Total Knee Arthroplasty Infiltration Study for Postoperative Analgesia

Study Overview
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Brief Summary
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This is a Phase 2b, randomized, double-blind, saline placebo- and active-controlled, multicenter study in subjects undergoing primary unilateral total knee arthroplasty (TKA) to evaluate the analgesic efficacy, safety, and pharmacokinetics (PK) of HTX-011 administered via infiltration to the surgical site.

Official Title
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A Phase 2b, Randomized, Double-Blind, Saline Placebo- and Active-Controlled, Multicenter Study of HTX-011 Via Infiltration for Postoperative Analgesia in Subjects Undergoing Total Knee Arthroplasty

Conditions
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Postoperative Pain

Intervention / Treatment
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* Drug: HTX-011
* Drug: Saline Placebo
* Drug: Bupivicaine HCl
* Drug: Ropivacaine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Is scheduled to undergo primary unilateral TKA under general anesthesia. Has not previously undergone TKA in either knee. Has an American Society of Anesthesiologists Physical Status of I, II, or III. Is able to demonstrate motor function by performing a timed 20-meter walk unassisted, but with the optional use of a 4-legged walker for balance. 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: Has a planned concurrent surgical procedure (eg, bilateral TKA). Has a pre-existing concurrent acute or chronic painful/restrictive physical condition that may require analgesic treatment in the postoperative period for pain. Has a contraindication or a known or suspected history of hypersensitivity or idiosyncratic reaction to required study medications. Has known or suspected daily use of opioids for 7 or more consecutive days within the previous 6 months. Has taken NSAIDs within 10 days prior to the scheduled surgery. Has taken opioids within 24 hours prior to the scheduled surgery (3 days for long-acting). Has been administered bupivacaine within 5 days prior to the scheduled surgery. Has initiated treatment with medications within 1 month prior to study drug administration that can impact pain control. Has been administered systemic steroids within 5 half-lives or 10 days prior to administration of study drug. Has a medical condition such that, in the opinion of the Investigator, participating in the study would pose a health risk to the subject or confound the postoperative assessments. Has a known history of Hepatitis B, human immunodeficiency virus (HIV), or active Hepatitis C. Has uncontrolled anxiety, psychiatric, or neurological disorder that might interfere with study assessments. Has any chronic neuromuscular deficit of either femoral nerve function or thigh musculature. Has any chronic condition or disease that would compromise neurological or vascular assessments. Had a malignancy in the last year, with the exception of non-metastatic basal cell or squamous cell carcinoma of the skin or localized carcinoma in situ of the cervix. 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. Received an investigational product or device in a clinical trial within 30 days or within 5 elimination half lives. Has undergone 3 or more surgeries within 12 months. Has a body mass index (BMI) >38 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1, Group 1: HTX-011<br>HTX-011 (bupivacaine/meloxicam), 200 mg/6 mg via instillation | Drug: HTX-011<br>* HTX-011 (bupivacaine/meloxicam), via instillation<br>|
| Experimental: Cohort 1, Group 2: HTX-011<br>HTX-011 (bupivacaine/meloxicam), 200 mg/6 mg via injection and instillation (combination) | Drug: HTX-011<br>* HTX-011 (bupivacaine/meloxicam), via instillation<br>|
| Placebo Comparator: Cohort 1, Group 3: Saline Placebo<br>Saline placebo via injection | Drug: Saline Placebo<br>* Saline placebo via injection<br>|
| Active Comparator: Cohort 1, Group 4: Bupivacaine HCI<br>Bupivacaine HCl without epinephrine, 125 mg via injection | Drug: Bupivicaine HCl<br>* Bupivacaine HCl without epinephrine<br>|
| Experimental: Cohort 2, Group 1: HTX-011<br>HTX-011 (bupivacaine/meloxicam), 400 mg/12 mg via instillation | Drug: HTX-011<br>* HTX-011 (bupivacaine/meloxicam), via instillation<br>|
| Experimental: Cohort 2, Group 2: HTX-011 + Ropivacaine<br>HTX-011 (bupivacaine/meloxicam), 400 mg/12 mg via instillation; Ropivacaine, 50 mg via injection | Drug: HTX-011<br>* HTX-011 (bupivacaine/meloxicam), via instillation<br>Drug: Ropivacaine<br>* Ropivacaine, via injection<br>|
| Placebo Comparator: Cohort 2, Group 3: Saline Placebo<br>Saline placebo via injection | Drug: Saline Placebo<br>* Saline placebo via injection<br>|
| Active Comparator: Cohort 2, Group 4: Bupivacaine HCI<br>Bupivacaine HCl without epinephrine, 125 mg via injection | Drug: Bupivicaine HCl<br>* Bupivacaine HCl without epinephrine<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Area Under the Curve (AUC) of the NRS-R (Windowed Worst Observation Carried Forward) Pain Intensity Scores | Pain intensity scores are assessed using an 11-point Numeric Rating Scale (NRS) (0-10) where 0 represents no pain and 10 represents worst pain imaginable. NRS scores are recorded at rest (NRS-R). | 48 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Area Under the Curve (AUC) of the NRS-R (Windowed Worst Observation Carried Forward) Pain Intensity Scores | Pain intensity scores are assessed using an 11-point Numeric Rating Scale (NRS) (0-10) where 0 represents no pain and 10 represents worst pain imaginable. NRS scores are recorded at rest (NRS-R). | 72 hours | 
| Mean Total Postoperative Opioid Consumption (in Morphine Equivalents) |  | 72 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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knee, knee replacement, arthroplasty, joint replacement, knee pain