Evaluation of the Efficacy and Safety of HTX-011 for Postoperative Analgesia Following Abdominoplasty Surgery

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase 2, Randomized, Controlled Evaluation of the Efficacy and Safety of HTX-011 or HTX-002 for Post-Operative Analgesia Following Abdominoplasty Surgery

Conditions
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Postoperative Pain

Intervention / Treatment
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* Drug: HTX-011B
* Drug: Placebo
* Drug: HTX-011A
* Drug: HTX-002
* Drug: Bupivicaine HCl


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must meet all of the following criteria to be considered eligible to participate in the study: Be scheduled to undergo abdominoplasty surgery that is amenable to treatment with a long acting local anesthetic as per the anesthesia protocol Be American Society of Anesthesiology (ASA) physical Class I or II Subjects 18 years of age or older 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. Have a body mass index ≤ 30 kg/m2 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 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 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 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: Have a contraindication or be allergic to any medication to be used during the trial period Have another painful physical condition that, in the opinion of the investigator, may confound the assessments of post-operative pain Have a history of migraine or frequent headaches, seizures, or are currently taking anticonvulsants 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 Previous abdominal surgery, as determined by the investigator, that would preclude participation in the study Subjects that require liposuction as part of the abdominoplasty procedure in Part A of the protocol Subjects that are to have ancillary procedures performed during the abdominoplasty surgery that are unrelated to the abdominal area (breast reduction, breast augmentation, etc.) 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 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 Have a known or suspected history of alcohol or drug abuse 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 Have evidence of a clinically significant 12-lead ECG abnormality according to the judgment of the investigator Have received any investigational product within 30 days before start of study Have previously received HTX-011 in clinical trials 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. Subjects with sleep apnea or are on home continuous positive airway pressure (CPAP) Subjects who are receiving oxygen therapy at the time of screening

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A, Cohort A: HTX-011A<br>HTX- 011A (bupivacaine/meloxicam), 200 mg/6 mg via injection | Drug: HTX-011A<br>* HTX- 011A (bupivacaine/meloxicam) via injection<br>|
| Placebo Comparator: Parts A and B, Cohort B: Saline Placebo<br>Saline placebo via injection | Drug: Placebo<br>* Saline placebo via injection<br>|
| Experimental: Part A, Cohort C: HTX-011B<br>HTX- 011B (bupivacaine/meloxicam), 200 mg/6 mg via injection | Drug: HTX-011B<br>* HTX- 011B (bupivacaine/meloxicam) via injection<br>|
| Experimental: Part A, Cohort D: HTX-011B<br>HTX- 011B (bupivacaine/meloxicam), 400 mg/12 mg via injection | Drug: HTX-011B<br>* HTX- 011B (bupivacaine/meloxicam) via injection<br>|
| Experimental: Part A, Cohort E: HTX-011B<br>HTX- 011B (bupivacaine/meloxicam), 400 mg/12 mg via combination | Drug: HTX-011B<br>* HTX- 011B (bupivacaine/meloxicam) via injection<br>|
| Experimental: Part A, Cohort F: HTX-011B<br>HTX- 011B (bupivacaine/meloxicam), 600 mg/18 mg via injection | Drug: HTX-011B<br>* HTX- 011B (bupivacaine/meloxicam) via injection<br>|
| Experimental: Part B, Cohort A: HTX-002<br>HTX-002, 400 mg via combination | Drug: HTX-002<br>* HTX-002 via combination<br>|
| Experimental: Part C, Cohort A: HTX-011B<br>HTX-011B (bupivacaine/meloxicam), 400 mg/12 mg via instillation | Drug: HTX-011B<br>* HTX- 011B (bupivacaine/meloxicam) via injection<br>|
| Experimental: Part C, Cohort B: HTX-011B<br>HTX-011B (bupivacaine/meloxicam), 400 mg/12 mg via combination | Drug: HTX-011B<br>* HTX- 011B (bupivacaine/meloxicam) via injection<br>|
| Experimental: Part C, Cohort C: HTX-011B<br>HTX-011B (bupivacaine/meloxicam), 300 mg/9 mg via combination | Drug: HTX-011B<br>* HTX- 011B (bupivacaine/meloxicam) via injection<br>|
| Active Comparator: Part C, Cohort D: Bupivacaine HCI<br>Bupivacaine HCl, 100 mg via injection | Drug: Bupivicaine HCl<br>* Bupivacaine HCl via injection<br>|
| Placebo Comparator: Part C, Cohort E: Saline Placebo<br>Saline placebo via injection | Drug: Placebo<br>* Saline placebo via injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | 24 hours |