Total Knee Arthroplasty
Conditions
Brief summary
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 periarticular analgesia after primary total knee arthroplasty (weight based dosing of Ropivacaine, epinephrine and ketorolac diluted with saline). We are doing this research study to find out if this new medication provides superior pain control within 72 hours following surgery.
Interventions
DRUGHTX-011
Single dose administration periarticular 400mg bupivacaine and 12mg meloxicam extended release solution
DRUGropivacaine , epinephrine , ketorolac diluted in sodium chloride
Single dose administration in 100cc of standard formulation, there is 225mg of ropivacaine 5mg/mL, 0.6mg epinephrine 1mg/mL, 30mg ketorolac 30mg/mL diluted in sodium chloride
Sponsors
Mayo Clinic
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* ASA classification I to III, older than or equal to 18 years old. * Presenting for primary total knee replacement for degenerative joint disease. * Patient capable of providing their own informed consent.
Exclusion criteria
* Vulnerable study populations including prisoners. * Patients with a contralateral total knee arthroplasty \< 2 years prior to the index procedure. * Compromised health barring them from proceeding with surgery including acute or chronic kidney injury identified pre-operative. * Patients unable to provide their own informed consent. * Pregnancy. * Patients with documented chronic pain syndromes. * Patients with a history of prolonged daily opioids (more than 1 month) with an oral morphine equivalent of greater than 5mg/day. * BMI \> 45 kg/m\^2. * Allergies to any component of the study medications, including specific history of type 1 hypersensitivities to any NSAID. * Patients with impaired cognitive function. * Major systemic illnesses such as severe renal (estimated glomerular filtration rate less than 50ml/min), coronary artery disease requiring a bypass graft (CABG), other cardiac problems including congestive heart failure (CHF New York Heart Association class III to IV), or severe hepatic disorders defined as current or past diagnosis of acute/subacute liver necrosis, acute hepatic failure, chronic liver disease, liver abscess, hepatic coma, hepatorenal syndrome and other disorders of the liver.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pain Control at 72 Hours Postoperatively | 72-hours postoperatively after total knee arthroplasty | Area Under the Curve (AUC) of the graph for mean Numerical Rated Score (NRS) for pain (0-10) over time (0-72 hours) / NRS AUC 0-72. Pain scores were collected by patient self-report 15 times over the 72 hours after surgery, and averaged amongst the patients for each study arm. Lower values represent better pain control based on lower mean 0-10 pain scores over the 72 hour period after surgery. The minimum value is 0, meaning patients reported 0 pain on a 0-10 scale at all 15 time points within 72 hours. The maximum value would be 720, meaning patients reported a 10 for pain on a 0-10 scale at all 15 time points within 72 hours. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Opioid Consumption 72 Hours Postoperatively | 72-hours postoperative total knee arthroplasty | Total postoperative opioid consumption standardized into morphine milligram equivalents (MMEs) |
| Opioid Consumption 48 Hours Postoperatively | 48 hours postoperative total knee arthroplasty | Total postoperative opioid consumption standardized into morphine milligram equivalents (MMEs) |
| Pain Control at 48 Hours Postoperatively | 48-hours postoperative total knee arthroplasty | Area Under the Curve (AUC) of the graph for mean Numerical Rated Score (NRS) for pain (0-10) over time (0-48 hours) / NRS AUC 0-48. Pain scores were collected by patient self-report 11 times over the 48 hours after surgery, and averaged amongst the patients for each study arm. Lower values represent better pain control based on lower mean 0-10 pain scores over the 48 hour period after surgery. The minimum value is 0, meaning patients reported 0 pain on a 0-10 scale at all 11 time points within 48 hours. The maximum value would be 480, meaning patients reported a 10 for pain on a 0-10 scale at all 11 time points within 48 hours |
Countries
United States
Participant flow
Recruitment details
Recruitment for this study ran from 3/11/2022 until 4/9/2024 when the final patient was enrolled. Patients were enrolled from the Orthopedic clinical practice at Mayo Clinic.
Pre-assignment details
An initial pilot of 18 patients ran from 3/11/2022 to 8/30/2022 after which a protocol change caused these patients to be withdrawn and not assigned to a treatment arm in the final study count. One additional patient was withdrawn prior to randomization as allergy results returned which excluded participation.
Participants by arm
| Arm | Count |
|---|---|
| HTX-011 Treatment Group Subjects undergoing a total knee arthroplasty will receive HTX-011 (Zynrelef) for perioperative analgesia
HTX-011: Single dose administration periarticular 400mg bupivacaine and 12mg meloxicam extended release solution | 95 |
| Standard Block Control Group Subjects undergoing a total knee arthroplasty will receive standard of care arthroplasty block for perioperative analgesia
ropivacaine , epinephrine , ketorolac diluted in sodium chloride: Single dose administration in 100cc of standard formulation, there is 225mg of ropivacaine 5mg/mL, 0.6mg epinephrine 1mg/mL, 30mg ketorolac 30mg/mL diluted in sodium chloride | 95 |
| Total | 190 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 23 | 30 |
| Overall Study | Physician Decision | 3 | 0 |
| Overall Study | Protocol Violation | 16 | 16 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | HTX-011 Treatment Group | Standard Block Control Group | Total |
|---|---|---|---|
| Age, Continuous | 69.6 years STANDARD_DEVIATION 8.1 | 69.9 years STANDARD_DEVIATION 8.6 | 69.7 years STANDARD_DEVIATION 8.3 |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Sex: Female, Male Female | 54 Participants | 54 Participants | 108 Participants |
| Sex: Female, Male Male | 41 Participants | 41 Participants | 82 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 53 | 0 / 48 |
| other Total, other adverse events | 1 / 53 | 2 / 48 |
| serious Total, serious adverse events | 0 / 53 | 0 / 48 |
Outcome results
Primary
Pain Control at 72 Hours Postoperatively
Area Under the Curve (AUC) of the graph for mean Numerical Rated Score (NRS) for pain (0-10) over time (0-72 hours) / NRS AUC 0-72. Pain scores were collected by patient self-report 15 times over the 72 hours after surgery, and averaged amongst the patients for each study arm. Lower values represent better pain control based on lower mean 0-10 pain scores over the 72 hour period after surgery. The minimum value is 0, meaning patients reported 0 pain on a 0-10 scale at all 15 time points within 72 hours. The maximum value would be 720, meaning patients reported a 10 for pain on a 0-10 scale at all 15 time points within 72 hours.
Time frame: 72-hours postoperatively after total knee arthroplasty
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| HTX-011 Treatment Group | Pain Control at 72 Hours Postoperatively | 334 score on a scale * hours | Standard Deviation 16 |
| Standard Block Control Group | Pain Control at 72 Hours Postoperatively | 370 score on a scale * hours | Standard Deviation 21 |
Comparison: Two-sample t-test with unequal variance. The null hypothesis is that there was no statistically significant difference between the two treatment groups based on a standard alpha value of 0.05.p-value: 0.17t-test, 2 sided
Secondary
Opioid Consumption 48 Hours Postoperatively
Total postoperative opioid consumption standardized into morphine milligram equivalents (MMEs)
Time frame: 48 hours postoperative total knee arthroplasty
Population: patients who returned a completed pain diary
| Arm | Measure | Value (MEAN) |
|---|---|---|
| HTX-011 Treatment Group | Opioid Consumption 48 Hours Postoperatively | 67 MME |
| Standard Block Control Group | Opioid Consumption 48 Hours Postoperatively | 60 MME |
Secondary
Opioid Consumption 72 Hours Postoperatively
Total postoperative opioid consumption standardized into morphine milligram equivalents (MMEs)
Time frame: 72-hours postoperative total knee arthroplasty
Population: patient who returned a complete pain diary
| Arm | Measure | Value (MEAN) |
|---|---|---|
| HTX-011 Treatment Group | Opioid Consumption 72 Hours Postoperatively | 85 MME |
| Standard Block Control Group | Opioid Consumption 72 Hours Postoperatively | 77 MME |
Secondary
Pain Control at 48 Hours Postoperatively
Area Under the Curve (AUC) of the graph for mean Numerical Rated Score (NRS) for pain (0-10) over time (0-48 hours) / NRS AUC 0-48. Pain scores were collected by patient self-report 11 times over the 48 hours after surgery, and averaged amongst the patients for each study arm. Lower values represent better pain control based on lower mean 0-10 pain scores over the 48 hour period after surgery. The minimum value is 0, meaning patients reported 0 pain on a 0-10 scale at all 11 time points within 48 hours. The maximum value would be 480, meaning patients reported a 10 for pain on a 0-10 scale at all 11 time points within 48 hours
Time frame: 48-hours postoperative total knee arthroplasty
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| HTX-011 Treatment Group | Pain Control at 48 Hours Postoperatively | 237 score on a scale * hours | Standard Deviation 14 |
| Standard Block Control Group | Pain Control at 48 Hours Postoperatively | 268 score on a scale * hours | Standard Deviation 13 |