Total Knee Arthroplasty
Conditions
Brief summary
This study is designed to investigate whether iovera° treatment prior to TKA decreases cumulative participant opioid use over the course of 6 weeks following TKA while maintaining similar levels of pain relief. The study will also investigate whether there is a relationship between participants treated with iovera° and participant reported pain and function as measured by knee injury and osteoarthritis outcomes score (KOOS JR), numeric rating scale (NRS) for pain; use of hospital services post-TKA and improved physical rehabilitation as measured by range of motion.
Interventions
DEVICEiovera°
The iovera° device applies cold to a target nerve to cause a temporary peripheral nerve block based on a process called Wallerian degeneration (2nd degree axonotmesis) without disrupting connective nerve tissue.
Sponsors
Pacira Pharmaceuticals, Inc
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
The active group will receive the iovera° treatment prior to a TKA. The control group will receive a TKA and no iovera° treatment.
Eligibility
Sex/Gender
ALL
Age
22 Years to 79 Years
Healthy volunteers
Yes
Inclusion criteria
1. 22 to 79 years of age 2. Scheduled to undergo primary unilateral TKA under spinal anesthesia for primary diagnosis of osteoarthritis 3. Participant is a class I-III on the American Society of Anesthesiology (ASA) Physical Classification System 4. Anticipation of discharge to home after inpatient acute post-op phase based on age, co-morbidities, home environment, and social support are in favor of discharge to home in the opinion of the Investigator. 5. Participant is willing and able to give written informed consent. 6. Participant is fluent in verbal and written English. 7. Participant is willing and able to comply with study instructions and commit to all follow-up visits for the duration of the study. 8. Participant is in good general health and free of any systemic disease state or physical condition that might impair evaluation or which in the Investigator's opinion, exposes the participant to an unacceptable risk by study participation.
Exclusion criteria
1. Chronic opioid use (defined as daily or almost daily use of opioids for \>3 months). 2. Concurrent painful physical condition, surgery, or musculoskeletal disease that requires analgesic treatment during study follow-up that is not strictly related to the target knee being treated with iovera°, which have the potential to confound the postoperative assessments (e.g., significant pain from other joints, chronic neuropathic pain, concurrent or planned contralateral TKA, concurrent foot, neck, spine, hip, or other musculoskeletal disease, arthritis, or planned surgery, etc.). 3. Greater than 15° malalignment (varus or valgus) on pre-operative radiograph. 4. Previous Myoscience treatment. 5. Previous Partial or Total Knee Arthroplasty. Partial or Total Knee Arthroplasty of the contralateral knee is permitted if surgery was completed at least nine (9) months prior to Screening. 6. Body Mass Index ≥ 40 7. Prior surgery in the treatment areas that may alter the anatomy of the infrapatellar branch of the saphenous nerve (ISN) or the anterior femoral cutaneous nerve (AFCN) or result in scar tissue in the treatment area. 8. Any clotting disorder and/or use of an anticoagulant (e.g. warfarin, clopidogrel, etc.) within seven (7) days prior to administration of the device. Low dose aspirin (81mg or less daily) for cardiac prophylaxis allowed. 9. Any local skin condition at the treatment sites that in the Investigator's opinion would adversely affect treatment or outcomes. 10. Open and/or infected wound in the treatment areas. 11. Allergy to lidocaine. 12. History of cryoglobulinemia 13. History of paroxysmal cold hemoglobinuria. 14. History of cold urticaria. 15. History of Raynaud's disease. 16. History of opioid or alcohol abuse. 17. Participant is pregnant or planning to become pregnant while enrolled in the study. 18. Current enrollment in any investigational drug or device study or participation within 30 days prior to screening. 19. Currently being treated for related knee injury under worker's compensation claim or equivalent (i.e. legal case). 20. Any chronic medical condition that in the Investigator's opinion would prevent adequate participation. 21. Any chronic medication use (prescription, over-the-counter, etc.) that in the Investigator's opinion would affect study participation or participant safety. 22. For any reason, in the opinion of the Investigator, the participant may not be a suitable candidate for study participation (i.e., history of noncompliance, drug dependency, etc.).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cumulative Opioid Consumption | From the time of TKA surgery to 6 weeks post-TKA surgery | The cumulative consumption of opioids was determined from the time of Total Knee Arthroplasty (TKA) surgery to 6 weeks post-TKA surgery. Opioid consumption was converted to morphine milligram equivalents (MME) and participant consumption was verified by pill count at follow-up visits. The cumulative morphine equivalent was divided by the number of days to provide the total daily morphine equivalent (TME) for the participant, |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Curve (AUC)/Time for Change From Baseline in Knee Injury and Osteoarthritis Outcomes Score (KOOS JR.) Overall Score Through 6 Weeks Post-TKA | Baseline to 6 weeks post-TKA surgery | The KOOS JR. was a participant completed questionnaire that consists of 7 questions from 3 subscales: stiffness (1 question), pain (4 questions), and function in daily living (2 questions). Standardized answer options are given (5 Likert boxes) and each question was assigned a score from none (0) to extreme (4). A normalized score (100 indicating no symptoms and 0 indicating extreme symptoms) was calculated. A positive change from baseline indicates improvement. AUC/time based on Changes from Baseline in KOOS JR. scores through 6 weeks post-TKA, is the AUC of Change in KOOS JR. scores from the Baseline visit through the 6-week visit divided by the number of days from TKA until the 6-week visit. AUC was calculated using the trapezoidal rule and the changes in the KOOS JR. score at the following time points: Baseline (change=0), 72 hours, 2 weeks, and 6 weeks post-TKA. |
| AUC/Time for Change From Baseline in Numeric Rating Scale (NRS) for Pain Through 6 Weeks Post-TKA | Baseline to 6 weeks post-TKA surgery | NRS was an 11-point scale for self-reporting of pain intensity by participants. Scores range from 0 to 10, where 0 points equals no pain and 10 points equals the worst pain imaginable. A positive change represented improvement (or reduction) in pain intensity. AUC/time based on Changes from Baseline in NRS Pain score through 6 weeks post-TKA, is the AUC of Change in NRS for Pain score from the Baseline visit through the 6-week visit divided by the number of days from TKA until the 6-week visit. AUC was calculated using the trapezoidal rule and the changes in the NRS for Pain score at the following time points: Baseline (change=0), 72 hours, 2 weeks, and 6 weeks post-TKA. |
| AUC/Time for Change From Baseline in Timed Get Up and Go (TUG) Tests Through 6 Weeks Post-TKA | Baseline to 6 weeks post-TKA surgery | The time required by the participants to raise from sitting, walk 10 feet, turn around, walk back and sit back down was measured in seconds. A positive change from baseline indicates improvement. AUC/time based on Changes from Baseline in the TUG test through 6 weeks post-TKA, is the AUC of Change in TUG test from the Baseline visit through the 6-week visit divided by the number of days from TKA until the 6-week visit. AUC was calculated using the trapezoidal rule and the changes in the TUG test at the following time points: Baseline (change=0), 72 hours, 2 weeks, and 6 weeks post-TKA. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Iovera° Device Treatment Group Iovera° device presurgical cryoneurolysis treatment, 5 (+/- 2) days prior to TKA. Additionally, all participants received treatment as per all the standard pre-, peri-, and post-operative surgical protocols. | 62 |
| Standard of Care Treatment Group All participants received treatment as per all the standard pre-, peri-, and post-operative surgical protocols. | 62 |
| Total | 124 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event (AE)/Serious Adverse Event (SAE) | 1 | 2 |
| Overall Study | Discharged to Rehabilitation | 0 | 1 |
| Overall Study | Fungal infection | 1 | 0 |
| Overall Study | Investigator Decision | 2 | 0 |
| Overall Study | Missed Visit 6 (Week 6 Visit) | 0 | 1 |
| Overall Study | Missing | 1 | 0 |
Baseline characteristics
| Characteristic | Standard of Care Treatment Group | Total | Iovera° Device Treatment Group |
|---|---|---|---|
| Age, Continuous | 66.2 years STANDARD_DEVIATION 7.1 | 65.9 years STANDARD_DEVIATION 7.6 | 65.5 years STANDARD_DEVIATION 8.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 62 Participants | 124 Participants | 62 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized Black or African American | 15 participants | 25 participants | 10 participants |
| Race/Ethnicity, Customized White | 47 participants | 99 participants | 52 participants |
| Sex: Female, Male Female | 36 Participants | 67 Participants | 31 Participants |
| Sex: Female, Male Male | 26 Participants | 57 Participants | 31 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 62 | 0 / 62 |
| other Total, other adverse events | 4 / 59 | 3 / 60 |
| serious Total, serious adverse events | 2 / 59 | 2 / 60 |
Outcome results
Primary
Cumulative Opioid Consumption
The cumulative consumption of opioids was determined from the time of Total Knee Arthroplasty (TKA) surgery to 6 weeks post-TKA surgery. Opioid consumption was converted to morphine milligram equivalents (MME) and participant consumption was verified by pill count at follow-up visits. The cumulative morphine equivalent was divided by the number of days to provide the total daily morphine equivalent (TME) for the participant,
Time frame: From the time of TKA surgery to 6 weeks post-TKA surgery
Population: Intent-to-treat (ITT) population included all participants who were randomized into the study. Overall number analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Iovera° Device Treatment Group | Cumulative Opioid Consumption | 4.8 TME | Standard Error 0.7 |
| Standard of Care Treatment Group | Cumulative Opioid Consumption | 6.1 TME | Standard Error 0.7 |
Comparison: Testing null hypothesis that true iovera° mean was greater than or equal to the true standard of care mean versus the alternative hypothesis that true iovera° mean was less than true standard of care mean.p-value: 0.084195% CI: [-0.6, 3.2]t-test, 1 sided
Secondary
Area Under the Curve (AUC)/Time for Change From Baseline in Knee Injury and Osteoarthritis Outcomes Score (KOOS JR.) Overall Score Through 6 Weeks Post-TKA
The KOOS JR. was a participant completed questionnaire that consists of 7 questions from 3 subscales: stiffness (1 question), pain (4 questions), and function in daily living (2 questions). Standardized answer options are given (5 Likert boxes) and each question was assigned a score from none (0) to extreme (4). A normalized score (100 indicating no symptoms and 0 indicating extreme symptoms) was calculated. A positive change from baseline indicates improvement. AUC/time based on Changes from Baseline in KOOS JR. scores through 6 weeks post-TKA, is the AUC of Change in KOOS JR. scores from the Baseline visit through the 6-week visit divided by the number of days from TKA until the 6-week visit. AUC was calculated using the trapezoidal rule and the changes in the KOOS JR. score at the following time points: Baseline (change=0), 72 hours, 2 weeks, and 6 weeks post-TKA.
Time frame: Baseline to 6 weeks post-TKA surgery
Population: ITT population included all participants who were randomized into the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Iovera° Device Treatment Group | Area Under the Curve (AUC)/Time for Change From Baseline in Knee Injury and Osteoarthritis Outcomes Score (KOOS JR.) Overall Score Through 6 Weeks Post-TKA | 10.3 score on a scale/days | Standard Error 1.6 |
| Standard of Care Treatment Group | Area Under the Curve (AUC)/Time for Change From Baseline in Knee Injury and Osteoarthritis Outcomes Score (KOOS JR.) Overall Score Through 6 Weeks Post-TKA | 8.4 score on a scale/days | Standard Error 1.4 |
Comparison: Testing null hypothesis that Standard of Care mean minus the iovera° mean was greater than or equal to non-inferiority margin of 14 versus alternative hypothesis that difference in means was less than 14.p-value: <0.000195% CI: [-2.3, 6.1]t-test, 1 sided
Secondary
AUC/Time for Change From Baseline in Numeric Rating Scale (NRS) for Pain Through 6 Weeks Post-TKA
NRS was an 11-point scale for self-reporting of pain intensity by participants. Scores range from 0 to 10, where 0 points equals no pain and 10 points equals the worst pain imaginable. A positive change represented improvement (or reduction) in pain intensity. AUC/time based on Changes from Baseline in NRS Pain score through 6 weeks post-TKA, is the AUC of Change in NRS for Pain score from the Baseline visit through the 6-week visit divided by the number of days from TKA until the 6-week visit. AUC was calculated using the trapezoidal rule and the changes in the NRS for Pain score at the following time points: Baseline (change=0), 72 hours, 2 weeks, and 6 weeks post-TKA.
Time frame: Baseline to 6 weeks post-TKA surgery
Population: ITT population included all participants who were randomized into the study. Overall number analyzed is the number of participants with data available for analysis at the given timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Iovera° Device Treatment Group | AUC/Time for Change From Baseline in Numeric Rating Scale (NRS) for Pain Through 6 Weeks Post-TKA | Pain in The Past 7 Days | 2.2 score on a scale/days | Standard Deviation 2.1 |
| Iovera° Device Treatment Group | AUC/Time for Change From Baseline in Numeric Rating Scale (NRS) for Pain Through 6 Weeks Post-TKA | Pain Right Now | 1.9 score on a scale/days | Standard Deviation 2.7 |
| Standard of Care Treatment Group | AUC/Time for Change From Baseline in Numeric Rating Scale (NRS) for Pain Through 6 Weeks Post-TKA | Pain in The Past 7 Days | 1.7 score on a scale/days | Standard Deviation 1.9 |
| Standard of Care Treatment Group | AUC/Time for Change From Baseline in Numeric Rating Scale (NRS) for Pain Through 6 Weeks Post-TKA | Pain Right Now | 1.5 score on a scale/days | Standard Deviation 2.3 |
Comparison: Pain in the Past 7 days - Testing the null hypothesis that the iovera° mean was less than or equal to the Standard of Care mean versus the alternative hypothesis that the iovera° mean was greater than the Standard of Care mean.p-value: 0.094695% CI: [-0.2, 1.2]t-test, 1 sided
p-value: 0.220495% CI: [-0.6, 1.3]t-test, 1 sided
Secondary
AUC/Time for Change From Baseline in Timed Get Up and Go (TUG) Tests Through 6 Weeks Post-TKA
The time required by the participants to raise from sitting, walk 10 feet, turn around, walk back and sit back down was measured in seconds. A positive change from baseline indicates improvement. AUC/time based on Changes from Baseline in the TUG test through 6 weeks post-TKA, is the AUC of Change in TUG test from the Baseline visit through the 6-week visit divided by the number of days from TKA until the 6-week visit. AUC was calculated using the trapezoidal rule and the changes in the TUG test at the following time points: Baseline (change=0), 72 hours, 2 weeks, and 6 weeks post-TKA.
Time frame: Baseline to 6 weeks post-TKA surgery
Population: ITT population included all participants who were randomized into the study. Overall number analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Iovera° Device Treatment Group | AUC/Time for Change From Baseline in Timed Get Up and Go (TUG) Tests Through 6 Weeks Post-TKA | -1.2 seconds/days | Standard Deviation 5.5 |
| Standard of Care Treatment Group | AUC/Time for Change From Baseline in Timed Get Up and Go (TUG) Tests Through 6 Weeks Post-TKA | -0.4 seconds/days | Standard Deviation 11.3 |
Comparison: Testing the null hypothesis that the iovera° mean was less than or equal to the Standard of Care mean versus the alternative hypothesis that the iovera° mean was greater than the Standard of Care mean.p-value: 0.323195% CI: [-4, 2.5]t-test, 1 sided