Dental Pain
Conditions
Brief summary
This is a Phase 3, randomized, double-blind, placebo-controlled study in subjects scheduled to undergo elective bilateral third molar extraction under local anesthesia. At least one lower mandibular third molar must involve full or partial bony impaction confirmed by visual or radiographic evidence.
Detailed description
Subjects will be screened within 30 days prior to surgery. Randomized subjects will receive a dental nerve block with lidocaine 2% with epinephrine 1:100,000 before undergoing bilateral third molar extraction under local anesthesia. In addition to the lidocaine nerve block, the Investigator may choose to add topical benzocaine or intraoperative nitrous oxide. At the end of surgery, and at least 20 minutes after the lidocaine administration, blinded study drug will be infiltrated to provide postsurgical analgesia. Subjects will be required to remain in the research facility for 96 hours after study drug administration. Postsurgical efficacy, safety, and pharmacokinetic (PK) assessments will be conducted. All subjects will return for a follow-up visits on Days 7 and 10. A phone call will be made to each subject on Day 30 for an adverse event (AE) assessment and to inquire as to whether the subject made any unscheduled phone calls or office visits related to pain.
Interventions
Local administration
DRUGPlacebo
Local administration
Sponsors
Lotus Clinical Research, LLC
Pacira Pharmaceuticals, Inc
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, 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 at screening. 2. Scheduled to undergo bilateral third molar extractions (i.e., extraction of all four third molars) under local anesthesia. At least one lower mandibular third molar must involve full or partial bony impaction confirmed by visual or radiological evidence. 3. American Society of Anesthesiology (ASA) physical status 1, 2, or 3. 4. Female subjects must be either surgically sterile, using a medically acceptable method of birth control, or at least 2 years postmenopausal, and must have a documented negative pregnancy test result during screening and on Day 1 prior to surgery. 5. Able to provide informed consent, adhere to the study visit schedule, and complete all study assessments.
Exclusion criteria
1. History of hypersensitivity or idiosyncratic reaction to amide-type local anesthetics or opioids. 2. Contraindication to lidocaine, epinephrine, bupivacaine, or oxycodone. 3. History of significant drug allergy (e.g., anaphylaxis or hepatotoxicity). 4. Positive test result from the urine drug screen at screening or prior to the surgical procedure. 5. Currently pregnant, nursing, or planning to become pregnant during the study or within 1 month after study drug administration. 6. History or active psychiatric illness (including major depression, bipolar disorder, or anxiety); Type 1 or Type 2 diabetes; severe renal or hepatic impairment; significant cardiovascular disease (including cardiac rhythm disturbance); migraine headaches, frequent headaches, other pain conditions, or other medical condition that, in the opinion of the Investigator, may increase the risk of surgery or interfere with the evaluation of the study drug. 7. History of infection requiring intravenous (IV) antibiotics within 45 days or oral (PO) antibiotics within 30 days prior to study drug administration for reasons other than dental prophylaxis. Subjects must be afebrile, without signs or symptoms indicative of active infection. 8. Use of any of the following medications within the times specified before surgery: long-acting opioid medication, nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin (except for low-dose aspirin used for cardioprotection), or acetaminophen within 3 days, or any opioid medication within 24 hours. 9. Initiation of treatment with any of the following medications within 1 month of EXPAREL infiltration 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 EXPAREL administration. 10. Current use of systemic glucocorticosteroids within 1 month of enrollment in this study. 11. Use of any concurrent therapy that could interfere with the evaluation of efficacy or safety, such as any drugs which in the Investigator's opinion may exert significant analgesic properties or act synergistically with the investigational product. 12. 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 Numeric Rating Scale (NRS) Pain Intensity Scores Through 48 Hours | 0-48 hours | AUC of NRS pain intensity scores through 48 hours. Pain intensity scores were measured on a 10-point scale (0=no pain and 10=worst possible pain) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Curve (AUC) of Numeric Rating Scale (NRS) Pain Intensity Scores Through 24 Hours | 0-24 hours | AUC of NRS pain intensity scores through 24 hours. Pain intensity scores were measured on a 10-point scale (0=no pain and 10=worst possible pain) 0-24 hours |
| Area Under the Curve (AUC) of Numeric Rating Scale (NRS) Pain Intensity Scores Through 72 Hours | 0-72 hours | AUC of NRS pain intensity scores through 72 hours. Pain intensity scores were measured on a 10-point scale (0=no pain and 10=worst possible pain) |
| Percentage of Opioid-free Subjects Through 24 Hours. | 0-24 hours | Percentage of opioid-free subjects through 24 hours. |
| Percentage of Opioid-free Subjects Through 48 Hours. | 0-48 hours | Percentage of opioid-free subjects through 48 hours. |
| Percentage of Opioid-free Subjects Through 72 Hours. | 0-72 hours | Percentage of opioid-free subjects through 72 hours. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| EXPAREL 133 mg 10 mL EXPAREL (bupivacaine liposome injectable suspension) injected into the maxilla (4 mL; 2 mL per side) and mandible (6 mL; 3 mL per side) at the end of surgery and ≥20 min after lidocaine administration
Bupivacaine liposome: Local administration | 105 |
| Placebo 10 mL normal saline injected into the maxilla (4 mL; 2 mL per side) and mandible (6 mL; 3 mL per side) at the end of surgery and ≥20 min after lidocaine administration
Placebo: Local administration | 57 |
| Total | 162 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 4 | 0 |
| Overall Study | Screen failure | 2 | 2 |
| Overall Study | Withdrawal by Subject | 4 | 0 |
Baseline characteristics
| Characteristic | EXPAREL 133 mg | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 20.9 years STANDARD_DEVIATION 3.81 | 20.9 years STANDARD_DEVIATION 4.15 | 20.9 years STANDARD_DEVIATION 4.76 |
| Body Mass Index | 25.8 kg/m2 STANDARD_DEVIATION 6.87 | 25.3 kg/m2 STANDARD_DEVIATION 6.21 | 24.5 kg/m2 STANDARD_DEVIATION 4.72 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 16 Participants | 23 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 89 Participants | 139 Participants | 50 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Impaction Scores 1 fully bony impacted tooth | 2 Participants | 4 Participants | 2 Participants |
| Impaction Scores 1 fully bony impacted tooth, 1 partially impacted | 8 Participants | 13 Participants | 5 Participants |
| Impaction Scores 1 fully bony impacted tooth, 2 partially impacted | 7 Participants | 10 Participants | 3 Participants |
| Impaction Scores 1 fully bony impacted tooth, 3 partially impacted | 4 Participants | 5 Participants | 1 Participants |
| Impaction Scores 1 partially impacted tooth | 1 Participants | 2 Participants | 1 Participants |
| Impaction Scores 2 fully bony impacted teeth | 3 Participants | 9 Participants | 6 Participants |
| Impaction Scores 2 fully bony impacted teeth, 1 partially impacted | 9 Participants | 11 Participants | 2 Participants |
| Impaction Scores 2 fully bony impacted teeth, 2 partially impacted | 10 Participants | 17 Participants | 7 Participants |
| Impaction Scores 2 partially impacted teeth | 16 Participants | 17 Participants | 1 Participants |
| Impaction Scores 3 fully bony impacted teeth | 1 Participants | 4 Participants | 3 Participants |
| Impaction Scores 3 fully bony impacted teeth, 1 partially impacted | 14 Participants | 21 Participants | 7 Participants |
| Impaction Scores 3 partially impacted teeth | 4 Participants | 4 Participants | 0 Participants |
| Impaction Scores 4 fully bony impacted teeth | 23 Participants | 42 Participants | 19 Participants |
| Impaction Scores 4 partially impacted teeth | 3 Participants | 3 Participants | 0 Participants |
| Impaction Scores No impactions | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 9 Participants | 10 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 94 Participants | 147 Participants | 53 Participants |
| Region of Enrollment United States | 105 participants | 162 participants | 57 participants |
| Sex: Female, Male Female | 53 Participants | 86 Participants | 33 Participants |
| Sex: Female, Male Male | 52 Participants | 76 Participants | 24 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 105 | 0 / 57 |
| other Total, other adverse events | 105 / 105 | 57 / 57 |
| serious Total, serious adverse events | 0 / 105 | 0 / 57 |
Outcome results
Primary
Area Under the Curve (AUC) of Numeric Rating Scale (NRS) Pain Intensity Scores Through 48 Hours
AUC of NRS pain intensity scores through 48 hours. Pain intensity scores were measured on a 10-point scale (0=no pain and 10=worst possible pain)
Time frame: 0-48 hours
Population: Primary efficacy population: all participants who received study drug, underwent the surgery, and were enrolled under protocol amendment 2, according to which pain intensity scores were collected before each use of rescue medication. Analysis was based on randomized treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| EXPAREL 133 mg | Area Under the Curve (AUC) of Numeric Rating Scale (NRS) Pain Intensity Scores Through 48 Hours | 178.9 units on NRS scale*hr | Standard Error 10.3 |
| Placebo | Area Under the Curve (AUC) of Numeric Rating Scale (NRS) Pain Intensity Scores Through 48 Hours | 181.6 units on NRS scale*hr | Standard Error 13.63 |
p-value: 0.866195% CI: [-33.5, 28.2]ANOVA
Secondary
Area Under the Curve (AUC) of Numeric Rating Scale (NRS) Pain Intensity Scores Through 24 Hours
AUC of NRS pain intensity scores through 24 hours. Pain intensity scores were measured on a 10-point scale (0=no pain and 10=worst possible pain) 0-24 hours
Time frame: 0-24 hours
Population: Primary efficacy population: all participants who received study drug, underwent the surgery, and were enrolled under protocol amendment 2, according to which pain intensity scores were collected before each use of rescue medication. Analysis was based on randomized treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| EXPAREL 133 mg | Area Under the Curve (AUC) of Numeric Rating Scale (NRS) Pain Intensity Scores Through 24 Hours | 102.4 units on NRS scale*hr | Standard Error 4.73 |
| Placebo | Area Under the Curve (AUC) of Numeric Rating Scale (NRS) Pain Intensity Scores Through 24 Hours | 106.4 units on NRS scale*hr | Standard Error 6.26 |
p-value: 0.57895% CI: [-18.2, 10.2]ANOVA
Secondary
Area Under the Curve (AUC) of Numeric Rating Scale (NRS) Pain Intensity Scores Through 72 Hours
AUC of NRS pain intensity scores through 72 hours. Pain intensity scores were measured on a 10-point scale (0=no pain and 10=worst possible pain)
Time frame: 0-72 hours
Population: Primary efficacy population: all participants who received study drug, underwent the surgery, and were enrolled under protocol amendment 2, according to which pain intensity scores were collected before each use of rescue medication. Analysis was based on randomized treatment.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| EXPAREL 133 mg | Area Under the Curve (AUC) of Numeric Rating Scale (NRS) Pain Intensity Scores Through 72 Hours | 241.5 units on NRS scale*hr | Standard Error 15.4 |
| Placebo | Area Under the Curve (AUC) of Numeric Rating Scale (NRS) Pain Intensity Scores Through 72 Hours | 235.6 units on NRS scale*hr | Standard Error 20.38 |
p-value: 0.80195% CI: [-40.2, 52.1]ANOVA
Secondary
Percentage of Opioid-free Subjects Through 24 Hours.
Percentage of opioid-free subjects through 24 hours.
Time frame: 0-24 hours
Population: Primary efficacy population: all participants who received study drug, underwent the surgery, and were enrolled under protocol amendment 2, according to which pain intensity scores were collected before each use of rescue medication. Analysis was based on randomized treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| EXPAREL 133 mg | Percentage of Opioid-free Subjects Through 24 Hours. | 19 Participants |
| Placebo | Percentage of Opioid-free Subjects Through 24 Hours. | 12 Participants |
Secondary
Percentage of Opioid-free Subjects Through 48 Hours.
Percentage of opioid-free subjects through 48 hours.
Time frame: 0-48 hours
Population: Primary efficacy population: all participants who received study drug, underwent the surgery, and were enrolled under protocol amendment 2, according to which pain intensity scores were collected before each use of rescue medication. Analysis was based on randomized treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| EXPAREL 133 mg | Percentage of Opioid-free Subjects Through 48 Hours. | 19 Participants |
| Placebo | Percentage of Opioid-free Subjects Through 48 Hours. | 12 Participants |
Secondary
Percentage of Opioid-free Subjects Through 72 Hours.
Percentage of opioid-free subjects through 72 hours.
Time frame: 0-72 hours
Population: Primary efficacy population: all participants who received study drug, underwent the surgery, and were enrolled under protocol amendment 2, according to which pain intensity scores were collected before each use of rescue medication. Analysis was based on randomized treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| EXPAREL 133 mg | Percentage of Opioid-free Subjects Through 72 Hours. | 18 Participants |
| Placebo | Percentage of Opioid-free Subjects Through 72 Hours. | 12 Participants |