United States
facility: Montefiore Medical Center
state: New York
city: Cleveland
country: United States
facility: Fairview Hospital
state: Ohio
city: Indiana
country: United States
facility: Indiana Regional Medical Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: Thomas Jefferson University Hospital
state: Pennsylvania
city: Windber
country: United States
facility: Chan Soon-Shiong Medical Center
state: Pennsylvania
city: Houston
country: United States
facility: Hermann Drive Surgical Hospital
state: Texas
city: Houston
country: United States
facility: Westside Surgical Hospital
state: Texas
city: Franklin
country: United States
facility: Southampton Orthopaedics Sports Medicine
state: Virginia
city: Genk
country: Belgium
facility: Ziekenhuis Oost-Limburg
city: Aarhus C
country: Denmark
facility: Aarhus University Hospital
city: Silkeborg
country: Denmark
facility: Regionshospital Silkeborg
Study officials:
affiliation: Pacira Pharmaceuticals, Inc
name: James B Jones, MD, PharmD
role: STUDY_DIRECTOR
References: