Pain
Conditions
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.
Interventions
bupivacaine liposome injectable suspension 133 mg expanded with normal saline to 20 mL or 266 mg in 20 mL
DRUGPlacebo
Normal saline.
Sponsors
Pacira Pharmaceuticals, Inc
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Curve (AUC) of Visual Analog Scale (VAS) Pain Intensity Scores Through 72 Hours | 0-72 hours | AUC of VAS pain intensity scores through 72 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Total Postsurgical Opioid Consumption Through 72 Hours | 0-72 hours | Total postsurgical opioid consumption (converted to IV morphine equivalents) through 72 hours |
| Percentage of Opioid-free Participants Through 72 Hours | 0-72 hours | Percentage of participants who did not receive opioid medication through 72 hours |
| Time to First Opioid Rescue Through 72 Hours | 0-72 hours | Time to first opioid rescue medication consumed through 72 hours. The time to rescue is estimated for each quartile from the Kaplan-Meier analysis, in which first quartile represents the time it took for the first 25% of the population to receive rescue medication, median quartile represents the time it took 50% of the population to receive rescue medication, and third quartile represents the time it took 75% of the population to receive rescue medication. |
Countries
Belgium, Denmark, United States
Participant flow
Recruitment details
Participants were recruited between June 3, 2016 and June 30, 2017 at 13 sites in the US and Europe
Participants by arm
| Arm | Count |
|---|---|
| EXPAREL 133 mg 10 mL EXPAREL (bupivacaine liposome injectable suspension) expanded with 10 mL normal saline as single-injection femoral nerve block ≥1 h preoperatively | 75 |
| EXPAREL 266 mg 20 mL EXPAREL (bupivacaine liposome injectable suspension) as single-injection femoral nerve block ≥1 h preoperatively | 76 |
| Placebo 20 mL normal saline as single-injection femoral nerve block ≥1 h preoperatively | 79 |
| Total | 230 |
Baseline characteristics
| Characteristic | Placebo | Total | EXPAREL 133 mg | EXPAREL 266 mg |
|---|---|---|---|---|
| Age, Continuous | 65.4 years STANDARD_DEVIATION 8.69 | 65.3 years STANDARD_DEVIATION 8.26 | 64.6 years STANDARD_DEVIATION 6.94 | 66.0 years STANDARD_DEVIATION 9.01 |
| American Society of Anesthesiologists classification Score: 1 | 10 Participants | 30 Participants | 11 Participants | 9 Participants |
| American Society of Anesthesiologists classification Score: 2 | 46 Participants | 128 Participants | 41 Participants | 41 Participants |
| American Society of Anesthesiologists classification Score: 3 | 23 Participants | 72 Participants | 23 Participants | 26 Participants |
| American Society of Anesthesiologists classification Score: Greater than or equal to 4 | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 6 Participants | 2 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 75 Participants | 222 Participants | 73 Participants | 74 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 2 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 12 Participants | 25 Participants | 8 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 67 Participants | 202 Participants | 66 Participants | 69 Participants |
| Region of Enrollment Belgium | 36 participants | 109 participants | 36 participants | 37 participants |
| Region of Enrollment Denmark | 3 participants | 5 participants | 1 participants | 1 participants |
| Region of Enrollment United States | 40 participants | 116 participants | 38 participants | 38 participants |
| Sex: Female, Male Female | 53 Participants | 132 Participants | 36 Participants | 43 Participants |
| Sex: Female, Male Male | 26 Participants | 98 Participants | 39 Participants | 33 Participants |
| Visual analog scale pain score | 1.80 cm STANDARD_DEVIATION 2.195 | 1.99 cm STANDARD_DEVIATION 2.458 | 2.12 cm STANDARD_DEVIATION 2.656 | 2.08 cm STANDARD_DEVIATION 2.546 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 75 | 0 / 76 | 0 / 79 |
| other Total, other adverse events | 73 / 75 | 74 / 76 | 76 / 79 |
| serious Total, serious adverse events | 5 / 75 | 8 / 76 | 6 / 79 |
Outcome results
Primary
Area Under the Curve (AUC) of Visual Analog Scale (VAS) Pain Intensity Scores Through 72 Hours
AUC of VAS pain intensity scores through 72 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.
Time frame: 0-72 hours
Population: Efficacy population: all participants who received study drug and underwent the surgery, with analysis based on randomized treatment
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| EXPAREL 133 mg | Area Under the Curve (AUC) of Visual Analog Scale (VAS) Pain Intensity Scores Through 72 Hours | 259.545 cm*hr | Standard Error 19.011 |
| EXPAREL 266 mg | Area Under the Curve (AUC) of Visual Analog Scale (VAS) Pain Intensity Scores Through 72 Hours | 250.998 cm*hr | Standard Error 18.849 |
| Placebo | Area Under the Curve (AUC) of Visual Analog Scale (VAS) Pain Intensity Scores Through 72 Hours | 279.794 cm*hr | Standard Error 18.493 |
p-value: 0.446395% CI: [-72.361, 31.864]ANOVA
p-value: 0.274995% CI: [-80.483, 22.892]ANOVA
Secondary
Percentage of Opioid-free Participants Through 72 Hours
Percentage of participants who did not receive opioid medication through 72 hours
Time frame: 0-72 hours
Population: Efficacy population: all participants who received study drug and underwent the surgery, with analysis based on randomized treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| EXPAREL 133 mg | Percentage of Opioid-free Participants Through 72 Hours | 0 Participants |
| EXPAREL 266 mg | Percentage of Opioid-free Participants Through 72 Hours | 0 Participants |
| Placebo | Percentage of Opioid-free Participants Through 72 Hours | 0 Participants |
Secondary
Time to First Opioid Rescue Through 72 Hours
Time to first opioid rescue medication consumed through 72 hours. The time to rescue is estimated for each quartile from the Kaplan-Meier analysis, in which first quartile represents the time it took for the first 25% of the population to receive rescue medication, median quartile represents the time it took 50% of the population to receive rescue medication, and third quartile represents the time it took 75% of the population to receive rescue medication.
Time frame: 0-72 hours
Population: Efficacy population: all participants who received study drug and underwent the surgery, with analysis based on randomized treatment
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| EXPAREL 133 mg | Time to First Opioid Rescue Through 72 Hours | Second quartile | 3.03 h |
| EXPAREL 133 mg | Time to First Opioid Rescue Through 72 Hours | First quartile | 1.80 h |
| EXPAREL 133 mg | Time to First Opioid Rescue Through 72 Hours | Third quartile | 5.07 h |
| EXPAREL 266 mg | Time to First Opioid Rescue Through 72 Hours | Second quartile | 2.87 h |
| EXPAREL 266 mg | Time to First Opioid Rescue Through 72 Hours | First quartile | 1.53 h |
| EXPAREL 266 mg | Time to First Opioid Rescue Through 72 Hours | Third quartile | 5.78 h |
| Placebo | Time to First Opioid Rescue Through 72 Hours | First quartile | 1.08 h |
| Placebo | Time to First Opioid Rescue Through 72 Hours | Third quartile | 3.72 h |
| Placebo | Time to First Opioid Rescue Through 72 Hours | Second quartile | 2.40 h |
Comparison: The overall distribution as estimated by the Kaplan-Meier analysis was compared between the EXPAREL arm and the placebo arm.p-value: 0.1896Log Rank
Comparison: The overall distribution as estimated by the Kaplan-Meier analysis was compared between the EXPAREL arm and the placebo arm.p-value: 0.2549Log Rank
Secondary
Total Postsurgical Opioid Consumption Through 72 Hours
Total postsurgical opioid consumption (converted to IV morphine equivalents) through 72 hours
Time frame: 0-72 hours
Population: Efficacy population: all participants who received study drug and underwent the surgery, with analysis based on randomized treatment
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| EXPAREL 133 mg | Total Postsurgical Opioid Consumption Through 72 Hours | 69.466 mg | Standard Error 4.403 |
| EXPAREL 266 mg | Total Postsurgical Opioid Consumption Through 72 Hours | 74.393 mg | Standard Error 4.669 |
| Placebo | Total Postsurgical Opioid Consumption Through 72 Hours | 81.469 mg | Standard Error 5.006 |
p-value: 0.071695% CI: [0.717, 1.014]ANOVA
p-value: 0.300495% CI: [0.769, 1.084]ANOVA