Dose-Escalation Study of HTX-034 Following Bunionectomy

Study Overview
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Brief Summary
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This is a Phase 1b/2, randomized, blinded, active-controlled study. Phase 1b will evaluate escalating doses of HTX-034 compared with bupivacaine HCl. Phase 2 will be a dose-expansion phase to evaluate additional subjects treated with the HTX-034 dose selected based on Phase 1b compared with bupivacaine HCl.

Official Title
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A Phase 1b/2, Randomized, Blinded, Active-Controlled Study of Escalating Doses of HTX-034 for Postoperative Analgesia in Subjects Undergoing Unilateral, First Metatarsal Bunionectomy With Osteotomy and Internal Fixation

Conditions
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Bunions

Intervention / Treatment
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* Drug: HTX-034
* Drug: HTX-034
* Device: Luer lock applicator
* Drug: Bupivacaine HCl


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Is medically fit to undergo an elective unilateral, first metatarsal bunionectomy with osteotomy and internal fixation under regional anesthesia; no neuraxial technique (eg, no spinal, epidural, or general anesthesia). Has an American Society of Anesthesiologists (ASA) Physical Status of I, II, or III. Female subjects are eligible only if not pregnant, not lactating, not planning to become pregnant during the study; sterile, or using acceptable contraceptives. Exclusion Criteria: Had contralateral foot bunionectomy in the past 3 months. Has a planned concurrent surgical procedure. Has a contraindication or a known or suspected history of hypersensitivity or clinically significant idiosyncratic reaction to required study medications. Has a pre-existing concurrent acute or chronic painful physical/restrictive condition expected to require analgesic treatment in the postoperative period for pain. Has received or is taking a contraindicated or prohibited medications. Received an investigational product or device in a clinical trial within 30 days or within 5 elimination half lives. Has a known or suspected history of drug abuse, a positive drug screen on the day of surgery, or a recent history of alcohol abuse. Has a history of clinically significant cardiac abnormality such as myocardial infarction within 6 months. Has a history of coronary artery bypass graft surgery within 12 months. Has a history of known or suspected coagulopathy. As per subject history and/or medical records, has active infection or is currently undergoing treatment for Hepatitis B, Hepatitis C, or human immunodeficiency virus (HIV). Has uncontrolled anxiety, psychiatric, or neurological disorder. Had a malignancy in the last year, with the exception of nonmetastatic basal cell or squamous cell carcinoma of the skin or localized carcinoma in situ of the cervix. Has undergone 3 or more surgeries within 12 months. Has a known history of glucose-6-phosphate dehydrogenase deficiency. Has any of the following laboratory abnormalities during Screening (1 retest permitted): Severe liver function impairment. Severe kidney function impairment. Platelet count <100,000/μL, hemoglobin <12 g/dL, or hematocrit <35%. Has 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: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1b (Cohort 1)<br>Fixed dose of HTX-034. | Drug: HTX-034<br>* HTX-034, low dose<br>Device: Luer lock applicator<br>* Applicator for instillation<br>|
| Experimental: Phase 1b (Cohort 2)<br>Individualized dose of HTX-034. | Drug: HTX-034<br>* HTX-034, high dose<br>Device: Luer lock applicator<br>* Applicator for instillation<br>|
| Experimental: Phase 2 (Expansion): Low Dose<br>Fixed dose of HTX-034. | Drug: HTX-034<br>* HTX-034, low dose<br>Device: Luer lock applicator<br>* Applicator for instillation<br>|
| Experimental: Phase 2 (Expansion): High Dose<br>Individualized dose of HTX-034. | Drug: HTX-034<br>* HTX-034, high dose<br>Device: Luer lock applicator<br>* Applicator for instillation<br>|
| Active Comparator: Phase 1b and Phase 2<br>Bupivacaine HCl. | Drug: Bupivacaine HCl<br>* Bupivacaine HCl, 50 mg<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment-emergent adverse events (TEAE's) (Phase 1B) |  | 42 days | 
| Mean area under the curve (AUC) of the NRS scores through 72 hours (AUC0-72) for the pooled Phase 1b and Phase 2 |  | 7 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum plasma concentration (Cmax) of HTX-034 |  | 29 days | 
| Time of maximum plasma concentration (Tmax) of HTX-034 |  | 29 days | 
| Area under the concentration-time curve from Time 0 to the time of the last quantitative concentration (AUClast) of HTX-034 |  | 29 days | 
| Area under the concentration-time curve from Time 0 extrapolated to infinity (AUCinf) of HTX-034 (Phase 1B) |  | 22 days | 
| Apparent terminal half-life (t½) of HTX-034 (Phase 1B) |  | 22 days | 
| Mean AUC of the NRS pain intensity scores |  | 7 days | 
| Total postoperative opioid consumption (in IV Morphine Milligram Equivalents) |  | 7 days | 
| Proportion of subjects who are opioid-free |  | 14 days | 
| Incidence of serious adverse Events (SAE's) |  | 42 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Analgesia, Bunionectomy