A Pilot Study to Investigate the Safety, Efficacy, Pharmacokinetics and Bioavailability of HTX-011, HTX-002, or HTX-009 Administered Via Injection and/or Topical Application Following Unilateral Open Inguinal Herniorrhaphy

Study Overview
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Brief Summary
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A Phase 2, Randomized, Pilot Study to Investigate the Safety, Efficacy, Pharmacokinetics and Bioavailability of HTX-011, HTX-002, or HTX-009 Administered Via Injection and/or Topical Application Following Unilateral Open Inguinal Herniorrhaphy

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 each component. HTX-011 is the initial formulation studied (HTX-011-19). 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, and HTX-009, a meloxicam-only formulation in the same HTX-011 proprietary polymer, were evaluated.

Official Title
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A Phase 2, Randomized, Pilot Study to Investigate the Safety, Efficacy, Pharmacokinetics and Bioavailability of HTX-011, HTX-002, or HTX-009 Administered Via Injection and/or Topical Application Following Unilateral Open Inguinal Herniorrhaphy

Conditions
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Postoperative Pain

Intervention / Treatment
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* Drug: HTX-011
* Drug: Placebo
* Drug: HTX-002
* Drug: Bupivacaine HCI (Marcaine)
* Drug: HTX-011A
* Drug: HTX-011B
* Drug: HTX-009


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Be male or female 18 years of age or older. 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 test 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 and for 30 days from completion of the study Male: o 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 until at least 1 week after the administration of study medication. Plan to undergo a unilateral inguinal herniorrhaphy Have the ability and be willing to comply with the study procedures Must be able to understand study procedures and give informed consent for the conduct for all study procedures, using an IRB approved consent form. Exclusion Criteria: Unwilling to sign informed consent or not willing or able to complete all study procedures Have a contraindication or be allergic to any medication to be used during the trial period Have clinically significant cardiac abnormalities, that in the opinion of the investigator would pose a health risk to the subject should they participate in the trial Have American Society of Anesthesiologists (ASA) Physical Status classification system category 4 or greater (Appendix E) Have clinically significant renal or hepatic abnormalities (defined as an AST or ALT > 3x ULN, creatinine > 2x ULN) Have another painful condition that may confound pain assessments Have another surgery planned within 30 days of procedure, or presents with bilateral or recurrent inguinal hernia, other hernia presentations, or hernias with large scrotal component that would be difficult to reduce surgically Have a known or suspected history of alcohol or drug abuse, or a positive drug screen 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 Subjects with documented sleep apnea or are on home continuous positive airway pressure (CPAP) Female subjects who are pregnant (positive pregnancy test at screening or on the day of surgery) Subjects who are receiving oxygen therapy at the time of screening Have participated in a clinical trial within 30 days of planned surgery Have a body mass index (BMI) > 39 kg/m2

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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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A, Cohort A<br>HTX-011 (bupivacaine/meloxicam), 200 mg/6 mg by injection. | Drug: HTX-011<br>* HTX-011 (bupivacaine/meloxicam) by injection.<br>|
| Experimental: Part A, Cohort B<br>HTX-011(bupivacaine/meloxicam), 400 mg/12 mg by injection. | Drug: HTX-011<br>* HTX-011 (bupivacaine/meloxicam) by injection.<br>|
| Experimental: Part A, Cohort C<br>HTX-011 (bupivacaine/meloxicam), 200 mg/6 mg by instillation. | Drug: HTX-011<br>* HTX-011 (bupivacaine/meloxicam) by injection.<br>|
| Experimental: Part A, Cohort D<br>HTX-011 (bupivacaine/meloxicam), 400 mg/12 mg by instillation. | Drug: HTX-011<br>* HTX-011 (bupivacaine/meloxicam) by injection.<br>|
| Experimental: Part A, Cohort E<br>HTX-011 (bupivacaine/meloxicam), 400 mg/12 mg by injection and instillation (combination). | Drug: HTX-011<br>* HTX-011 (bupivacaine/meloxicam) by injection.<br>|
| Placebo Comparator: Part A, Cohort F<br>Saline placebo by injection. | Drug: Placebo<br>* Saline placebo by injection.<br>|
| Experimental: Part B, Cohort A<br>HTX-011A (bupivacaine/meloxicam), 200 mg/6 mg by injection. | Drug: HTX-011A<br>* HTX-011A (bupivacaine/meloxicam) by injection.<br>|
| Experimental: Part B, Cohort B<br>HTX-011A (bupivacaine/meloxicam) 400 mg12 mg by injection. | Drug: HTX-011A<br>* HTX-011A (bupivacaine/meloxicam) by injection.<br>|
| Experimental: Part B, Cohort C<br>HTX-011B (bupivacaine/meloxicam), 200 mg/6 mg by injection. | Drug: HTX-011B<br>* HTX-011B (bupivacaine/meloxicam) by injection, instillation or combination.<br>|
| Experimental: Part B, Cohort D<br>HTX-011B (bupivacaine/meloxicam), 400 mg/12 mg by injection. | Drug: HTX-011B<br>* HTX-011B (bupivacaine/meloxicam) by injection, instillation or combination.<br>|
| Placebo Comparator: Part B, Cohort E<br>Saline placebo by injection. | Drug: Placebo<br>* Saline placebo by injection.<br>|
| Experimental: Part C, Cohort A<br>HTX-002, 200 mg by injection or instillation. | Drug: HTX-002<br>* HTX-002, by injection or instillation (pooled).<br>|
| Experimental: Part B, Cohort F<br>HTX-002, 400 mg by injection or instillation. | Drug: HTX-002<br>* HTX-002, by injection or instillation (pooled).<br>|
| Experimental: Part C, Cohort B<br>HTX-011B (bupivacaine/meloxicam), 200 mg/6 mg by instillation. | Drug: HTX-011B<br>* HTX-011B (bupivacaine/meloxicam) by injection, instillation or combination.<br>|
| Experimental: Part B, Cohort G<br>HTX-011B (bupivacaine/meloxicam), 400 mg/12 mg by instillation. | Drug: HTX-011B<br>* HTX-011B (bupivacaine/meloxicam) by injection, instillation or combination.<br>|
| Placebo Comparator: Part C, Cohort C<br>Saline placebo by instillation. | Drug: Placebo<br>* Saline placebo by injection.<br>|
| Active Comparator: Part C, Cohort D<br>Bupivacaine HCI (Marcaine), 75 mg by injection. | Drug: Bupivacaine HCI (Marcaine)<br>* Bupivacaine HCI (Marcaine) by injection.<br>|
| Experimental: Part D, Cohort A<br>HTX-011B (bupivacaine/meloxicam), 400 mg/13 mg via a combination of injection and instillation. | Drug: HTX-011B<br>* HTX-011B (bupivacaine/meloxicam) by injection, instillation or combination.<br>|
| Experimental: Part E, Cohort A<br>HTX-009, 12 mg by injection and instillation (combination). | Drug: HTX-009<br>* HTX-009 by injection and instillation (combination).<br>|
| Experimental: Part F, Cohort A<br>HTX-011B (bupivacaine/meloxicam), 300 mg/9 mg by instillation. | Drug: HTX-011B<br>* HTX-011B (bupivacaine/meloxicam) by injection, instillation or combination.<br>|
| Experimental: Part F, Cohort B<br>Bupivacaine HCI (Marcaine), 75 mg by injection. | Drug: Bupivacaine HCI (Marcaine)<br>* Bupivacaine HCI (Marcaine) by injection.<br>|
| Placebo Comparator: Part F, Cohort C<br>Saline placebo by injection. | Drug: Placebo<br>* Saline placebo by injection.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Summed Pain Intensity (SPI) Score. | 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 |