HTX-011 for Pain Management in Total Knee Replacement

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Mayo Clinic

Must not be taking: Opioids, NSAIDs

Disqualifiers: Chronic pain, Severe renal, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 1 week

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new medication, HTX-011, to determine if it manages pain more effectively after total knee replacement surgery than usual pain relief methods. The trial aims to assess whether HTX-011 provides superior pain control within the first 72 hours post-surgery. Suitable candidates for this trial include those planning their first total knee replacement due to degenerative joint disease and who do not have other serious health issues or chronic pain conditions. As a Phase 4 trial, HTX-011 has already received FDA approval and proven effective, and this research seeks to understand its benefits for a broader patient population.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, if you have a history of prolonged daily opioid use or allergies to NSAIDs, you may not be eligible to participate.

What is the safety track record for these treatments?

Research has shown that HTX-011 is generally safe for people. In a previous study, HTX-011, a combination of bupivacaine and meloxicam, reduced pain and the need for opioids after knee surgery. The study found no major safety issues with this treatment.

The FDA has approved HTX-011 for managing pain, indicating confidence in its safety. This approval means thorough testing has ensured its safety for patients. Any reported side effects were manageable and not serious.

Overall, evidence suggests that HTX-011 is a safe choice for managing pain after surgery. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Unlike the standard of care for pain management in total knee replacements, which often involves nerve blocks with local anesthetics like bupivacaine, HTX-011 combines a unique mix of bupivacaine and the anti-inflammatory ketorolac for extended pain relief. This treatment is also enhanced with epinephrine to prolong its effects, providing targeted, long-lasting pain control directly at the surgical site. Researchers are excited about HTX-011 because it offers the potential to reduce the need for opioids after surgery, which can help minimize side effects and the risk of dependency.

What evidence suggests that HTX-011 is effective for pain management in total knee replacement?

Research has shown that HTX-011, which participants in this trial may receive, helps manage pain after total knee replacement surgery. Studies have found it significantly reduces pain within 72 hours post-surgery. One study discovered that HTX-011, a combination of the numbing medicine bupivacaine and the anti-inflammatory meloxicam, provided better pain relief than standard treatments. Patients using HTX-011 also required fewer strong painkillers, such as opioids. The FDA has already approved this medication, demonstrating its effectiveness in managing post-surgical pain. ^{1 2 6 7 8}

Who Is on the Research Team?

Matthew P Abdel, MD

Principal Investigator

Mayo Clinic

Are You a Good Fit for This Trial?

This trial is for adults over 18 years old needing a primary total knee replacement due to joint disease, who can consent and have an ASA classification I to III. It's not for those with severe health issues like kidney injury, high opioid use, extreme obesity (BMI > 45), allergies to NSAIDs, cognitive impairments, or major illnesses such as advanced heart or liver diseases.

Inclusion Criteria

I am getting a knee replacement due to arthritis.

I am able to understand and agree to the study's procedures and risks.

I am 18 or older with a health status that allows for safe surgery.

Exclusion Criteria

Your body mass index (BMI) is higher than 45, which means you are very overweight.

I have been taking strong painkillers daily for over a month.

I am unable to give my own consent for medical procedures.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants undergo total knee arthroplasty and receive either HTX-011 or standard of care for perioperative analgesia

1 week

Inpatient surgery and monitoring

Follow-up

Participants are monitored for pain control and opioid consumption postoperatively

1 week

Postoperative monitoring and assessments

What Are the Treatments Tested in This Trial?

Interventions

• Bupivacaine
• Epinephrine
• Ketorolac
• Meloxicam ER Solution
• Ropivacaine

Trial Overview The study tests HTX-011 against standard pain control practices after knee surgery. HTX-011 is FDA-approved and may offer better pain management within the first 72 hours post-surgery compared to the usual mix of ropivacaine, epinephrine, ketorolac in saline.

How Is the Trial Designed?

Group I: HTX-011 Treatment Group Experimental Treatment 1 Intervention

Subjects undergoing a total knee arthroplasty will receive HTX-011 (Zynrelef) for perioperative analgesia

Group II: Standard Block Control Group Active Control 1 Intervention

Subjects undergoing a total knee arthroplasty will receive standard of care arthroplasty block for perioperative analgesia

Epinephrine is already approved in European Union, United States, Canada for the following indications:

Approved in European Union as Epinephrine for:

• Anaphylaxis
• Cardiac arrest
• Severe allergic reactions

Approved in United States as Epinephrine for:

• Anaphylaxis
• Cardiac arrest
• Severe allergic reactions

Approved in Canada as Epinephrine for:

• Anaphylaxis
• Cardiac arrest
• Severe allergic reactions

Who Is Running the Clinical Trial?

Mayo Clinic

Lead Sponsor

Trials

3,427

Recruited

3,221,000+

Published Research Related to This Trial

HTX-011, an extended-release local anesthetic, effectively reduced postoperative pain and opioid use in bunionectomy patients, with 77% of participants remaining opioid-free during recovery.

The combination of HTX-011 with scheduled ibuprofen and acetaminophen maintained mild pain levels (NRS <4) for 72 hours post-surgery, demonstrating its safety and efficacy as part of a multimodal analgesia regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Opioid-Free Recovery from Bunionectomy with HTX-011, a Dual-Acting Local Anesthetic Combining Bupivacaine and Meloxicam, as the Foundation of Non-Opioid Multimodal Analgesia. Pollak, R., Cai, D., Gan, TJ.[2021]

The intranasal formulation of ketorolac tromethamine, known as SPRIX, provides a similar pharmacokinetic profile to intramuscular administration, making it an effective option for treating moderately severe acute pain.

Toxicology studies in rats and rabbits indicate that SPRIX has a safety profile comparable to other administration routes, with no adverse effects observed on the nasal passages or respiratory system.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A novel formulation of ketorolac tromethamine for intranasal administration: preclinical safety evaluation. Boyer, KC., McDonald, P., Zoetis, T.[2013]

In a study of 4086 patients undergoing elective neurosurgery, those who received ketorolac had a significantly lower incidence of symptomatic intracranial hemorrhage (ICH) at 0.5% compared to 1.3% in those who did not receive the drug, suggesting a potential protective effect against bleeding.

Despite the lower observed risk of ICH in patients taking ketorolac, the adjusted odds ratio was close to 1, indicating that the findings may not be conclusive enough to definitively establish the safety of ketorolac in this surgical context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intracranial hemorrhage requiring surgery in neurosurgical patients given ketorolac: a case-control study within a cohort (2001-2010). Magni, G., La Rosa, I., Melillo, G., et al.[2022]

Ketorolac tromethamine is an effective nonsteroidal anti-inflammatory drug (NSAID) for managing moderate to severe postoperative pain, reducing the need for opioid analgesics, which can help minimize opioid-related side effects.

Administered intramuscularly, ketorolac reaches peak plasma levels in about 45 to 50 minutes and has a low incidence of side effects, making it a promising option for both inpatient and outpatient pain management, although further research is needed to fully understand its role.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketorolac: a new parenteral nonsteroidal anti-inflammatory drug for postoperative pain management. Lassen, K., Epstein-Stiles, M., Olsson, GL.[2013]

In a study involving 155 patients, ketorolac tromethamine was found to provide better pain relief than morphine sulfate at lower doses (30 and 90 mg) for moderate to severe postoperative pain, especially after the first hour.

Ketorolac demonstrated a favorable safety profile, with no serious side effects reported, while morphine was associated with somnolence in 8% of patients, highlighting ketorolac as a safe and effective alternative for pain management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketorolac tromethamine as compared with morphine sulfate for treatment of postoperative pain. O'Hara, DA., Fragen, RJ., Kinzer, M., et al.[2022]

In a randomized study involving patients after extensive colonic resections, the combination of intramuscular ketorolac and patient-controlled intravenous morphine provided equal pain relief compared to morphine alone, without increasing side effects.

The use of ketorolac significantly reduced the need for narcotics by an average of 45%, making it a valuable option for patients at risk of narcotic-related complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketorolac and patient controlled analgesia in the treatment of postoperative pain. Cataldo, PA., Senagore, AJ., Kilbride, MJ.[2013]

In a study of 51 patients undergoing total knee arthroplasty (TKA), the dual-acting local anesthetic HTX-011, combined with a multimodal analgesic (MMA) regimen, significantly reduced postoperative pain and opioid consumption compared to previous treatments.

The majority of patients reported mild pain levels, with 39% being discharged without an opioid prescription, indicating that HTX-011 with MMA is both effective and well-tolerated, with no additional safety risks observed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

HTX-011 in Combination with Multimodal Analgesic Regimen Minimized Severe Pain and Opioid Use after Total Knee Arthroplasty in an Open-Label Study. Lee, GC., Berkowitz, R., Hacker, S., et al.[2023]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10289832/

HTX-011 in Combination with Multimodal Analgesic ... This open-label study (NCT03974932) evaluated the efficacy and safety of HTX-011 combined with an MMA regimen in patients undergoing TKA under spinal ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S0883540320305842

HTX-011 Reduced Pain and Opioid Use After Primary Total ... Needle-free application of HTX-011 400 mg bupivacaine/12 mg meloxicam provided superior pain reduction through 72 hours after total knee arthroplasty.

3. cdn.clinicaltrials.gov cdn.clinicaltrials.gov/large-docs/53/NCT05188053/Prot_SAP_000.pdf

Periarticular Bupivacaine + Meloxicam ER Solution Versus ... HTX-011 Reduced Pain and Opioid. Use After Primary Total Knee Arthroplasty: Results of a Randomized Phase 2b Trial. J. Arthroplasty. 2020;35(10):2843-2851. 5 ...

4. zynrelef.com zynrelef.com/efficacy-pain-reduction/

72 Hours of Postoperative Pain Relief HTX-011 reduced pain and opioid use after primary total knee arthroplasty: results of a randomized Phase 2b trial. J Arthroplasty. 2020;35(10):2843-2851 ...

5. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40711999/

A Randomized Clinical Trial Showing Similar Efficacy in ... Results: Similar postoperative analgesia was observed, with an AUC for the adjusted NRS pain score up to 72 hours of 331 in the experimental ...

6. zynrelef.com zynrelef.com/safety/

Safety HTX-011 reduced pain and opioid use after primary total knee arthroplasty: results of a randomized Phase 2b trial. J Arthroplasty. 2020;35(10):2843-2851. doi: ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT05188053?term=BUPIVACAINE%20AND%20MELOXICAM&viewType=Table&rank=5

Periarticular Bupivacaine + Meloxicam ER Solution Versus ... The purpose of this study is to compare an FDA-approved medication for post-operative pain control (HTX-011) to the standard of care institutional practice for ...

8. zynrelef.com zynrelef.com/pdf/3-Reimbursement-Distro/PP-HTX011-0317-MMA-Protocol-FTK-TKA-2.0.0.pdf

MMA PROTOCOL TOTAL KNEE ARTHROPLASTY HTX-011 reduced pain and opioid use after primary total knee arthroplasty: results of a randomized. Phase 2b trial. J Arthroplasty. 2020;35(10):2843-2851 ...