Total Knee Arthroplasty Infiltration Study for Postoperative Analgesia

• HTX-011 (Drug): HTX-011 (bupivacaine/meloxicam), via instillation
• Saline Placebo (Drug): Saline placebo via injection
• Bupivicaine HCl (Drug): Bupivacaine HCl without epinephrine
• Ropivacaine (Drug): Ropivacaine, via injection

Primary outcomes

• Mean Area Under the Curve (AUC) of the Numeric Rating Scale (NRS) Pain Intensity Scores at Rest (NRS-R) Through 48 Hours Postsurgery (AUC0-48). [48 hours]: Pain intensity is assessed at rest using an 11-point NRS (0-10) where 0 represents "no pain" and 10 represents "worst pain imaginable" (using windowed worst observation carried forward to adjust for opioid rescue medication use). The theoretical range of AUC0-48 is 0-480.

Secondary outcomes

• Mean Area Under the Curve (AUC) of the Numeric Rating Scale (NRS) Pain Intensity Scores at Rest (NRS-R) Through 72 Hours Postsurgery (AUC0-72). [72 hours]: Pain intensity is assessed at rest using an 11-point NRS (0-10) where 0 represents "no pain" and 10 represents "worst pain imaginable" (using windowed worst observation carried forward to adjust for opioid rescue medication use). The theoretical range of AUC0-72 is 0-720.
• Mean Total Postoperative Opioid Consumption (in Morphine Equivalents) [72 hours]

Sex: All, ages: 18 Years to any

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.

Participant flow

Outcome results

• Mean Area Under the Curve (AUC) of the Numeric Rating Scale (NRS) Pain Intensity Scores at Rest (NRS-R) Through 48 Hours Postsurgery (AUC0-48). (Primary), Mean, pain intensity score*hr: Cohort 1, Group 1: HTX-011 386.12 +/- 82.930; Cohort 1, Group 2: HTX-011 391.56 +/- 84.450; Cohort 1, Group 3: Saline Placebo 405.82 +/- 97.549; Cohort 1, Group 4: Bupivacaine HCI 347.56 +/- 103.422; Cohort 2, Group 1: HTX-011 322.08 +/- 99.669; Cohort 2, Group 2: HTX-011 + Ropivacaine 307.25 +/- 127.674; Cohort 2, Group 3: Saline Placebo 396.36 +/- 77.468; Cohort 2, Group 4: Bupivacaine HCI 352.74 +/- 100.887
• Mean Area Under the Curve (AUC) of the Numeric Rating Scale (NRS) Pain Intensity Scores at Rest (NRS-R) Through 72 Hours Postsurgery (AUC0-72). (Secondary), Mean, pain intensity score*hr: Cohort 1, Group 1: HTX-011 543.14 +/- 142.566; Cohort 1, Group 2: HTX-011 560.85 +/- 136.099; Cohort 1, Group 3: Saline Placebo 576.44 +/- 150.815; Cohort 1, Group 4: Bupivacaine HCI 468.58 +/- 179.687; Cohort 2, Group 1: HTX-011 471.19 +/- 149.443; Cohort 2, Group 2: HTX-011 + Ropivacaine 452.54 +/- 194.095; Cohort 2, Group 3: Saline Placebo 577.93 +/- 125.102; Cohort 2, Group 4: Bupivacaine HCI 516.93 +/- 152.512
• Mean Total Postoperative Opioid Consumption (in Morphine Equivalents) (Secondary), Mean, morphine milligram equivalent (MME): Cohort 1, Group 1: HTX-011 65.53 +/- 31.615; Cohort 1, Group 2: HTX-011 66.86 +/- 31.154; Cohort 1, Group 3: Saline Placebo 70.41 +/- 18.057; Cohort 1, Group 4: Bupivacaine HCI 60.70 +/- 29.903; Cohort 2, Group 1: HTX-011 64.39 +/- 27.889; Cohort 2, Group 2: HTX-011 + Ropivacaine 60.32 +/- 34.949; Cohort 2, Group 3: Saline Placebo 73.55 +/- 34.448; Cohort 2, Group 4: Bupivacaine HCI 68.35 +/- 29.169

Adverse events

Time frame: 28 Days.

Serious adverse events by term

Other adverse events by term

3 more terms not shown.

• Results publication: Lachiewicz PF, Lee GC, Pollak RA, Leiman DG, Hu J, Sah AP. HTX-011 Reduced Pain and Opioid Use After Primary Total Knee Arthroplasty: Results of a Randomized Phase 2b Trial. J Arthroplasty. 2020 Oct;35(10):2843-2851. doi: 10.1016/j.arth.2020.05.044. Epub 2020 May 27. PMID 32561266

• Study Protocol (PDF, 2017-12-21)
• Statistical Analysis Plan (PDF, 2018-01-05)