Phase 2B Study Assessing Pain Relief After Replacement of the Knee

• ATX101 (Drug): ATX101 bupivacaine implants, total of 1,500 mg into the surgical site
• bupivacaine hydrochloride (Drug): bupivacaine hydrochloride 0.25% without epinephrine/adrenaline, total 125 mg in 50 mL via local periarticular infiltration
• saline placebo (Drug): normal saline (0.9%) sodium chloride, total volume of up to 17 mL via local periarticular infiltration

Primary outcomes

• Area Under the Curve (AUC) for the Numerical Rating Scale at Rest (NRS-R) of Pain Intensity From 30 Minutes Through 168 Hours (Day 8) Compared to Placebo [from 30 minutes through 168 hours (Day 8)]: Numeric Rating Scale at Rest (NRS-R) for Pain Intensity is an 11-item scale from 0 to10 where participants rank the level of pain intensity. The NRS scale goes from No Pain (0) to Worst Imaginable Pain (10).

Secondary outcomes

• AUC for the NRS-R of Pain Intensity From 30 Minutes Through 336 Hours (Day 15) Compared to Placebo [From 30 minutes through 336 hours (Day 15)]: Numeric Rating Scale at Rest (NRS-R) for Pain Intensity is an 11-item scale from 0 to10 where participants rank the level of pain intensity. The NRS scale goes from No Pain (0) to Worst Imaginable Pain (10).
• AUC for the NRS-R of Pain Intensity From 30 Minutes Through 504 Hours (Day 22) Compared to Placebo [From 30 minutes through 504 hours (Day 22)]: Numeric Rating Scale at Rest (NRS-R) for Pain Intensity is an 11-item scale from 0 to10 where participants rank the level of pain intensity. The NRS scale goes from No Pain (0) to Worst Imaginable Pain (10).
• Total Post-surgical Consumption of Opioid Medications From 30 Minutes Through 336 Hours (Day 15) Compared to Placebo [From 30 minutes through 336 hours (Day 15)]: Total post-surgical consumption of rescue opioid medications in morphine milligrams equivalent (MME) dose from 30 minutes through 336 hours (Day 15)
• AUC for the NRS-R of Pain Intensity From 30 Minutes Through 336 Hours (Day 15) Compared to Active Comparator [From 30 minutes through 336 hours (Day 15)]: Numeric Rating Scale at Rest (NRS-R) for Pain Intensity is an 11-item scale from 0 to10 where participants rank the level of pain intensity. The NRS scale goes from No Pain (0) to Worst Imaginable Pain (10).
• Difference in NRS-A Pain Intensity Scores During the Timed Up and Go (TUG) Test at Day 15 Compared to Placebo [Day 15]: The NRS with activity (NRS-A) for pain intensity is an 11-item scale from 0 to 10 where participants rank the level of pain intensity after an activity. The NRS scale goes from No Pain (0) to Worst Imaginable Pain (10).

Sex: All, ages: 18 Years to 80 Years

Key Inclusion Criteria:

* Primary indication of TKA is knee pain due to osteoarthritis or post-traumatic arthritis
* Scheduled to undergo primary unilateral TKA with a cemented prosthesis, without use of a surgical drain, and under bupivacaine spinal anesthesia (dextrose is permitted)
* American Society of Anesthesiology (ASA) Physical Classification System of class 1, 2, or 3
* Capable, able, and willing to comply with all trial visits and procedures. Participant must also be able to use trial required e-diary and demonstrate completion compliance during the screening period
* English or Spanish speaking, willing, and capable of providing written informed consent

Key Exclusion Criteria:

* Has a planned concurrent surgical procedure (e.g. bilateral TKA) at the time of surgery or a planned surgical procedure before the last trial visit
* Has had any previous open surgery, (e.g., ORIF for fracture, osteotomy, arthroplasty, unicompartmental knee arthroplasty, or TKA), in the trial knee at any time in the past or arthroscopic surgery within 12 months. Has had any previous surgery in the contralateral knee within 6 months prior to screening
* Has been administered any type of intra-articular injection within 3 months of surgery in the trial knee
* Unable to abstain from opioid use for knee pain (including codeine) within 2 weeks (14 days) of surgery
* Has a Body Mass Index (BMI) ≥45 kg/m²
* Is unwilling or unable to discontinue use of medications or products that can impact pain control from the Screening Visit until the last trial visit (e.g. cannabidiol (CBD) oil, Kratom)
* Has a medical condition or receiving medication such that, in the opinion of the Investigator, participating in the trial would pose a health risk to the participant or confound the postsurgical assessments or might confound or interfere with the outcome of the trial
* Has received/used an investigational drug, product, or device for a clinical trial within 30 days of screening. COVID-19 vaccines (approved or under emergency use authorization locally) are permitted if the participant is not in a clinical trial for the vaccine
* Has a positive drug screen at the Screening Visit or on the day of surgery
* Has participated in an ATX101 clinical trial
* Pregnant, breastfeeding, or planning to become pregnant during the trial or before the last trial visit

Other protocol defined Inclusion/Exclusion criteria may apply

Participant flow

Outcome results

• Area Under the Curve (AUC) for the Numerical Rating Scale at Rest (NRS-R) of Pain Intensity From 30 Minutes Through 168 Hours (Day 8) Compared to Placebo (Primary), Mean, score on a scale*hours: ATX101 980.61 +/- 280.748; Saline Placebo 985.19 +/- 264.943 (p 0.9011)
• AUC for the NRS-R of Pain Intensity From 30 Minutes Through 336 Hours (Day 15) Compared to Placebo (Secondary), Mean, score on a scale*hours: ATX101 1811.50 +/- 572.586; Saline Placebo 1812.66 +/- 547.247 (p 0.9859)
• AUC for the NRS-R of Pain Intensity From 30 Minutes Through 504 Hours (Day 22) Compared to Placebo (Secondary), Mean, score on a scale*hours: ATX101 2545.41 +/- 875.961; Saline Placebo 2536.75 +/- 843.180 (p 0.9445)
• Total Post-surgical Consumption of Opioid Medications From 30 Minutes Through 336 Hours (Day 15) Compared to Placebo (Secondary), Mean, Morphine Milligram Equivalents: ATX101 233.416 +/- 208.8313; Saline Placebo 229.261 +/- 187.0728 (p 0.7328)
• AUC for the NRS-R of Pain Intensity From 30 Minutes Through 336 Hours (Day 15) Compared to Active Comparator (Secondary), Mean, score on a scale*hours: ATX101 1811.50 +/- 572.586; Bupivacaine Hydrochloride 1852.07 +/- 610.273 (p 0.7182)
• Difference in NRS-A Pain Intensity Scores During the Timed Up and Go (TUG) Test at Day 15 Compared to Placebo (Secondary), Mean, score on a scale: ATX101 3.4 +/- 2.10; Saline Placebo 3.6 +/- 2.06 (p 0.4180)

Adverse events

Time frame: Day 45

Serious adverse events by term

Other adverse events by term

• Study Protocol (PDF, 2025-07-11)
• Statistical Analysis Plan (PDF, 2025-10-28)

• David Hewitt, MD, Study director, Allay Therapeutics, Inc.