Total Knee Arthroplasty (TKA) Study of HTX-011 in an Multimodal Analgesic Regimen (MMA) Regimen

Study Overview
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Brief Summary
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Phase 3b, open-label single-arm study in which all subjects receive HTX-011 as part of a scheduled non-opioid MMA regimen.

Official Title
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A Phase 3b, Open-Label Study of HTX-011 as Part of a Scheduled Non-Opioid Multimodal Analgesic Regimen in Subjects Undergoing Total Knee Arthroplasty

Conditions
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Analgesia

Intervention / Treatment
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* Drug: HTX-011
* Drug: Ibuprofen
* Drug: Acetaminophen
* Drug: Celecoxib
* Drug: +/- Bupivacaine HCl
* Device: Luer Lock Applicator
* Drug: HTX-011


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Is scheduled to undergo primary unilateral TKA under spinal anesthesia. Has not previously undergone TKA in either knee. Has an American Society of Anesthesiologists (ASA) Physical Status of I, II, or III. Is able to walk at least 20 feet with 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 is at least 2 years post-menopausal; or is in a monogamous relationship with a partner who is surgically sterile; or using acceptable contraceptives. Exclusion Criteria: Has a planned concurrent surgical procedure. Has other pre-existing concurrent acute or chronic painful physical/restrictive condition expected to require analgesic treatment in the postoperative period for pain. Has a contraindication or a known or suspected history of hypersensitivity or clinically significant idiosyncratic reaction to required study medications. Using or expected to use Factor IX Complex or anti-inhibitor coagulant concentrates during the study. 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 with the exception of subjects on low-dose (≤100 mg) daily acetylsalicylic acid for cardioprotection. 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 been administered any local anesthetic within 72 hours 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. 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 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. Is currently undergoing treatment for hepatitis B, hepatitis C, or HIV. Has uncontrolled anxiety, psychiatric, or neurological disorder that, in the opinion of the Investigator, might interfere with study assessments. Has acquired defective color vision or acute gastrointestinal ulcers, either of which could interfere with scheduled study medications. 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 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 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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>HTX-011 + MMA | Drug: HTX-011<br>* Dual-acting local anesthetic. Dose 1.<br>Drug: Ibuprofen<br>* NSAID.<br>Drug: Acetaminophen<br>* Analgesic.<br>Drug: Celecoxib<br>* NSAID.<br>Device: Luer Lock Applicator<br>* Applicator for instillation.<br>|
| Experimental: Cohort 2<br>HTX-011 + MMA | Drug: HTX-011<br>* Dual-acting local anesthetic. Dose 1.<br>Drug: Ibuprofen<br>* NSAID.<br>Drug: Acetaminophen<br>* Analgesic.<br>Drug: Celecoxib<br>* NSAID.<br>Device: Luer Lock Applicator<br>* Applicator for instillation.<br>|
| Experimental: Cohort 3<br>HTX-011 + MMA | Drug: Ibuprofen<br>* NSAID.<br>Drug: Acetaminophen<br>* Analgesic.<br>Drug: Celecoxib<br>* NSAID.<br>Drug: +/- Bupivacaine HCl<br>* Local anesthetic.<br>Device: Luer Lock Applicator<br>* Applicator for instillation.<br>Drug: HTX-011<br>* Dual-acting local anesthetic. Dose 2.<br>|
| Experimental: Cohort 4<br>HTX-011 + MMA | Drug: HTX-011<br>* Dual-acting local anesthetic. Dose 1.<br>Drug: Ibuprofen<br>* NSAID.<br>Drug: Acetaminophen<br>* Analgesic.<br>Device: Luer Lock Applicator<br>* Applicator for instillation.<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 Visual Analogue Scale (VAS). | The Visual Analog Scale (VAS) consists of a straight 10-cm line that represents pain ranging from no pain to pain as bad as it could be. Subjects were asked to mark their current pain level on the line. | 12 through 48 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean AUC of VAS Scores. | The Visual Analog Scale (VAS) consists of a straight 10-cm line that represents pain ranging from no pain to pain as bad as it could be. Subjects were asked to mark their current pain level on the line. | 72 hours | 
| Mean AUC of the NRS of Pain Intensity at Rest (NRS-R). | 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. NRS scores are measured at rest. | 72 hours | 
| Percentage of Subjects With Severe Pain. | Severe Pain defined as a VAS score ≥7.5 cm. | 24 hours, 48 hours, 72 hours | 
| Mean Total Postoperative Opioid Consumption (in IV Morphine Milligram Equivalents [MME]). |  | 72 hours | 
| Percentage of Subjects Who Are Opioid-free |  | 72 Hours to Day 11 | 
| Percentage of Subjects Who Are Opioid-free Through 72 Hours Who Remain Opioid-free Through Day 11. |  | 72 hours through Day 11 | 
| Median Time to First Opioid Rescue Medication. |  | Through 72 hours | 
| Percentage of Subjects Who do Not Receive an Opioid Prescription at Discharge. |  | 72 hours | 
| Percentage of Subjects Who do Not Receive an Opioid Prescription Between Discharge and the Day 11 Visit. |  | 72 hours through Day 11 | 
| Percentage of Subjects Achieving a Score of Good or Better (>1) Pain Control Based on Patient Global Assessment (PGA). | Patient's Global Assessment (PGA) of pain control is a 4-point scale in which subjects rate how well their pain has been controlled (0 = Poor; 1 = Fair; 2 = Good; 3 = Excellent). | 24 hours, 48 hours, 72 hours, Day 11 | 
| Median Time to First Ambulation Postsurgery. |  | 72 hours | 
| Percentage of Subjects Unable to Participate in Each Rehabilitation Session Because of Pain. |  | 72 hours | 
| Percentage of Subjects Who First Achieve an MPADSS Score ≥9. | Subjects were assessed for readiness for discharge using the Modified Post-Anesthesia Discharge Scoring System (MPADSS) that assesses 5 clinical variables: vital signs, ambulation, nausea/vomiting, pain, and surgical bleeding, each on a 3-point scale of 0, 1, or 2 with 0 being the worst score and 2 being the best score. Subjects with an MPADSS score of 9 or 10 were considered ready for discharge. | 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24, hours, 36 hours, 48 hours, 60 hours, 72 hours | 
| Percentage of Subjects Who Are Discharged Home vs to a Skilled Nursing Facility. | Number Analyzed represents Subjects who were discharged home. | 72 hours | 
| Mean Overall Benefit of Analgesia Score (OBAS). | Subjects were questioned about their overall benefit of analgesia. Overall benefit of analgesia score (OBAS) assesses current pain at rest, vomiting, itching, sweating, freezing, dizziness, and overall satisfaction with postoperative pain during the previous 24 hours. To calculate the OBAS score, each of the subscale scores (0=minimum; 4=maximum) are summed for a combined OBAS score. Possible scores could range from 0 to 28 with a lower score indicating greater benefit. | 24 hours, 48 hours, 72 hours, Day 11 | 
| Mean Total TSQM-9 Score | The Treatment Satisfaction Questionnaire for Medication (TSQM-9) contains 9 items assessing Effectiveness, Convenience, and Global Satisfaction domains. Responses to items are rated on a 5-point or 7-point rating scale. Scores for each domain are computed by adding the TSQM items in each domain and then transforming the values in to a composite score ranging from 0 to 100, with higher scores representing higher satisfaction. | 72 hours through Day 11 | 
| Maximum Concentration (Cmax) |  | 72 hours | 
| Time of Occurrence of Maximum Concentration (Tmax) |  | 72 hours | 

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