A Multi-surgery Assessment of ZYNRELEF (HTX-011), AMAZE. Master Protocol HTX-011-401.

Study Overview
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Brief Summary
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This is a Phase 4, randomized, blinded, active-controlled, multicohort study to evaluate HTX-011 compared with bupivacaine HCl in subjects undergoing different surgical procedures. Each parallel cohort will enroll subjects undergoing a unique surgical procedure: total shoulder arthroplasty (TSA) in Cohort 1 and abdominoplasty in Cohort 2.

Official Title
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A Phase 4, Randomized, Blinded, Active-Controlled Study of HTX-011 in Subjects Undergoing Different Surgical Procedures

Conditions
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Analgesia

Intervention / Treatment
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* Drug: Bupivacaine Hydrochloride
* Drug: Bupivacaine Hydrochloride
* Drug: HTX-011
* Device: Luer lock applicator
* Drug: Ibuprofen
* Drug: Acetaminophen


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has American Society of Anesthesiologists (ASA) Physical Status of I, II, or III. Is scheduled to undergo a unilateral Total Shoulder Arthroplasty (TSA) or abdominoplasty. Exclusion Criteria: Is undergoing a revision surgery. Has a known or suspected history of hypersensitivity or clinically significant idiosyncratic reaction to bupivacaine (or other local anesthetics), NSAIDs, acetaminophen, oxycodone, morphine, or hydromorphone. History of severe allergic reaction to aspirin or other NSAIDs, or known history of severe gastrointestinal adverse reactions associated with NSAID use. Has taken meloxicam within 10 days prior to the scheduled surgery, or any NSAID within 24 hours prior to the scheduled surgery, with the exception of subjects on low-dose (≤100 mg) daily acetylsalicylic acid for cardioprotection. Opioid use for most days within the last 3 months prior to Screening in the opinion of the Investigator. Has been administered immediate-release bupivacaine HCl within 5 days prior to the scheduled surgery, or a modified-release bupivacaine product within 14 days prior to the scheduled surgery. Has initiated treatment with any of the following medications within 1 month prior to study drug administration: selective serotonin reuptake inhibitors, selective norepinephrine reuptake inhibitors, gabapentin, pregabalin, duloxetine, or cyclooxygenase-2 inhibitors. Has been administered systemic steroids within 5 half-lives or 10 days prior to the scheduled surgery (whichever is longer). Has a known or suspected history of drug abuse, a positive drug screen (except for cannabinoids) on the day of surgery, or a history of alcohol abuse within the past 5 years. Suspected or confirmed active coronavirus disease 2019 (COVID-19) infection. 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, other than for diagnostic procedures (eg, colonoscopy). Has a body mass index (BMI) >40 kg/m2. Had undergone prior abdominoplasty or major abdominal wall surgery.

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
Interventional Model Description: In each cohort, subjects will be randomized in a 2:1 ratio to HTX-011 or bupivacaine HCl, respectively. All subjects will receive a scheduled postoperative non opioid multimodal analgesic (MMA) regimen.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Group 1 Cohort 1<br>HTX-011 + multimodal analgesic (MMA) regimen | Drug: HTX-011<br>* 400 mg<br>Device: Luer lock applicator<br>* Applicator for instillation<br>Drug: Ibuprofen<br>* 400 mg<br>Drug: Acetaminophen<br>* 1 g<br>|
| Active Comparator: Treatment Group 2 Cohort 1<br>Bupivacaine HCl + MMA | Drug: Bupivacaine Hydrochloride<br>* 100 mg<br>Drug: Ibuprofen<br>* 400 mg<br>Drug: Acetaminophen<br>* 1 g<br>|
| Experimental: Treatment Group 1 Cohort 2<br>HTX-011 + MMA | Drug: HTX-011<br>* 400 mg<br>Device: Luer lock applicator<br>* Applicator for instillation<br>Drug: Ibuprofen<br>* 400 mg<br>Drug: Acetaminophen<br>* 1 g<br>|
| Active Comparator: Treatment Group 2 Cohort 2<br>Bupivacaine HCl + MMA | Drug: Bupivacaine Hydrochloride<br>* 125 mg<br>Drug: Ibuprofen<br>* 400 mg<br>Drug: Acetaminophen<br>* 1 g<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 (TEAEs). |  | Through Day 15 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum concentration (Cmax) of bupivacaine and meloxicam |  | Through 144 hours | 
| Time of occurrence of maximum concentration (Tmax) of bupivacaine and meloxicam |  | Through 144 hours | 
| Area under the concentration-time curve from Time 0 to the time of the last quantifiable concentration (AUClast) of bupivacaine and meloxicam |  | Through 144 hours | 
| Area under the concentration-time curve from Time 0 extrapolated to infinity (AUCinf) of bupivacaine and meloxicam |  | Through 144 hours | 
| Apparent terminal half-life (t½) of bupivacaine and meloxicam |  | Through 144 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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postoperative pain, total shoulder arthroplasty, abdominoplasty, multimodal analgesia