Postoperative Pain
Conditions
Keywords
Total knee arthroplasty, Analgesia, Pain management
Brief summary
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).
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.
Interventions
DRUGPlacebo
Normal saline 20 mL as single-injection femoral nerve block prior to total knee arthroplasty
DRUGEXPAREL 67 mg
5 mL EXPAREL expanded with 15 mL normal saline as single-injection femoral nerve block prior to total knee arthroplasty
DRUGEXPAREL 133 mg
10 mL EXPAREL expanded with 10 mL normal saline as single-injection femoral nerve block prior to total knee arthroplasty
DRUGEXPAREL 266 mg
20 mL EXPAREL as single-injection femoral nerve block prior to total knee arthroplasty
Sponsors
Pacira Pharmaceuticals, Inc
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Curve (AUC) of Numeric Rating Scale at Rest (NRS-R) Pain Intensity Scores Through 72 Hours | 0-72 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) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Total Postsurgical Opioid Consumption Through 72 Hours | 0-72 hours | Total postsurgical opioid consumption of opioid rescue pain medication (converted to IV morphine equivalents) through 72 hours |
| Time to First Opioid Rescue Through 72 Hours | 0-72 hours | Time to first opioid rescue medication consumed through 72 hours |
Countries
United States
Participant flow
Recruitment details
Participants were recruited between September 24, 2012 and December 20, 2013 at 23 sites in the US
Pre-assignment details
An unblinded dose selection committee reviewed Part 1 results for the primary endpoint, total postsurgical opioid consumption, time to first opioid rescue, and safety data, and recommended a dose level and sample size for Part 2.
Participants by arm
| Arm | Count |
|---|---|
| (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 | 22 |
| (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 | 24 |
| (Part 1) EXPAREL 266 mg 20 mL EXPAREL (bupivacaine liposome injectable suspension) as single-injection femoral nerve block ≤2 h preoperatively | 24 |
| (Part 1) Placebo 20 mL normal saline as single-injection femoral nerve block ≤2 h preoperatively | 24 |
| (Part 2) EXPAREL 266 mg 20 mL EXPAREL (bupivacaine liposome injectable suspension) as single-injection femoral nerve block ≤2 h preoperatively | 92 |
| (Part 2) Placebo 20 mL normal saline as single-injection femoral nerve block ≤2 h preoperatively | 92 |
| Total | 278 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Part 1 | Did not receive study drug | 1 | 0 | 0 | 1 | 0 | 0 |
| Part 1 | Early termination; met exclusion criteria | 0 | 2 | 1 | 0 | 0 | 0 |
| Part 1 | Lack of Efficacy | 1 | 0 | 0 | 3 | 0 | 0 |
| Part 1 | Surgery Cancelled | 1 | 0 | 0 | 0 | 0 | 0 |
| Part 1 | Withdrawal by Subject | 1 | 2 | 2 | 1 | 0 | 0 |
| Part 2 | Did not receive study drug | 0 | 0 | 0 | 0 | 2 | 1 |
| Part 2 | Lack of Efficacy | 0 | 0 | 0 | 0 | 3 | 4 |
| Part 2 | Lost to Follow-up | 0 | 0 | 0 | 0 | 2 | 0 |
| Part 2 | Met exclusion criterion | 0 | 0 | 0 | 0 | 1 | 1 |
| Part 2 | Protocol deviation | 0 | 0 | 0 | 0 | 1 | 2 |
| Part 2 | Surgery cancelled | 0 | 0 | 0 | 0 | 4 | 2 |
| Part 2 | Withdrawal by investigator decision | 0 | 0 | 0 | 0 | 1 | 2 |
| Part 2 | Withdrawal by Subject | 0 | 0 | 0 | 0 | 3 | 3 |
Baseline characteristics
| Characteristic | (Part 2) Placebo | (Part 1) EXPAREL 67 mg | (Part 1) EXPAREL 133 mg | (Part 1) EXPAREL 266 mg | (Part 1) Placebo | (Part 2) EXPAREL 266 mg | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 63.6 years STANDARD_DEVIATION 8.76 | 68.5 years STANDARD_DEVIATION 8.41 | 65.7 years STANDARD_DEVIATION 7.3 | 66.4 years STANDARD_DEVIATION 8.94 | 66.1 years STANDARD_DEVIATION 12.17 | 66.4 years STANDARD_DEVIATION 10.35 | 65.0 years STANDARD_DEVIATION 9.67 |
| American Society of Anesthesiologists (ASA) classification 1 | 3 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 7 Participants | 11 Participants |
| American Society of Anesthesiologists (ASA) classification 2 | 49 Participants | 11 Participants | 16 Participants | 13 Participants | 15 Participants | 38 Participants | 142 Participants |
| American Society of Anesthesiologists (ASA) classification 3 | 40 Participants | 11 Participants | 8 Participants | 10 Participants | 9 Participants | 47 Participants | 125 Participants |
| American Society of Anesthesiologists (ASA) classification >/= 4 | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Duration of Surgery | 94.9 minutes STANDARD_DEVIATION 37.54 | 85.8 minutes STANDARD_DEVIATION 25.53 | 88.5 minutes STANDARD_DEVIATION 27.96 | 96.0 minutes STANDARD_DEVIATION 37.94 | 85.0 minutes STANDARD_DEVIATION 35.53 | 94.1 minutes STANDARD_DEVIATION 34.43 | 94.5 minutes STANDARD_DEVIATION 35.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 9 Participants | 1 Participants | 1 Participants | 2 Participants | 3 Participants | 8 Participants | 24 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 83 Participants | 21 Participants | 23 Participants | 22 Participants | 21 Participants | 84 Participants | 254 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Incision length | 16.29 cm STANDARD_DEVIATION 5.189 | 16.51 cm STANDARD_DEVIATION 2.457 | 14.98 cm STANDARD_DEVIATION 3.65 | 15.23 cm STANDARD_DEVIATION 2.834 | 18.25 cm STANDARD_DEVIATION 3.87 | 16.92 cm STANDARD_DEVIATION 4.987 | 16.6 cm STANDARD_DEVIATION 5.08 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 14 Participants | 1 Participants | 2 Participants | 2 Participants | 4 Participants | 15 Participants | 38 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 76 Participants | 20 Participants | 22 Participants | 21 Participants | 20 Participants | 75 Participants | 234 Participants |
| Region of Enrollment United States | 92 participants | 22 participants | 24 participants | 24 participants | 24 participants | 92 participants | 278 participants |
| Sex: Female, Male Female | 57 Participants | 8 Participants | 16 Participants | 14 Participants | 14 Participants | 52 Participants | 161 Participants |
| Sex: Female, Male Male | 35 Participants | 14 Participants | 8 Participants | 10 Participants | 10 Participants | 40 Participants | 117 Participants |
| Type of Anesthesia General | 56 Participants | 15 Participants | 17 Participants | 12 Participants | 21 Participants | 62 Participants | 183 Participants |
| Type of Anesthesia Other | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 3 Participants |
| Type of Anesthesia Spinal | 35 Participants | 6 Participants | 7 Participants | 12 Participants | 3 Participants | 28 Participants | 91 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 22 | 0 / 24 | 0 / 24 | 0 / 24 | 0 / 92 | 0 / 92 |
| other Total, other adverse events | 19 / 22 | 20 / 24 | 21 / 24 | 21 / 24 | 82 / 92 | 83 / 92 |
| serious Total, serious adverse events | 4 / 22 | 2 / 24 | 1 / 24 | 3 / 24 | 8 / 92 | 9 / 92 |
Outcome results
Primary
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)
Time frame: 0-72 hours
Population: Efficacy population: all participants in the safety analysis set who underwent the planned surgery, with analysis based on randomized treatment (regardless of treatment received)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| (Part 1) EXPAREL 67 mg | Area Under the Curve (AUC) of Numeric Rating Scale at Rest (NRS-R) Pain Intensity Scores Through 72 Hours | 533.4 score on a scale * hr | Standard Deviation 33.15 |
| (Part 1) EXPAREL 133 mg | Area Under the Curve (AUC) of Numeric Rating Scale at Rest (NRS-R) Pain Intensity Scores Through 72 Hours | 427.2 score on a scale * hr | Standard Deviation 31.73 |
| (Part 1) EXPAREL 266 mg | Area Under the Curve (AUC) of Numeric Rating Scale at Rest (NRS-R) Pain Intensity Scores Through 72 Hours | 436.2 score on a scale * hr | Standard Deviation 31.79 |
| (Part 1) Placebo | Area Under the Curve (AUC) of Numeric Rating Scale at Rest (NRS-R) Pain Intensity Scores Through 72 Hours | 530.5 score on a scale * hr | Standard Deviation 31.73 |
| (Part 2) EXPAREL 266 mg | Area Under the Curve (AUC) of Numeric Rating Scale at Rest (NRS-R) Pain Intensity Scores Through 72 Hours | 418.9 score on a scale * hr | Standard Deviation 16.86 |
| (Part 2) Placebo | Area Under the Curve (AUC) of Numeric Rating Scale at Rest (NRS-R) Pain Intensity Scores Through 72 Hours | 515.5 score on a scale * hr | Standard Deviation 16.95 |
p-value: 0.949495% CI: [-88, 94]ANCOVA
p-value: 0.023795% CI: [-192, -14]ANCOVA
p-value: 0.038695% CI: [-184, -5]ANCOVA
p-value: <0.000195% CI: [-144, -49]ANCOVA
Secondary
Time to First Opioid Rescue Through 72 Hours
Time to first opioid rescue medication consumed through 72 hours
Time frame: 0-72 hours
Population: Efficacy population: all participants in the safety analysis set who underwent the planned surgery, with analysis based on randomized treatment (regardless of treatment received)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| (Part 1) EXPAREL 67 mg | Time to First Opioid Rescue Through 72 Hours | 0.49 hours |
| (Part 1) EXPAREL 133 mg | Time to First Opioid Rescue Through 72 Hours | 0.37 hours |
| (Part 1) EXPAREL 266 mg | Time to First Opioid Rescue Through 72 Hours | 1.29 hours |
| (Part 1) Placebo | Time to First Opioid Rescue Through 72 Hours | 0.41 hours |
| (Part 2) EXPAREL 266 mg | Time to First Opioid Rescue Through 72 Hours | 0.44 hours |
| (Part 2) Placebo | Time to First Opioid Rescue Through 72 Hours | 0.43 hours |
Secondary
Total Postsurgical Opioid Consumption Through 72 Hours
Total postsurgical opioid consumption of opioid rescue pain medication (converted to IV morphine equivalents) through 72 hours
Time frame: 0-72 hours
Population: Efficacy population: all participants in the safety analysis set who underwent the planned surgery, with analysis based on randomized treatment (regardless of treatment received)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| (Part 1) EXPAREL 67 mg | Total Postsurgical Opioid Consumption Through 72 Hours | 126.69 mg morphine equivalents | Standard Deviation 75.972 |
| (Part 1) EXPAREL 133 mg | Total Postsurgical Opioid Consumption Through 72 Hours | 100.35 mg morphine equivalents | Standard Deviation 53.177 |
| (Part 1) EXPAREL 266 mg | Total Postsurgical Opioid Consumption Through 72 Hours | 105.96 mg morphine equivalents | Standard Deviation 53.402 |
| (Part 1) Placebo | Total Postsurgical Opioid Consumption Through 72 Hours | 124.78 mg morphine equivalents | Standard Deviation 58.743 |
| (Part 2) EXPAREL 266 mg | Total Postsurgical Opioid Consumption Through 72 Hours | 93.19 mg morphine equivalents | Standard Deviation 58.133 |
| (Part 2) Placebo | Total Postsurgical Opioid Consumption Through 72 Hours | 122.08 mg morphine equivalents | Standard Deviation 70.312 |
p-value: 0.618295% CI: [0.6, 1.3]ANOVA
p-value: 0.109795% CI: [0.5, 1.1]ANOVA
p-value: 0.404695% CI: [0.6, 1.3]ANOVA
p-value: 0.001695% CI: [0.6, 0.9]ANOVA