Postoperative Pain
Conditions
Brief summary
A Phase 2, Randomized, Controlled Evaluation of the Efficacy and Safety of HTX-011 or HTX-002 for Post-Operative Analgesia Following Abdominoplasty Surgery
Detailed description
This study includes multiple formulations for formulation selection of the fixed-combination product and for the factorial design assessment of the contribution of the bupivacaine component. HTX-011A is the second formulation studied (HTX-011-49). HTX-011B is the final formulation studied (HTX-011-56), which was also included in subsequent Phase 2b and Phase 3 studies. For the factorial design assessment, HTX-002, a bupivacaine-only formulation in the same HTX-011 proprietary polymer was evaluated.
Interventions
DRUGHTX-011B
HTX- 011B (bupivacaine/meloxicam) via injection
DRUGPlacebo
Saline placebo via injection
DRUGHTX-011A
HTX- 011A (bupivacaine/meloxicam) via injection
DRUGHTX-002
HTX-002 via combination
DRUGBupivicaine HCl
Bupivacaine HCl via injection
Sponsors
Heron Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
DOUBLE (Subject, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
Subjects must meet all of the following criteria to be considered eligible to participate in the study: 1. Be scheduled to undergo abdominoplasty surgery that is amenable to treatment with a long acting local anesthetic as per the anesthesia protocol 2. Be American Society of Anesthesiology (ASA) physical Class I or II 3. Subjects 18 years of age or older 4. Have clinical laboratory values that are within normal limits (WNL); subjects with AST/ALT \< 3 x ULN, and/or creatinine \< 2 x ULN are acceptable. 5. Have a body mass index ≤ 30 kg/m2 6. Female subjects are eligible only if all of the following apply: * Not pregnant (female subject of child bearing potential must have a negative serum pregnancy tests at screening and negative urine pregnancy test before surgery) * Not lactating * Not planning to become pregnant during the study * Be surgically sterile; or at least two years post-menopausal; or have a monogamous partner who is surgically sterile; or is 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 visits and commits to the use of an acceptable form of birth control for the duration of the study 7. Male subjects must be surgically sterile (biologically or surgically) or commit to the use of a reliable method of birth control for the duration of the study 8. Does NOT have, as determined by the investigator or the study's medical monitor, a history or clinical manifestations of significant renal, hepatic, cardiovascular, metabolic, neurologic, psychiatric, or other condition that would preclude participation in the study 9. Must be able to understand study procedures and be willing to comply and give informed consent for the conduct of all study procedures, using an IRB approved consent
Exclusion criteria
Subjects who meet any of the following criteria will be excluded from participating in the study: 1. Have a contraindication or be allergic to any medication to be used during the trial period 2. Have another painful physical condition that, in the opinion of the investigator, may confound the assessments of post-operative pain 3. Have a history of migraine or frequent headaches, seizures, or are currently taking anticonvulsants 4. Currently taking analgesics for a chronically painful condition, or has taken long acting opioids within 3 days of surgery, or taken any opioids within 24 hours of surgery 5. Previous abdominal surgery, as determined by the investigator, that would preclude participation in the study 6. Subjects that require liposuction as part of the abdominoplasty procedure in Part A of the protocol 7. Subjects that are to have ancillary procedures performed during the abdominoplasty surgery that are unrelated to the abdominal area (breast reduction, breast augmentation, etc.) 8. Subjects unable to discontinue medications that have not been at a stable dose for at least 14 days prior to the scheduled abdominoplasty procedure and before dosing with investigational product 9. Subjects taking the following medications; anticonvulsants, sedatives (including benzodiazepines) corticosteroids (by any means of administration), nonsteroidal anti-inflammatory drugs (NSAIDS) within 24 hours of study drug dosing, morphine, monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), neuroleptics, or serotonin-norepinephrine reuptake inhibitors (SNRIs). Gabapentin and pregabalin are not permitted 10. Have a known or suspected history of alcohol or drug abuse 11. Have positive results on the alcohol breath test indicative of alcohol abuse or urine drug screen indicative of illicit drug use (unless results can be explained by a current prescription or acceptable over-the-counter medication at screening as determined by the investigator). The urine drug screen prior to surgery must be negative 12. Have evidence of a clinically significant 12-lead ECG abnormality according to the judgment of the investigator 13. Have received any investigational product within 30 days before start of study 14. Have previously received HTX-011 in clinical trials 15. Experiences a clinically significant event during surgery prior to the administration of the investigational product (e.g., excessive bleeding, hemodynamic instability) that would render the subject medically unstable, complicate their post-surgical course, or significantly increase the risk of study drug administration as per the judgment of the investigator. This will result in the subject being reported as randomized, not treated. 16. Subjects with sleep apnea or are on home continuous positive airway pressure (CPAP) 17. Subjects who are receiving oxygen therapy at the time of screening
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Summed Pain Intensity Scores Collected Over 24 Hours | 24 hours | The SPI is derived by summing the pain intensity score weighted by the scheduled time duration. SPI0-24 will be calculated by summing the Pain intensity (PI) score at the relevant time points weighted by the scheduled time duration since the prior PI assessment as follows: SPI0-24= PI1+PI2+2\*PI4+2\*PI6+2\*PI8+2\*PI10+2\*PI12+2\*PI14+4\*PI18+6\*PI24. Min = 0 (if PI=0 at every time) and Max = 240 (if PI=10 at every time). |
Countries
United States
Participant flow
Pre-assignment details
1 Subject underwent complete abdominoplasty and was unintentionally randomized to receive HTX-002 (intended for mini-abdominoplasty procedure only). This subject is included in the Safety, ITT, and mITT Populations.
Participants by arm
| Arm | Count |
|---|---|
| Part A, Cohort A: HTX-011A HTX- 011A (bupivacaine/meloxicam), 200 mg/6 mg via injection. | 20 |
| Parts A and B, Cohort B: Saline Placebo Saline placebo via injection. | 63 |
| Part A, Cohorts C Through F: HTX-011B Cohort C: HTX- 011B (bupivacaine/meloxicam), 200 mg/6 mg via injection; Cohort D: HTX- 011B (bupivacaine/meloxicam), 400 mg/12 mg via injection; Cohort E: HTX- 011B (bupivacaine/meloxicam), 400 mg/12 mg via combination; Cohort F: HTX- 011B (bupivacaine/meloxicam), 600 mg/18 mg via injection. | 48 |
| Part B, Cohort A: HTX-002 HTX-002, 400 mg via combination. | 17 |
| Part C, Cohort A Through C: HTX-011B Cohort A: HTX-011B (bupivacaine/meloxicam), 400 mg/12 mg via instillation; Cohort B: HTX-011B (bupivacaine/meloxicam), 400 mg/12 mg via combination; Cohort C: HTX-011B (bupivacaine/meloxicam), 300 mg/9 mg via combination. | 77 |
| Part C, Cohort D: Bupivacaine HCI Bupivacaine HCl 100 mg via injection. | 17 |
| Part C, Cohort E: Saline Placebo Saline placebo via injection. | 32 |
| Total | 274 |
Baseline characteristics
| Characteristic | Part A, Cohort A: HTX-011A | Total | Part C, Cohort E: Saline Placebo | Part C, Cohort D: Bupivacaine HCI | Part C, Cohort A Through C: HTX-011B | Part B, Cohort A: HTX-002 | Part A, Cohorts C Through F: HTX-011B | Parts A and B, Cohort B: Saline Placebo |
|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 40.3 years STANDARD_DEVIATION 10.11 | 41.8 years STANDARD_DEVIATION 9.67 | 43.2 years STANDARD_DEVIATION 8.53 | 40.6 years STANDARD_DEVIATION 6.38 | 39.9 years STANDARD_DEVIATION 9.44 | 47.3 years STANDARD_DEVIATION 9.77 | 41.0 years STANDARD_DEVIATION 9.66 | 43.3 years STANDARD_DEVIATION 10.56 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 11 Participants | 0 Participants | 0 Participants | 3 Participants | 1 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 64 Participants | 9 Participants | 4 Participants | 16 Participants | 4 Participants | 13 Participants | 13 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 3 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 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 | 0 Participants |
| Race (NIH/OMB) White | 13 Participants | 194 Participants | 23 Participants | 13 Participants | 57 Participants | 12 Participants | 31 Participants | 45 Participants |
| Region of Enrollment United States | 20 participants | 274 participants | 32 participants | 17 participants | 77 participants | 17 participants | 48 participants | 63 participants |
| Sex: Female, Male Female | 20 Participants | 272 Participants | 32 Participants | 17 Participants | 77 Participants | 17 Participants | 46 Participants | 63 Participants |
| Sex: Female, Male Male | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 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 | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 0 / 63 | 0 / 48 | 0 / 17 | 0 / 77 | 0 / 17 | 0 / 32 |
| other Total, other adverse events | 19 / 20 | 50 / 63 | 42 / 48 | 13 / 17 | 67 / 77 | 15 / 17 | 27 / 32 |
| serious Total, serious adverse events | 0 / 20 | 0 / 63 | 0 / 48 | 0 / 17 | 1 / 77 | 1 / 17 | 0 / 32 |
Outcome results
Primary
Summed Pain Intensity Scores Collected Over 24 Hours
The SPI is derived by summing the pain intensity score weighted by the scheduled time duration. SPI0-24 will be calculated by summing the Pain intensity (PI) score at the relevant time points weighted by the scheduled time duration since the prior PI assessment as follows: SPI0-24= PI1+PI2+2\*PI4+2\*PI6+2\*PI8+2\*PI10+2\*PI12+2\*PI14+4\*PI18+6\*PI24. Min = 0 (if PI=0 at every time) and Max = 240 (if PI=10 at every time).
Time frame: 24 hours
Population: mITT Population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A, Cohort A: HTX-011A | Summed Pain Intensity Scores Collected Over 24 Hours | 92.60 Units on a scale | Standard Deviation 47.531 |
| Parts A and B, Cohort B: Saline Placebo | Summed Pain Intensity Scores Collected Over 24 Hours | 96.16 Units on a scale | Standard Deviation 43.775 |
Primary
Summed Pain Intensity Scores Collected Over 24 Hours
The SPI is derived by summing the pain intensity score weighted by the scheduled time duration. SPI0-24 will be calculated by summing the Pain intensity (PI) score at the relevant time points weighted by the scheduled time duration since the prior PI assessment as follows: SPI0-24= PI1+PI2+2\*PI4+2\*PI6+2\*PI8+2\*PI10+2\*PI12+2\*PI14+4\*PI18+6\*PI24. Min = 0 (if PI=0 at every time) and Max = 240 (if PI=10 at every time).
Time frame: 24 Hours
Population: mITT Population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A, Cohort A: HTX-011A | Summed Pain Intensity Scores Collected Over 24 Hours | 79.53 Units on a scale | Standard Deviation 40.458 |
| Parts A and B, Cohort B: Saline Placebo | Summed Pain Intensity Scores Collected Over 24 Hours | 74.64 Units on a scale | Standard Deviation 46.893 |
| Part A, Cohort E: HTX-011B | Summed Pain Intensity Scores Collected Over 24 Hours | 66.38 Units on a scale | Standard Deviation 53.214 |
| Part A, Cohort F: HTX-011B | Summed Pain Intensity Scores Collected Over 24 Hours | 89.46 Units on a scale | Standard Deviation 45.402 |
| Part B, Cohort A: HTX-002 | Summed Pain Intensity Scores Collected Over 24 Hours | 83.85 Units on a scale | Standard Deviation 37.326 |
Primary
Summed Pain Intensity Scores Collected Over 24 Hours
The SPI is derived by summing the pain intensity score weighted by the scheduled time duration. SPI0-24 will be calculated by summing the Pain intensity (PI) score at the relevant time points weighted by the scheduled time duration since the prior PI assessment as follows: SPI0-24= PI1+PI2+2\*PI4+2\*PI6+2\*PI8+2\*PI10+2\*PI12+2\*PI14+4\*PI18+6\*PI24. Min = 0 (if PI=0 at every time) and Max = 240 (if PI=10 at every time).
Time frame: 24 Hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A, Cohort A: HTX-011A | Summed Pain Intensity Scores Collected Over 24 Hours | 113.72 Units on a scale | Standard Deviation 49.109 |
| Parts A and B, Cohort B: Saline Placebo | Summed Pain Intensity Scores Collected Over 24 Hours | 83.23 Units on a scale | Standard Deviation 43.966 |
| Part A, Cohort E: HTX-011B | Summed Pain Intensity Scores Collected Over 24 Hours | 104.65 Units on a scale | Standard Deviation 44.14 |
| Part A, Cohort F: HTX-011B | Summed Pain Intensity Scores Collected Over 24 Hours | 110.22 Units on a scale | Standard Deviation 41.98 |
| Part B, Cohort A: HTX-002 | Summed Pain Intensity Scores Collected Over 24 Hours | 121.93 Units on a scale | Standard Deviation 52.53 |