Sponsor withdrew study

This is a prospective, randomized control trial to evaluate the impacts of preoperative cryoneurolysis treatment on opioid consumption with prehabilitation and resulting postoperative functional improvement in patients undergoing elective primary total knee arthroplasty (TKA).

Patients eligible for the study will be undergoing elective primary TKA at Brigham and Women's Hospital in Boston, MA. Study participants which meet the inclusion criteria listed above will be introduced to the study by a member of the research team in clinic when they schedule their date for surgery. If patients do not schedule an exact date for surgery at the time of their clinic visit, a member of the research team will still discuss the study with the patient so they can be called to schedule iovera° treatment once they schedule their surgical date. Patients who are interested in the study will be asked for permission to be contacted by a member of the study staff by telephone. These patients who give permission to be contacted about the study further will be called on the telephone 4-8 weeks in advance of their surgical date to assess them for their eligibility. If patients agree to participate in the study, they will be randomized to receive or not receive preoperative iovera° treatment. If the patient is eligible and agrees to participate in the study, the patient will come into clinic where informed consent will be obtained in-person at that time by a physician investigator and the patient will then receive cryoneurolysis iovera° treatment by a trained member of the study staff. Dr. Antonia Chen, Mei Xu (Dr. Chen's Physician Assistant), Dr. Wolfgang Fitz, Dr. Jeffrey Lange, Dr. Thomas Thornhill, Dr. Richard Iorio, Dr.Vivek Shah, Pierre-Emmanuel Schwab, and Brielle Antonelli will undergo an in-depth and personalized training session with a representative from Myoscience Inc. who will meet with these members in clinic in-person and review the device, the treatment procedure, and bring supplies so these specific members of the study staff can practice administering cryoneurolysis treatment before beginning the study on patients. Demographic information will be collected including the patient name, medical record number, date of birth, age, height and weight, gender, primary language, marital status, living situation, body mass index (BMI), preoperative narcotic consumption, and existing comorbidities. Randomization of patients for treatment will occur via randomized computer assignments. Patients will be randomly assigned to either the iovera° treatment group or the standard of care (SOC) group with a randomization ratio of 1:1. Patients will come in one month prior to surgery to receive prehabilitation treatment with physical therapy and undergo physical tests including quadriceps strength, timed up and go test (TUG), single leg stance, balance, and timed horizontal leg hold (quadriceps endurance test). Patients will also fill-out patient reported outcome measures (PROMs), such as KOOS, PROMIS 10, visual analog scale (VAS), the Pain Catastrophizing Scale (PCS), and EQ-5D. The first functional test and completion of PROMs will occur before iovera° treatment takes place at the first visit when subjects come into the clinic to receive iovera° treatment. The second functional test and completion of PROMs will occur on subject's day of surgery before the procedure, and the third set of functional test and completion of PROMs will be postoperatively at the subject's follow-up visit in clinic between 2-6 weeks.

The iovera° device is FDA approved (510(k) [#K142866]) for treatment of peripheral nerves for pain and for treatment of the pain and symptoms of knee osteoarthritis for up to 90 days (K161835). This device will be used according to its FDA labeling in patients with pain - hence why they are having a knee replacement, which would be pain due to osteoarthritis.

Cryoneurolysis treatment using the iovera° device targeting the anterior femoral cutaneous nerve (AFCN) and the infrapatellar branch of the saphenous nerve (ISN) will occur approximately 4 weeks before surgery by a trained member of the study staff (as mentioned above). Treatment will occur in the clinic setting using suggested anatomical markings to target appropriate the AFCN and infrapatellar branch of the saphenous nerve (ISN) of the operative knee. Patients are not sedated and will be asked to identify the painful locations with one finger which will be marked. The study staff member administering treatment will push on these locations to confirm that the marked areas are where the patient experiences pain and responds regarding their sensation and cessation of the pain signaling. This will confirm the correct location for the investigators which will also be confirmed with the aforementioned anatomical locations of the appropriate nerve branches.

The iovera° device contains three 27- gauge needles, all 6.9mm in length which will indent the subjects' skin and be inserted under the subcutaneous fat about 7 mm. Other tissues which may be impacted in addition to the subcutaneous fat are the dermis and epidermis. Muscle is rarely involved. Given that the needles are only 6.9mm in length, there is minimal possibility of reaching and affecting fascia, muscle, or vascular structures in the area which will be treated. All of these tissues impacted, subcutaneous fat are the dermis and epidermis, recover or are unaffected by the cooling based on the safety profile of safety profile of cryoanalgesia. Some patients who may have variations in anatomy, particularly in thickness of subcutaneous fat, will undergo the same procedure, but the investigator will push the handpiece down to displace the subcutaneous fat. Furthermore, surgeons in this practice exercise a patient BMI cut off of 40 kg/m2, which will minimize the amount of subcutaneous fat. Lidocaine will be used for superficial anesthetic at the treatment site before the needled puncture the patient's skin and no additional nerve block will be used at this time. Each subject will undergo a total of 9 treatments, or cooling cycles, using the iovera° device since each nerve branch has 2-3 sites per branch due to the anatomy of these nerve branches determined using determined anatomical markings. Treatment will be performed unilaterally and will be guided by visualization and palpation of anatomical landmarks. With there being 3 nerve branches with about 3 treatment sites per branch, the total number of treatments per subject is 9 with each treatment lasting about 1 minute, totaling 9-10 minutes of active treatment. The amount of time estimated for the entire treatment is 20 minutes. Investigators will know that they are hitting the targeted nerve since the subject is not sedated and can report a parasthesia response in real-time when the nerve is frozen.

Surgical data including date of surgery, laterality, anesthesia type, pericapsular injections, tourniquet (yes/no), morphine equivalents used in hospital, and discharge location will be collected for each participant. All other standard of care FDA approved medications and nerve blocks will be used in the operating room and postoperatively as needed depending upon the need of each individual patient as determined by the surgeon. These medications and nerve blocks commonly include bupivacaine, ropivacaine, toradol, clonidine, epinephrine, meloxicam, tylenol, oxycodone, vicodin, percocet, tramadol, toradol, dilaudid, morphine, lyrica, celebrex, and gabapentin.

All participants will receive a standard 7 days of opioid medication with 40 pills after surgery. Subjects will be instructed to take their prescribed pain medication (Oxycodone 5-10mg or dilaudid 1-2mg) every 4-6 hours as need. Surveys distributed through RedCap will be sent to each patient daily via email to track and monitor opioid consumption and physical therapy sessions daily, once a day preoperatively with 7 short questions for approximately 4 weeks (from their iovera° treatment until their scheduled date of surgery), and once a day postoperatively with 10 short questions for 6 weeks for a total of 70 surveys per patient for the entire study. Each survey should take no longer than a few minutes to complete. Follow-up visits will take place at 2-6 weeks after surgery for every participant, with one more survey follow-up at 12 weeks. At each follow-up visit, participants will undergo the same preoperative physical tests and fill-out each PROM. The postoperative data that will be collected will consist of physical therapy utilized, narcotic consumption (morphine equivalents), if patients used opioid medication 60 days prior to surgery or not, time to return to activities of daily living, time off of assistive walking devices, and 90-day complications (readmission, reoperation, emergency room visits) which will determine estimated financial costs of both treatment groups. The investigators will follow patients postoperatively to evaluate their pain scores to determine if there are differences in pain scores between the SOC group and the iovera° group and to specifically see if there is increased pain in the iovera° group.

Inclusion Criteria:

• Subjects age >= 18 years of age and undergoing elective unilateral primary total knee arthroplasty
• All subjects who are willing to comply with the requirements of the study and provide informed consent prior to enrollment. Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study must be obtained before data collection.

Exclusion Criteria:

• Subjects that are undergoing bilateral TKA or revision TKA
• Pregnant women and vulnerable individuals.
• Patients who cannot undergo cryoneurolysis (i.e. Patients with cryoglobulinemia, paroxysmal cold hemoglobinuria, cold urticaria, Raynaud's disease, open/ infected wounds at or near the treatment site)

There will no IPD data shared, and only aggregated data will be used.