Pain
Conditions
Brief summary
This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled study in 155 adult subjects undergoing primary unilateral total shoulder arthroplasty or rotator cuff repair with general anesthesia
Detailed description
On Day 0, eligible subjects will be randomized in a 1:1 ratio to receive a single dose of EXPAREL 133 mg in 10 mL expanded in volume with 10 mL of normal saline for a total volume of 20 mL or placebo 20 mL. Study drug (EXPAREL or placebo) will be administered in a blinded manner via an ultrasound guided single-dose brachial plexus block at least 1 hour prior to surgery. 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; 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 is signed through postsurgical Day 29. Follow-up visits will be scheduled for all subjects on postsurgical Days 5 and 10. A follow-up phone call will be made on postsurgical Day 29. A population Pharmacokinetic (PK) analysis will be utilized to limit the number of blood draws with a sampling schedule of baseline (prior to the nerve block) through hospital discharge. There will be two collection sequences for this study and a subject can only be randomized to one sequence.
Interventions
10 mL EXPAREL (bupivacaine liposome injectable suspension) expanded with 10 mL normal saline
DRUGPlacebo
20 mL normal saline as single-injection
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 total shoulder arthroplasty or rotator cuff repair. 3. Subjects scheduled for rotator cuff repair must have a magnetic resonance imaging (MRI) with a reading confirming a tear of at least 1 cm. 4. American Society of Anesthesiologists (ASA) physical status 1, 2, or 3. 5. 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. 6. Able to demonstrate normal motor function (by obtaining a 5 on the Lovett Scale when exhibiting biceps, wrist, and thumb movement) and sensory function (by exhibiting sensitivity to cold, pinprick, and light touch) in the location where sensory function will be measured throughout the study: 2 cm superior to the coracoid process on the skin overlying the acromioclavicular joint. 7. 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. 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 shoulder surgery and which may confound the postsurgical assessments (e.g., significant pain from other joints, chronic neuropathic pain). 4. History of hypersensitivity or idiosyncratic reaction to amide-type local anesthetics. 5. Smoking history of greater than 25 pack-years. 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 medications 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 hydrochloride (HCl) (Precedex®) within 3 days of study drug administration. 11. History of impaired kidney function, emphysema or other 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 | 0-48 hours | AUC of VAS pain intensity scores through 48 hours, which represents total pain experienced through 48 hours. 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 48 Hours | 0-48 hours | Total postsurgical opioid consumption (converted to IV morphine equivalents) through 48 hours |
| Percentage of Opioid-free Participants Through 48 Hours | 0-48 hours | Percentage of participants who did not receive opioid medication through 48 hours |
| Time to First Opioid Rescue Through 48 Hours | 0-48 hours | Time to first opioid rescue medication consumed through 48 hours. Time to rescue was estimated from Kaplan-Meier analysis and presented as quartiles (ie, time to rescue for the first 25% / 50% / 75% of subjects within each treatment group). |
Countries
Belgium, Denmark, United States
Participant flow
Recruitment details
Participants were recruited between May 9, 2016 and July 7, 2017 at 16 sites in the US and Europe
Pre-assignment details
Started does not include one patient who was a screen failure, was not enrolled, and was randomized to placebo in error.
Participants by arm
| Arm | Count |
|---|---|
| EXPAREL 133 mg 10 mL EXPAREL (bupivacaine liposome injectable suspension) expanded with 10 mL normal saline as single-injection brachial plexus block (interscalene or supraclavicular) ≥1 h preoperatively | 69 |
| EXPAREL 266 mg 20 mL EXPAREL (bupivacaine liposome injectable suspension) as single-injection brachial plexus block (interscalene or supraclavicular) ≥1 h preoperatively | 15 |
| Placebo 20 mL normal saline as single-injection brachial plexus block (interscalene or supraclavicular) ≥1 h preoperatively | 71 |
| Total | 155 |
Baseline characteristics
| Characteristic | EXPAREL 133 mg | Total | Placebo | EXPAREL 266 mg |
|---|---|---|---|---|
| Age, Continuous | 60.6 years STANDARD_DEVIATION 9.94 | 59.7 years STANDARD_DEVIATION 9.55 | 58.5 years STANDARD_DEVIATION 9.48 | 61.4 years STANDARD_DEVIATION 7.73 |
| American Society of Anesthesiologists classification 1 | 15 Participants | 30 Participants | 14 Participants | 1 Participants |
| American Society of Anesthesiologists classification 2 | 36 Participants | 82 Participants | 37 Participants | 9 Participants |
| American Society of Anesthesiologists classification 3 | 18 Participants | 43 Participants | 20 Participants | 5 Participants |
| American Society of Anesthesiologists classification Greater than or equal to 4 | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Dominant hand Left hand | 10 Participants | 21 Participants | 10 Participants | 1 Participants |
| Dominant hand Right hand | 59 Participants | 134 Participants | 61 Participants | 14 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 8 Participants | 5 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 64 Participants | 144 Participants | 65 Participants | 15 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 3 Participants | 1 Participants | 0 Participants |
| Nerve block type Interscalene | 67 Participants | 152 Participants | 70 Participants | 15 Participants |
| Nerve block type Supraclavicular | 2 Participants | 3 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 13 Participants | 32 Participants | 15 Participants | 4 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 | 2 Participants | 4 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) White | 53 Participants | 118 Participants | 54 Participants | 11 Participants |
| Region of Enrollment Belgium | 7 Participants | 19 Participants | 9 Participants | 3 Participants |
| Region of Enrollment Denmark | 10 Participants | 21 Participants | 9 Participants | 2 Participants |
| Region of Enrollment United States | 52 Participants | 115 Participants | 53 Participants | 10 Participants |
| Sex: Female, Male Female | 25 Participants | 55 Participants | 23 Participants | 7 Participants |
| Sex: Female, Male Male | 44 Participants | 100 Participants | 48 Participants | 8 Participants |
| Type of surgery Rotator cuff surgery | 50 Participants | 112 Participants | 55 Participants | 7 Participants |
| Type of surgery Total shoulder arthroplasty | 19 Participants | 43 Participants | 16 Participants | 8 Participants |
| Visual Analog Scale Pain Score | 2.43 units on a scale STANDARD_DEVIATION 2.621 | 2.68 units on a scale STANDARD_DEVIATION 2.57 | 2.94 units on a scale STANDARD_DEVIATION 2.514 | 2.51 units on a scale STANDARD_DEVIATION 2.641 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 69 | 0 / 15 | 0 / 71 |
| other Total, other adverse events | 55 / 69 | 11 / 15 | 55 / 71 |
| serious Total, serious adverse events | 2 / 69 | 1 / 15 | 1 / 71 |
Outcome results
Primary
Area Under the Curve (AUC) of Visual Analog Scale (VAS) Pain Intensity Scores
AUC of VAS pain intensity scores through 48 hours, which represents total pain experienced through 48 hours. 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: 0-48 hours
Population: Efficacy population: all participants who received study drug and underwent the surgery, with analysis based on randomized treatment.~Under protocol amendment 2, the study arm 266 mg dose of EXPAREL was removed from randomization scheme and efficacy endpoints.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| EXPAREL 133 mg | Area Under the Curve (AUC) of Visual Analog Scale (VAS) Pain Intensity Scores | 136.431 cm*hr | Standard Error 12.09 |
| Placebo | Area Under the Curve (AUC) of Visual Analog Scale (VAS) Pain Intensity Scores | 254.119 cm*hr | Standard Error 11.768 |
p-value: <0.000195% CI: [-150.896, -84.48]ANOVA
Secondary
Percentage of Opioid-free Participants Through 48 Hours
Percentage of participants who did not receive opioid medication through 48 hours
Time frame: 0-48 hours
Population: Efficacy population: all participants who received study drug and underwent the surgery, with analysis based on randomized treatment.~Under protocol amendment 2, the study arm 266 mg dose of EXPAREL was removed from randomization scheme and efficacy endpoints.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| EXPAREL 133 mg | Percentage of Opioid-free Participants Through 48 Hours | 9 Participants |
| Placebo | Percentage of Opioid-free Participants Through 48 Hours | 1 Participants |
p-value: 0.00895% CI: [0.032, 0.2]Cochran-Mantel-Haenszel
Secondary
Time to First Opioid Rescue Through 48 Hours
Time to first opioid rescue medication consumed through 48 hours. Time to rescue was estimated from Kaplan-Meier analysis and presented as quartiles (ie, time to rescue for the first 25% / 50% / 75% of subjects within each treatment group).
Time frame: 0-48 hours
Population: Efficacy population: all participants who received study drug and underwent the surgery, with analysis based on randomized treatment.~Under protocol amendment 2, the study arm 266 mg dose of EXPAREL was removed from randomization scheme and efficacy endpoints.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| EXPAREL 133 mg | Time to First Opioid Rescue Through 48 Hours | First quartile | 0.70 hours |
| EXPAREL 133 mg | Time to First Opioid Rescue Through 48 Hours | Median quartile | 4.15 hours |
| EXPAREL 133 mg | Time to First Opioid Rescue Through 48 Hours | Third quartile | 18.82 hours |
| Placebo | Time to First Opioid Rescue Through 48 Hours | First quartile | 0.38 hours |
| Placebo | Time to First Opioid Rescue Through 48 Hours | Median quartile | 0.58 hours |
| Placebo | Time to First Opioid Rescue Through 48 Hours | Third quartile | 0.87 hours |
p-value: <0.0001Log Rank
Secondary
Total Postsurgical Opioid Consumption Through 48 Hours
Total postsurgical opioid consumption (converted to IV morphine equivalents) through 48 hours
Time frame: 0-48 hours
Population: Efficacy population: all participants who received study drug and underwent the surgery, with analysis based on randomized treatment.~Under protocol amendment 2, the study arm 266 mg dose of EXPAREL was removed from randomization scheme and efficacy endpoints.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| EXPAREL 133 mg | Total Postsurgical Opioid Consumption Through 48 Hours | 11.973 mg | Standard Error 2.265 |
| Placebo | Total Postsurgical Opioid Consumption Through 48 Hours | 54.303 mg | Standard Error 10.053 |
p-value: <0.000195% CI: [0.131, 0.371]ANOVA