Knee Osteoarthritis, Pain Management
Conditions
Keywords
EXPAREL, bupivacaine, analgesic, Adductor Canal Block, TKA, knee arthroplasty
Brief summary
The purpose of the study is to compare magnitude of postsurgical analgesic effect in different groups following a single dose of study drug when administered via adductor canal block in subjects undergoing primary unilateral total knee arthroplasty.
Detailed description
This is a Phase 3, multicenter, randomized, double-blind, active-controlled study in approximately 160 subjects undergoing primary unilateral TKA under spinal anesthesia. The study will have 2 cohorts, enrolling in parallel. Cohort 1 -Pharmacokinetics (PK), pharmacodynamics (PD), Efficacy, and Safety, Cohort 2 -Efficacy and Safety An adaptive study design will be used in this study. An interim analysis to evaluate the sample size assumptions and evaluate futility will occur when a total of approximately 80 subjects (40 subjects in each arm) combined from either Cohort 1 or Cohort 2 have enrolled and provided complete assessment data for the primary efficacy outcome. The time from study drug administration until the end of participation is Post-operative day (POD) 14 (±3 days). Therefore, subjects may participate in the study for up to 62 days.
Interventions
Adductor canal block with EXPAREL
DRUGBupivacaine Hydrochloride
Adductor Canal Block with bupivacaine HCl
Sponsors
Pacira Pharmaceuticals, Inc
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Masking description
Only study drug administrators (anesthesiologists) will be unblinded to perform the block procedures
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male or female, ages 18 or older at screening. 2. Indicated to undergo primary unilateral total knee arthroplasty under spinal anesthesia. 3. Primary indication for TKA is degenerative osteoarthritis of the knee. 4. American Society of Anesthesiologists (ASA) physical status 1, 2, or 3. 5. Able to provide informed consent, adhere to the study schedule, and complete all study assessments. 6. Body Mass Index (BMI) ≥18 and \<40 kg/m2.
Exclusion criteria
1. Allergy, hypersensitivity, intolerance, or contraindication to any of the study medications for which an alternative is not named in the protocol (e.g., amide-type local anesthetics, opioids, bupivacaine HCl, NSAIDs). 2. Planned concurrent surgical procedure (e.g., bilateral TKA). 3. Undergoing unicompartmental TKA or revision TKA. 4. Concurrent painful physical condition (e.g., arthritis, fibromyalgia, cancer) that may require analgesic treatment with NSAIDs or opioids in the post dosing period for pain that is not strictly related to the knee surgery and which, in the Investigator's opinion, may confound the post dosing assessments. 5. Inadequate sensory function below the knee as assessed by the Investigator. 6. History of contralateral TKA within 1 year. 7. Previous open knee surgery on the knee being considered for TKA. Prior arthroscopy is permitted. 8. History of, suspected, or known addiction to or abuse of illicit drug(s), prescription medicine(s), or alcohol within the past 2 years. 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 an EXPAREL study. 11. Uncontrolled anxiety, schizophrenia, or other psychiatric disorder that, in the opinion of the Investigator, could interfere with study assessments or compliance. 12. Currently pregnant, nursing, or planning to become pregnant during the study. 13. Clinically significant medical disease that, in the opinion of the Investigator, would make participation in a clinical study inappropriate. This includes diabetic neuropathy, coagulation or bleeding disorders, severe peripheral vascular disease, renal insufficiency, hepatic dysfunction, or other conditions that would constitute a contraindication to participation in the study. 14. Currently on a neuromodulating agent (e.g., gabapentin, pregabalin \[Lyrica\], duloxetine \[Cymbalta\], etc.)\]. 15. Current use of systemic glucocorticoids within 30 days of randomization in this study. 16. Use of dexmedetomidine HCl (Precedex®) or clonidine within 3 days of study drug administration. 17. Any use of marijuana \[including Tetrahydrocannabinol (THC) and Cannabidiol (CBD)\] within 30 days prior to randomization, or planned use during the course of the study. 18. Chronic opioid use (average ≥30 oral morphine equivalents/day) within 30 days prior to randomization. Given the coronavirus disease 2019 (COVID-19) pandemic, if there is a concern about a subject's recent or potential exposure to COVID-19, or if the subject is not medically fit/cleared for surgery due to suspected COVID-19 illness/symptoms, the subject must be excluded per Exclusion criterion #13.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| NRS Scores Through 96 Hours Post-surgery | 0 to 96 hours post-surgery | The numeric rating scale pain intensity scores ranging from 0 to 10, where 0 equals no pain and 10 equals the worst possible pain, from 0 to 96 hours post-surgery. For each subject, the area under the curve was derived using the trapezoidal rule on the pain scores adjusted for opioid pain medication using the observed and imputed values. Area under the curve started with the first pain assessment obtained after surgery and use all subsequent pain assessments up to 96 hours post-surgery. Pain scores were taken at 5 interval point: 0 hours, 24 hours, 48 hours, 72 hours, and 96 hours. There were also unscheduled pain scores measured before opioid consumption also included in the area under the curve calculation. The area under the curve ranged from 0 to 960. Higher scores represent a worse outcome. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Postsurgical Opioid Consumption Through 96 Hours Post-surgery | 0 to 96 hours post-surgery | Total postsurgical opioid consumption in mg oral morphine equivalents (OMED) from 0 to 96 hours post-surgery. |
| Time to First Opioid | 0 to 96 hours post-surgery | Time to first opioid consumption post-surgery |
| NRS Scores | 0-24hours, 24-48hours, 48-72hours, 72-96hours | Worst and average NRS pain intensity scores at 24h, 48h, 72h and 96h from the end of surgery Worst and average pain intensity scores on a numeric rating scale ranging from 0 to 10, where 0 equals no pain and 10 equals the worst possible pain, from 0 to 24 hours, 24 to 48 hours, 48 to 72 hours, and 72 to 96 hours. Mean scores at each timepoint are provided. The total range is 0 (no pain) to 10 (worst possible pain). Higher values on the scale represent worst outcome |
Countries
United States
Participant flow
Recruitment details
Participants were recruited based on physician referral at 6 sites between January 2022 and July 2022. The first participant was enrolled on January 18, 2022 and the last participant was enrolled in June 08, 2022.
Pre-assignment details
Of 340 screened participants, 167 met inclusion criteria and were randomized to treatment within Cohort 1 or Cohort 2. Overall results are presented per treatment arm including participants from both cohorts 1 + 2
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 + 2: EXPAREL Admix Arm subjects randomized to this treatment arm received 10 mL (133 mg) EXPAREL admixed with 10 mL (50 mg) 0.5% bupivacaine HCl
bupivacaine liposome injectable suspension: Adductor canal block with EXPAREL | 85 |
| Cohort 1 + 2: Bupivacaine HCl Arm subjects randomized to this treatment arm received 10 mL (50 mg) 0.5% bupivacaine HCl mixed with 10 mL normal saline
Bupivacaine Hydrochloride: Adductor Canal Block with bupivacaine HCl | 81 |
| Total | 166 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Failure to meet continuation criteria | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 3 |
Baseline characteristics
| Characteristic | Cohort 1 + 2: Bupivacaine HCl Arm | Cohort 1 + 2: EXPAREL Admix Arm | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 28 Participants | 31 Participants | 59 Participants |
| Age, Categorical Between 18 and 65 years | 53 Participants | 54 Participants | 107 Participants |
| Age, Continuous | 62.21 years STANDARD_DEVIATION 8.402 | 62.00 years STANDARD_DEVIATION 7.049 | 62.10 years STANDARD_DEVIATION 7.716 |
| ASA classification ASA 1 | 21 Participants | 21 Participants | 42 Participants |
| ASA classification ASA 2 | 56 Participants | 62 Participants | 118 Participants |
| ASA classification ASA 3 | 3 Participants | 2 Participants | 5 Participants |
| ASA classification Unknown | 1 Participants | 0 Participants | 1 Participants |
| Average pain intensity (NRS) | 5.3 units on a scale STANDARD_DEVIATION 2.22 | 5.2 units on a scale STANDARD_DEVIATION 2.32 | 5.2 units on a scale STANDARD_DEVIATION 2.27 |
| Body Mass Index | 32.74 kilograms/m^2 STANDARD_DEVIATION 4.955 | 31.43 kilograms/m^2 STANDARD_DEVIATION 4.786 | 32.07 kilograms/m^2 STANDARD_DEVIATION 4.899 |
| Body mass index, categorical <25 kg/m^2 | 7 Participants | 5 Participants | 12 Participants |
| Body mass index, categorical 25 to <30 kg/m^2 | 14 Participants | 32 Participants | 46 Participants |
| Body mass index, categorical >=30 kg/m^2 | 60 Participants | 48 Participants | 108 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 12 Participants | 21 Participants | 33 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 66 Participants | 64 Participants | 130 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized Race Black/African American | 15 Participants | 14 Participants | 29 Participants |
| Race/Ethnicity, Customized Race Other | 3 Participants | 4 Participants | 7 Participants |
| Race/Ethnicity, Customized Race White | 63 Participants | 67 Participants | 130 Participants |
| Region of Enrollment United States | 81 participants | 85 participants | 166 participants |
| Sex: Female, Male Female | 39 Participants | 42 Participants | 81 Participants |
| Sex: Female, Male Male | 42 Participants | 43 Participants | 85 Participants |
| Worst pain intensity (NRS) | 7.4 units on a scale STANDARD_DEVIATION 2.32 | 7.2 units on a scale STANDARD_DEVIATION 2.03 | 7.3 units on a scale STANDARD_DEVIATION 2.17 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 85 | 0 / 81 |
| other Total, other adverse events | 77 / 85 | 71 / 81 |
| serious Total, serious adverse events | 3 / 85 | 3 / 81 |
Outcome results
Primary
NRS Scores Through 96 Hours Post-surgery
The numeric rating scale pain intensity scores ranging from 0 to 10, where 0 equals no pain and 10 equals the worst possible pain, from 0 to 96 hours post-surgery. For each subject, the area under the curve was derived using the trapezoidal rule on the pain scores adjusted for opioid pain medication using the observed and imputed values. Area under the curve started with the first pain assessment obtained after surgery and use all subsequent pain assessments up to 96 hours post-surgery. Pain scores were taken at 5 interval point: 0 hours, 24 hours, 48 hours, 72 hours, and 96 hours. There were also unscheduled pain scores measured before opioid consumption also included in the area under the curve calculation. The area under the curve ranged from 0 to 960. Higher scores represent a worse outcome.
Time frame: 0 to 96 hours post-surgery
Population: The analysis was performed on the efficacy analysis set which included all participants in the safety analysis set who underwent the planned surgery and had at least one post-drug administration NRS pain assessment. Results presented correspond to the combined population for cohorts 1 + 2 of each treatment arm
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 + 2 EXPAREL ADMIX ARM | NRS Scores Through 96 Hours Post-surgery | 594.4 units on a scale*hours | Standard Deviation 191.65 |
| Cohort 1 + 2 BUPIVACAINE HCI ARM | NRS Scores Through 96 Hours Post-surgery | 650.1 units on a scale*hours | Standard Deviation 178.95 |
Comparison: The superiority of EXPAREL admixed to bupivacaine HCI was evaluated using the Efficacy Analysis Set.p-value: 0.007495% CI: [-118.7, -12.9]ANCOVA
Secondary
NRS Scores
Worst and average NRS pain intensity scores at 24h, 48h, 72h and 96h from the end of surgery Worst and average pain intensity scores on a numeric rating scale ranging from 0 to 10, where 0 equals no pain and 10 equals the worst possible pain, from 0 to 24 hours, 24 to 48 hours, 48 to 72 hours, and 72 to 96 hours. Mean scores at each timepoint are provided. The total range is 0 (no pain) to 10 (worst possible pain). Higher values on the scale represent worst outcome
Time frame: 0-24hours, 24-48hours, 48-72hours, 72-96hours
Population: The superiority of EXPAREL admixed to bupivacaine HCI was evaluated using the Efficacy Analysis Set with the worst observation carried forward (WOCF)/interpolation method. A one-sided hypothesis test was performed at alpha=0.025 level of significance comparing EXPAREL admix and bupivacaine HCI.~The number analyzed in one or more rows differs from overall number analyzed due to participant discontinuation in bupivacaine HCI arm and a missed assessment (protocol deviation) in EXPAREL admix arm.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 + 2 EXPAREL ADMIX ARM | NRS Scores | Average pain at 24 hours | 6.7 units on a scale | Standard Deviation 1.89 |
| Cohort 1 + 2 EXPAREL ADMIX ARM | NRS Scores | Worst pain at 24 hours | 8.6 units on a scale | Standard Deviation 1.63 |
| Cohort 1 + 2 EXPAREL ADMIX ARM | NRS Scores | Average pain at 72 hours | 5.2 units on a scale | Standard Deviation 2.14 |
| Cohort 1 + 2 EXPAREL ADMIX ARM | NRS Scores | Worst pain at 48 hours | 7.9 units on a scale | Standard Deviation 1.98 |
| Cohort 1 + 2 EXPAREL ADMIX ARM | NRS Scores | Average pain at 48 hours | 5.8 units on a scale | Standard Deviation 2.03 |
| Cohort 1 + 2 EXPAREL ADMIX ARM | NRS Scores | Worst pain at 72 hours | 6.8 units on a scale | Standard Deviation 2.33 |
| Cohort 1 + 2 EXPAREL ADMIX ARM | NRS Scores | Average pain at 96 hours | 4.8 units on a scale | Standard Deviation 2.18 |
| Cohort 1 + 2 EXPAREL ADMIX ARM | NRS Scores | Worst pain at 96 hours | 6.6 units on a scale | Standard Deviation 2.24 |
| Cohort 1 + 2 BUPIVACAINE HCI ARM | NRS Scores | Average pain at 96 hours | 5.2 units on a scale | Standard Deviation 1.96 |
| Cohort 1 + 2 BUPIVACAINE HCI ARM | NRS Scores | Average pain at 24 hours | 6.6 units on a scale | Standard Deviation 2 |
| Cohort 1 + 2 BUPIVACAINE HCI ARM | NRS Scores | Average pain at 48 hours | 6.2 units on a scale | Standard Deviation 1.84 |
| Cohort 1 + 2 BUPIVACAINE HCI ARM | NRS Scores | Average pain at 72 hours | 5.7 units on a scale | Standard Deviation 2.08 |
| Cohort 1 + 2 BUPIVACAINE HCI ARM | NRS Scores | Worst pain at 96 hours | 7.0 units on a scale | Standard Deviation 2.34 |
| Cohort 1 + 2 BUPIVACAINE HCI ARM | NRS Scores | Worst pain at 24 hours | 8.7 units on a scale | Standard Deviation 1.77 |
| Cohort 1 + 2 BUPIVACAINE HCI ARM | NRS Scores | Worst pain at 48 hours | 8.2 units on a scale | Standard Deviation 1.81 |
| Cohort 1 + 2 BUPIVACAINE HCI ARM | NRS Scores | Worst pain at 72 hours | 7.5 units on a scale | Standard Deviation 2.14 |
p-value: 0.367495% CI: [-0.6, 0.4]ANCOVA
p-value: 0.101695% CI: [-0.9, 0.2]ANCOVA
p-value: 0.021595% CI: [-1.4, 0]ANCOVA
p-value: 0.079495% CI: [-1.2, 0.2]ANCOVA
p-value: 0.360695% CI: [-0.7, 0.5]ANCOVA
p-value: 0.018495% CI: [-1.1, 0]ANCOVA
p-value: 0.047695% CI: [-1.1, 0.1]ANCOVA
p-value: 0.052995% CI: [-1.1, 0.1]ANCOVA
Secondary
Postsurgical Opioid Consumption Through 96 Hours Post-surgery
Total postsurgical opioid consumption in mg oral morphine equivalents (OMED) from 0 to 96 hours post-surgery.
Time frame: 0 to 96 hours post-surgery
Population: The analysis was performed on the efficacy analysis set which included all participants in the safety analysis set who underwent the planned surgery and had at least one post-drug administration NRS pain assessment. Results presented correspond to the combined population for cohorts 1 + 2 of each treatment arm
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 + 2 EXPAREL ADMIX ARM | Postsurgical Opioid Consumption Through 96 Hours Post-surgery | 109.19 milligrams oral morphine equivalents | Geometric Coefficient of Variation 54.42 |
| Cohort 1 + 2 BUPIVACAINE HCI ARM | Postsurgical Opioid Consumption Through 96 Hours Post-surgery | 136.91 milligrams oral morphine equivalents | Geometric Coefficient of Variation 48.284 |
Comparison: The superiority of EXPAREL admixed to bupivacaine HCI was evaluated using the Efficacy Analysis Set.p-value: 0.001895% CI: [0.64, 0.92]ANCOVA
Secondary
Time to First Opioid
Time to first opioid consumption post-surgery
Time frame: 0 to 96 hours post-surgery
Population: The analysis was performed on the efficacy analysis set which included all participants in the safety analysis set who underwent the planned surgery and had at least one post-drug administration NRS pain assessment. Results presented correspond to the combined population for cohorts 1 + 2 of each treatment arm
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 + 2 EXPAREL ADMIX ARM | Time to First Opioid | 4.15 hours |
| Cohort 1 + 2 BUPIVACAINE HCI ARM | Time to First Opioid | 3.63 hours |
p-value: 0.012795% CI: [0.51, 0.96]Cox proportional hazards model