Cooled Radiofrequency vs. Hyaluronic Acid to Manage Knee Pain

The COOLIEF™ system components utilized in the study are the same in form and function regardless of specific product branding (COOLIEF* or SInergy*). The COOLIEF™ system is comprised of three primary components (collectively known as 'disposables') and is used in conjunction with the Pain Management generator, pump unit, connector cables (collectively known as 'Hardware') and dispersive electrodes (also known as 'grounding pads'):

* Cooled Radiofrequency Sterile Tube Kit (sterile, single use, non-body contact): It is used for closed-loop circulation of sterile water through a Halyard Health* Cooled Radiofrequency Probe. It includes a burette and tubing.
* Cooled Radiofrequency Introducer (sterile, single use): It is to be used with the Probes only. The Cooled Radiofrequency Introducer provides a path for the Probe to the targeted nervous tissue.
* Cooled Radiofrequency Probe (sterile, single use): It is inserted through an Introducer into or near nervous tissue. The active tip extends 4mm from the introducer and delivers energy. Sterile water circulates internally to cool the Probe while it delivers radiofrequency energy. A thermocouple in the Probe measures the cooled electrode temperature throughout the procedure.

The product is comprised of an electrically insulated shaft with an active tip that functions as an electrode for radiofrequency energy delivery, a handle, tubes with luer locks and a cable with a 7-pin connector. The Introducer includes an insulated stainless steel cannula and a stylet. The Tube Kit is comprised of a burette and flexible tubing fitted with luer locks for connection to the Probe. The Probe, Introducer, and Tube Kit are ethylene oxide sterilized and supplied sterile. These components can be packaged together in a kit or as separate components. The devices should be stored in a cool, dry environment. The Instructions For Use (IFU) documents (Appendix 1) are included in each kit.

Halyard Health maintains a list of all model numbers and sizes for the system components.

The control product/device, Synvisc-One® (hylan G-F 20) (HA), is an elastoviscous high molecular weight fluid containing hylan A and hylan B polymers produced from chicken combs. Hylans are derivatives of hyaluronan (sodium hyaluronate). Hylan G-F 20 is unique in that the hyaluronan is chemically crosslinked. Hyaluronan is a long-chain polymer containing repeating disaccharide units of Na-glucuronate-N-acetylglucosamine.

Synvisc-One is a single injection regimen therapy indicated for the treatment of pain in Osteoarthritis of the knee in patients who have failed to respond adequately to conservative nonpharmacologic therapy and simple analgesics, e.g., acetaminophen.

Following treatment, subjects in the CRF treatment group will follow up at 1, 3, 6 and 12 months. These subjects will then have the option to return for two additional visits at 18 and 24 months. Subjects initially randomized to the comparison (HA) group will follow up at 1, 3, and 6 months, and then be given the option to receive crossover CRF treatment. If crossover CRF treatment was received, subjects will return for follow up visits at 1, 3, and 6 months post-treatment. If crossover treatment was not received, subjects will return for their final 12 month visit.

Study Duration:

* Treatment Group: Up to 24 months following index procedure
* Control Group: Up to 13 months, depending upon receipt of cross-over procedure.

Effectiveness Endpoints:

* Numeric Rating Scale (NRS, Usual Level of Pain)
* Western Ontario \& McMaster University Osteoarthritis Index (WOMAC)
* EQ-5D-5L Health-Related Quality of Life Questionnaire
* Global Perceived Effect Scale

• Cooled Radiofrequency (Device), also known as Coolief: Delivery of energy to ablate sensory nerves via cooled radiofrequency probe.
• Hyaluronic Acid Injection (Other), also known as Viscosupplementation: Delivery of hyaluronic acid into knee by injection with needle to reduce knee pain.
• Crossover from Hyaluronic Acid Injection to Cooled Radiofrequency (Other), also known as Viscosupplementation, Cooled Radiofrequency: Delivery of hyaluronic acid into knee by injection with needle to reduce knee pain. After 6 months, qualifying subjects in this group will have the option to crossover to receive cooled radiofrequency treatment.

Primary outcomes

• Numeric Rating Scale (NRS) [Baseline to 6 month study visit]: The proportion of subjects whose knee pain is reduced by ≥ 50% based on the NRS. The NRS is an 11-point scale (0 points to 10 points), where 0 points equals "no pain" and 10 points equals the "worst pain". There are no sub-scales.
• Safety: The Proportion of Subjects Experiencing Adverse Events Through Final Follow up. [Baseline to 12 month study visit]: Safety: The proportion of subjects experiencing adverse events through final follow up.

Secondary outcomes

• Numeric Rating Scale [Baseline (or date of crossover for Crossover group subjects) to 12 month study visit]: The proportion of subjects whose knee pain is reduced from baseline by ≥ 50% based on the NRS. The NRS is an 11-point scale (0 points to 10 points), where 0 points equals "no pain" and 10 points equals the "worst pain". There are no sub-scales.
• Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) [Baseline to 6 month study visit]: The change in WOMAC score from baseline to 6 months. This outcome instrument is composed of three sub-scales, including "Pain" (5 questions), "Stiffness" (2 questions), and "Physical Function" (17 questions). The point range for each sub-scale question is from 0 to 4, with "0" indicating the best study subject condition and "4" indicating the worst study subject condition. Thus, the minimum score per sub-scale is 0, and the maximum is 20, 8, and 68 for "Pain", Stiffness", and "Physical Function", respectively. The minimum and maximum possible scores for the entire instrument are 0 (best study subject condition) and 96 (worst study subject condition).
• Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) [Baseline (or date of crossover for Crossover group subjects) to 12 month study visit]: The change in WOMAC score from baseline to 12 months. This outcome instrument is composed of three sub-scales, including "Pain" (5 questions), "Stiffness" (2 questions), and "Physical Function" (17 questions). The point range for each sub-scale question is from 0 to 4, with "0" indicating the best study subject condition and "4" indicating the worst study subject condition. Thus, the minimum score per sub-scale is 0, and the maximum is 20, 8, and 68 for "Pain", Stiffness", and "Physical Function", respectively. The minimum and maximum possible scores for the entire instrument are 0 (best study subject condition) and 96 (worst study subject condition).

Other outcomes

• EQ-5D-5L [Baseline to 6 month study visit]: The change in measured EQ-5D-5L scale from baseline to 6 months. This outcome instrument is composed of five sub-scales containing five questions each. The point range for each sub-scale is from 1 to 5, with "1" indicating the best study subject condition and "5" indicating the worst study subject condition. Thus, the minimum and maximum scores per sub-scale are 1 and 5, respectively, and such scores for the entire instrument are 5 (best study subject condition) and 25 (worst study subject condition). The sub-scale topics are: Mobility, Self-Care, Usual Activities, Pain/Discomfort, and Anxiety/Depression.
• EQ-5D-5L [Baseline (or date of crossover for Crossover group subjects) to 12 month study visit]: The change in measured EQ-5D-5L scale from baseline to 12 months. This outcome instrument is composed of five sub-scales containing five questions each. The point range for each sub-scale is from 1 to 5, with "1" indicating the best study subject condition and "5" indicating the worst study subject condition. Thus, the minimum and maximum scores per sub-scale are 1 and 5, respectively, and such scores for the entire instrument are 5 (best study subject condition) and 25 (worst study subject condition). The sub-scale topics are: Mobility, Self-Care, Usual Activities, Pain/Discomfort, and Anxiety/Depression.
• Global Perceived Effect [Baseline to 6 month study visit]: Number of participants with improvement measured by the Global Perceived Effect scale. The Global Perceived Effect is a 7-point scale: 1 point = "worst ever", 2 points = "much worse", 3 points = "worse", 4 points = "not improved but not worse", 5 points = "improved", 6 points = "much improved", 7 points = "best ever". There are no sub-scales. Number of participants scoring at either 5, 6, or 7 points on the Global Perceived Effect scale are reported.
• Global Perceived Effect [Baseline (or date of crossover for Crossover group subjects) to 12 month study visit]: Number of participants with improvement measured by the Global Perceived Effect scale. The Global Perceived Effect is a 7-point scale: 1 point = "worst ever", 2 points = "much worse", 3 points = "worse", 4 points = "not improved but not worse", 5 points = "improved", 6 points = "much improved", 7 points = "best ever". There are no sub-scales. Number of participants scoring at either 5, 6, or 7 points on the Global Perceived Effect scale are reported.
• Numeric Rating Scale [Baseline to 18 month study visit]: The proportion of subjects whose knee pain is reduced from baseline by ≥ 50% based on the NRS. The NRS is an 11-point scale (0 points to 10 points), where 0 points equals "no pain" and 10 points equals the "worst pain". There are no sub-scales.
• Numeric Rating Scale [Baseline to 24 month study visit]: The proportion of subjects whose knee pain is reduced from baseline by ≥ 50% based on the NRS. The NRS is an 11-point scale (0 points to 10 points), where 0 points equals "no pain" and 10 points equals the "worst pain". There are no sub-scales.
• Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) [Baseline to 18 month study visit]: The change in WOMAC score from baseline to 18 months. This outcome instrument is composed of three sub-scales, including "Pain" (5 questions), "Stiffness" (2 questions), and "Physical Function" (17 questions). The point range for each sub-scale question is from 0 to 4, with "0" indicating the best study subject condition and "4" indicating the worst study subject condition. Thus, the minimum score per sub-scale is 0, and the maximum is 20, 8, and 68 for "Pain", Stiffness", and "Physical Function", respectively. The minimum and maximum possible scores for the entire instrument are 0 (best study subject condition) and 96 (worst study subject condition).
• Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) [Baseline to 24 month study visit]: The change in WOMAC score from baseline to 24 months. This outcome instrument is composed of three sub-scales, including "Pain" (5 questions), "Stiffness" (2 questions), and "Physical Function" (17 questions). The point range for each sub-scale question is from 0 to 4, with "0" indicating the best study subject condition and "4" indicating the worst study subject condition. Thus, the minimum score per sub-scale is 0, and the maximum is 20, 8, and 68 for "Pain", Stiffness", and "Physical Function", respectively. The minimum and maximum possible scores for the entire instrument are 0 (best study subject condition) and 96 (worst study subject condition).
• EQ-5D-5L [Baseline to 18 month study visit]: The change in measured EQ-5D-5L scale from baseline to 18 months. This outcome instrument is composed of five sub-scales containing five questions each. The point range for each sub-scale is from 1 to 5, with "1" indicating the best study subject condition and "5" indicating the worst study subject condition. Thus, the minimum and maximum scores per sub-scale are 1 and 5, respectively, and such scores for the entire instrument are 5 (best study subject condition) and 25 (worst study subject condition). The sub-scale topics are: Mobility, Self-Care, Usual Activities, Pain/Discomfort, and Anxiety/Depression.
• EQ-5D-5L [Baseline to 24 month study visit]: The change in measured EQ-5D-5L scale from baseline to 24 months. This outcome instrument is composed of five sub-scales containing five questions each. The point range for each sub-scale is from 1 to 5, with "1" indicating the best study subject condition and "5" indicating the worst study subject condition. Thus, the minimum and maximum scores per sub-scale are 1 and 5, respectively, and such scores for the entire instrument are 5 (best study subject condition) and 25 (worst study subject condition). The sub-scale topics are: Mobility, Self-Care, Usual Activities, Pain/Discomfort, and Anxiety/Depression.
• Global Perceived Effect [Baseline to 18 month study visit]: Number of participants with improvement measured by the Global Perceived Effect scale. The Global Perceived Effect is a 7-point scale: 1 point = "worst ever", 2 points = "much worse", 3 points = "worse", 4 points = "not improved but not worse", 5 points = "improved", 6 points = "much improved", 7 points = "best ever". There are no sub-scales. Number of participants scoring at either 5, 6, or 7 points on the Global Perceived Effect scale are reported.
• Global Perceived Effect [Baseline to 24 month study visit]: Number of participants with improvement measured by the Global Perceived Effect scale. The Global Perceived Effect is a 7-point scale: 1 point = "worst ever", 2 points = "much worse", 3 points = "worse", 4 points = "not improved but not worse", 5 points = "improved", 6 points = "much improved", 7 points = "best ever". There are no sub-scales. Number of participants scoring at either 5, 6, or 7 points on the Global Perceived Effect scale are reported.
• Safety: The Proportion of Subjects Experiencing Adverse Events Between 12 - 24 Months (Extension) [12 month study visit to 24 month study visit]: Safety: The proportion of subjects experiencing adverse events between 12 - 24 months (Extension)

Sex: All, ages: 21 Years to any

INCLUSION CRITERIA

1. Age ≥ 21 years
2. Able to understand the informed consent form and provide written informed consent and able to complete outcome measures
3. Chronic knee pain for longer than 6 months that interferes with functional activities (for example, ambulation, prolonged standing, etc.)
4. Continued pain in the target knee despite at least 3 months of conservative treatments, including activity modification, home exercise, protective weight bearing, and/or analgesics (for example, acetaminophen or non-steroidal anti-inflammatory drugs \[NSAIDs\])
5. Positive response (defined as a decrease in numeric pain scores of at least 50%) to a single genicular nerve block of the index knee
6. Pain on NRS ≥ 6 on an 11-point scale for the index knee
7. Radiologic confirmation of arthritis (x-ray/MRI/CT) of Osteoarthritis (OA) grade of 2 (mild), 3 (moderate) or 4 (severe) noted within 6 months for the index knee
8. An intra-articular hyaluronic acid injection is indicated as an appropriate treatment option
9. WOMAC Knee Score group at baseline of Score of ≥ 2 (0 to 4 scale) on WOMAC question 1 (Pain) and a mean score of ≥ 1.5 on all five questions of the WOMAC pain subscale.
10. Analgesics including membrane stabilizers such as Neurontin/gabapentin and antidepressants for pain such as Cymbalta/duloxetine must be clinically stable (defined as stable dosage for ≥ 6 weeks prior to the screening visit) and shall not change during the course of the study without approval of the investigator
11. Agree to see one physician (study physician) for knee pain during the study period
12. Willing to utilize double barrier contraceptive method if of child bearing potential.
13. Willing to delay any surgical intervention for the index knee for the period of the study follow up
14. Willingness to provide informed consent and to comply with the requirements of this protocol for the full duration of the study

EXCLUSION CRITERIA

1. Evidence of inflammatory arthritis (for example, rheumatoid arthritis) or other systemic inflammatory condition (for example, gout, fibromyalgia) that could cause knee pain
2. Evidence of neuropathic pain affecting the index knee
3. Previous or pending lower limb amputation
4. Intra-articular steroid injection into the index knee within 90 days from randomization
5. Hyaluronic acid injection, platelet rich plasma (PRP), stem cell, or arthroscopic debridement/lavage injection into the index knee within 180 days from randomization
6. Prior radiofrequency ablation of the genicular nerves of the index knee
7. Prior partial, resurfacing, or total knee arthroplasty of the index knee (residual hardware)
8. Clinically significant ligamentous laxity of the index knee
9. Clinically significant valgus/varus deformities or evidence of pathology (other than osteoarthritis of knee) that materially affects gait or function of the knee or is the underlying cause of the knee pain and/or functional limitations
10. Body mass index (BMI) > 40 kg/m2
11. Extremely thin patients and those with minimal subcutaneous tissue thickness that would not accommodate a radiofrequency lesion of up to 14 mm in diameter to limit the risk of skin burns
12. Pending or active compensation claim, litigation or disability remuneration (secondary gain)
13. Pregnant, nursing or intent on becoming pregnant during the study period
14. Chronic pain associated with significant psychosocial dysfunction
15. Beck's Depression Index score of > 22 (indicates clinically depressed state)
16. Allergies to any of the medications to be used during the procedures, including known hypersensitivity (allergy) to hyaluronate preparations or allergies to avian or avian-derived products (including eggs, feathers, or poultry)
17. Active joint infection or systemic or localized infection at needle entry sites (subject may be considered for inclusion once infection is resolved)
18. History of uncontrolled coagulopathy, ongoing coagulation treatment that cannot be safely interrupted for procedure, or unexplained or uncontrollable bleeding that is uncorrectable.
19. Identifiable anatomical variability that would materially alter the procedure as described in the protocol
20. Within the preceding 2 years, subject has suffered from active narcotic addiction, substance, or alcohol abuse
21. Current prescribed opioid medications greater than 60 morphine equivalent daily opioid dose
22. Uncontrolled immunosuppression (e.g. AIDS, cancer, diabetes, etc.)
23. Subject currently implanted with pacemaker, stimulator or defibrillator.
24. Participating in another clinical trial/investigation within 30 days prior to signing informed consent
25. Subject unwilling or unable to comply with follow up schedule or protocol requirements

Participant flow

Outcome results

• Numeric Rating Scale (NRS) (Primary), Count of participants, Participants: Cooled Radiofrequency 54; Hyaluronic Acid Injection, Then Cooled Radiofrequency Crossover Option 31
• Safety: The Proportion of Subjects Experiencing Adverse Events Through Final Follow up. (Primary), Count of participants, Participants: Cooled Radiofrequency 78; Hyaluronic Acid Injection 48; Crossover From Hyaluronic Acid Injection to Cooled Radiofrequency 38
• Numeric Rating Scale (Secondary), Count of participants, Participants: Cooled Radiofrequency 43; Hyaluronic Acid Injection 10; CROSSOVER From Hyaluronic Acid Injection to Cooled Radiofrequency 40
• Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) (Secondary), Mean, units on a scale: Cooled Radiofrequency 31.5 +/- 23.0; Hyaluronic Acid Injection 14.8 +/- 19.4
• Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) (Secondary), Mean, units on a scale: Cooled Radiofrequency 30.7 +/- 25.2; Hyaluronic Acid Injection 32.1 +/- 18.3; Crossover From Hyaluronic Acid Injection to Cooled Radiofrequency 18.1 +/- 22.1
• EQ-5D-5L (Other pre specified), Mean, units on a scale: Cooled Radiofrequency 0.12 +/- 0.14; Hyaluronic Acid Injection 0.06 +/- 0.15
• EQ-5D-5L (Other pre specified), Mean, units on a scale: Cooled Radiofrequency 0.12 +/- 0.14; Hyaluronic Acid Injection 0.14 +/- 0.14; Crossover From Hyaluronic Acid Injection to Cooled Radiofrequency 0.08 +/- 0.15
• Global Perceived Effect (Other pre specified), Count of participants, Participants: Cooled Radiofrequency 55; Hyaluronic Acid Injection 33
• Global Perceived Effect (Other pre specified), Count of participants, Participants: Cooled Radiofrequency 42; Hyaluronic Acid Injection 8; Crossover From Hyaluronic Acid Injection to Cooled Radiofrequency 39
• Numeric Rating Scale (Other pre specified), Count of participants, Participants: Cooled Radiofrequency 22
• Numeric Rating Scale (Other pre specified), Count of participants, Participants: Cooled Radiofrequency 17
• Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) (Other pre specified), Mean, units on a scale: Cooled Radiofrequency 29.3 +/- 25.3
• Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) (Other pre specified), Mean, units on a scale: Cooled Radiofrequency 41.3 +/- 29.9
• EQ-5D-5L (Other pre specified), Mean, units on a scale: Cooled Radiofrequency 0.15 +/- 0.14
• EQ-5D-5L (Other pre specified), Mean, units on a scale: Cooled Radiofrequency 0.07 +/- 0.14
• Global Perceived Effect (Other pre specified), Count of participants, Participants: Cooled Radiofrequency 24
• Global Perceived Effect (Other pre specified), Count of participants, Participants: Cooled Radiofrequency 17
• Safety: The Proportion of Subjects Experiencing Adverse Events Between 12 - 24 Months (Extension) (Other pre specified), Count of participants, Participants: Cooled Radiofrequency 19

Adverse events

Time frame: Total Study: Baseline to 24 months

Serious adverse events by term

Other adverse events by term

• Results publication: Chen AF, Khalouf F, Zora K, DePalma M, Kohan L, Guirguis M, Beall D, Loudermilk E, Pingree MJ, Badiola I, Lyman J. Cooled radiofrequency ablation provides extended clinical utility in the management of knee osteoarthritis: 12-month results from a prospective, multi-center, randomized, cross-over trial comparing cooled radiofrequency ablation to a single hyaluronic acid injection. BMC Musculoskelet Disord. 2020 Jun 9;21(1):363. doi: 10.1186/s12891-020-03380-5. PMID 32517739

• Study Protocol and Statistical Analysis Plan (PDF, 2019-03-28)

• Antonia F Chen, MD, Principal investigator, Brigham and Women's Hospital