A Prospective, Multi-center, Randomized, Clinical Trial Evaluating the Safety and Effectiveness of Using COOLIEF™ Cooled Radiofrequency Probe to Create Lesions of the Genicular Nerves and Comparing a Single Injection of Hyaluronic Acid in the Management of Knee Pain
Phase: NA
Conditions: Osteoarthritis of the Knee
Sponsor: Avanos Medical

 
 
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Clinical Study Protocol 
 
Protocol Title: 
A Prospective, Multi-center, Randomized, Clinical Trial Evaluating the Safety 
and Effectiveness of Using COOLIEF™ Cooled Radiofrequency Probe to 
Create Lesions of the Genicular Nerves and Comparing a Single Injection of 
Hyaluronic Acid in the Management of Knee Pain. 
Protocol #: 
105-17-0001 
Study Short Name: 
Genicular Nerve Lesion Study 
Test Article(s): 
Treatment Group: COOLIEF™ Cooled Radiofrequency Probe (CRFA) 
Control Group: Synvisc-One (HA) 
Regulatory 
Classification:  
Class II Medical Device: Probe (cleared under K053082) used in conjunction 
with radiofrequency generator (cleared under K072478). Specific clearance 
for use for osteoarthritis (OA) knee pain under K163461 
Study Phase: 
Pivotal 
Indications:  
Pain Management; Osteoarthritis of the knee; RF Ablation 
Sponsor: 
Avanos Medical 
5405 Windward Parkway 
Alpharetta, GA 30004  
Study Director: 
David Curd, MS 
5405 Windward Parkway  
Alpharetta, GA 30004  
Medical Monitor: 
Dr. Hilton Kaplan, MBBCh FCSSA PhD 
5405 Windward Parkway, Alpharetta, GA 30004  
Lead Principal 
Investigator 
Antonia F.  Chen, MD/MBA 
Current Protocol 
Version: 
Version 4.0 (dated 28Mar2019)  
Previous Protocol 
Versions: 
Version 3.0 (dated 8Feb2018) 
Version 2.0 (dated 06Dec2017) 
Version 1.0 (dated 20Sep2017) 
The study will be conducted in compliance with this protocol and the following applicable regulations & 
Good Clinical Practices (GCPs): 
21CFR 11 
21 CFR 50 
 
 
21 CFR 54 
 
 
21 CFR 56 
21 CFR 812.2 (b) 
 
 

 
 
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1 
GENERAL INFORMATION 
 
This study is being performed to assess the relative effectiveness of the COOLIEF™ Pain Management 
System (formerly owned by Halyard Health, and now owned by Avanos Medical; Alpharetta GA) to 
manage moderate to severe knee pain in patients with osteoarthritis (OA) of the knee when compared to 
a single Viscosupplementation injection.  The product under study is currently marketed in the United 
States and has been cleared via 510(k) by the FDA under application K053082 and K163461 in 
combination with the Halyard Radiofrequency (RF) Generator (PMG-115-TD/PMG-230-TD, or PMG-
BASIC/PMG-ADVANCED K072478) for use in creating radiofrequency lesions in nervous tissue. It is also 
indicated for creating radiofrequency lesions of the genicular nerves for the management of moderate to 
severe knee pain of more than 6 months with conservative therapy, including medication, in patients with 
radiographically-confirmed osteoarthritis (grade 2-4) and a positive response (≥ 50% reduction in pain) to 
a diagnostic genicular nerve block.   
 
A Long-Term Extension will capture data allowing the assessment of the long term clinical outcomes 
(such as current level of pain, function, and progression of disease) for patients who received COOLIEF* 
as their initial treatment. Subjects who received COOLIEF* as their initial treatment will be asked to return 
for 2 additional visits representing 18 and 24 months post initial treatment.  
 
 

 
 
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Investigator Acknowledgement Signature Page 
 
 
Title: A Prospective, Multi-center, Randomized, Clinical Trial Evaluating the Safety and 
Effectiveness of Using COOLIEF™ Cooled Radiofrequency Probe to Create Lesions of the 
Genicular Nerves and Comparing a Single Injection of Hyaluronic Acid in the Management of Knee 
Pain 
I have read the attached protocol and agree that it contains all the necessary details for performing the 
study.  I agree to conduct the study according to the protocol. 
I will provide copies of the protocol and of the pre-clinical information on the Study Device (e.g., 
Investigator Brochure or Report of Prior Investigations) that was furnished to me by the Sponsor to all 
members of the study team responsible to me.  I will discuss this material with them to assure that they 
are fully informed regarding the Study Device and the conduct of the study. 
Once the protocol has been approved by the IRB/IEC, I will not modify this protocol without obtaining the 
prior approval of the Sponsor and of the IRB/IEC.  I will submit all protocol modifications and/or any 
informed consent modifications to the Sponsor and the IRB /IEC, and approval will be obtained before 
any modifications are implemented.  I will also submit all Serious Adverse Events and Protocol Violations 
to the IRB/IEC per their requirements. 
 
 
 
 
 
 
 
Investigator Printed Name 
 
 
 
 
 
 
Signature 
 
 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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2 
SYNOPSIS 
 
Protocol Title: 
105-17-0001: A Prospective, Multi-center, Randomized, Clinical Trial Evaluating 
the Safety and Effectiveness of Using COOLIEF™ Cooled Radiofrequency 
Probe to Create Lesions of the Genicular Nerves and Comparing a Single 
Injection of Hyaluronic Acid) in the Management of Knee Pain. 
Test Article(s): 
Treatment Group: COOLIEF™ Cooled Radiofrequency Probe (CRFA) 
Control Group: Synvisc-One (HA) 
Planned Number of 
Sites: 
Up to 15 centers will be included in this study 
Planned Number of 
Subjects: 
Approximately 168 
Study Design: 
Prospective, Multicenter, Randomized, Comparison, Human, Interventional 
Study Duration: 
The primary study concludes at 12 months post randomized treatment, 
however; an extension study will be offered to those who received COOLIEF* 
as their originally randomized treatment to allow data collection through 24 
months.   
Treatment Group: Up to 24 months following index procedure  
Control Group: Up to 13 months, depending upon receipt of Crossover 
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 
Objectives: 
• 
To compare the effectiveness of CRFA to HA in the management of 
moderate to severe knee pain in patients with radiologically-confirmed 
osteoarthritis to treatment with Viscosupplementation injection.  
• 
To confirm the safety of CRFA for creating radiofrequency lesions of the 
genicular nerves for management of moderate to severe knee pain in 
patients with radiologically-confirmed osteoarthritis. 
• 
To capture the long term clinical outcomes (such as current level of pain, 
function, and progression of disease through 24 months) for patients who 
received CRFA as their initial treatment. 
Selection Criteria: 
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])  

 
 
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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 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 of becoming pregnant during the study 
period 
14. Chronic pain associated with significant psychosocial dysfunction 

 
 
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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 
Safety Parameters / 
Endpoints: 
Safety Endpoint: Proportion of subjects experiencing adverse events through 
final follow up. 
 
 
 
 

 
 
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Table of Contents 
1 
General Information ........................................................................................................................... 2 
2 
Synopsis ............................................................................................................................................ 4 
3 
List of Abbreviations and Definition of Terms .................................................................................. 10 
4 
Introduction ...................................................................................................................................... 11 
4.1 
Background / Study Population ....................................................................................................... 11 
4.2 
Product Descriptions and Intended Use .......................................................................................... 13 
4.3 
Exempt studies Determination ........................................................................................................ 14 
4.4 
Summary of Prior Investigations ..................................................................................................... 14 
4.5 
Rationale for Study .......................................................................................................................... 15 
4.6 
Potential Risks & Benefits ............................................................................................................... 15 
5 
Study Objectives .............................................................................................................................. 17 
6 
Investigational Plan ......................................................................................................................... 17 
6.1 
Study Design ................................................................................................................................... 17 
6.2 
Endpoints ......................................................................................................................................... 18 
6.2.1 Primary Endpoints ........................................................................................................................... 18 
6.2.2 Secondary Endpoints ...................................................................................................................... 18 
6.2.3 Tertiary Endpoints ........................................................................................................................... 18 
6.2.4 Exploratory Analyses ....................................................................................................................... 18 
6.3 
Measures to Minimize/Avoid Bias ................................................................................................... 18 
6.4 
Duration of Subject Participation ..................................................................................................... 19 
6.5 
Study-Stopping Criteria ................................................................................................................... 19 
6.6 
Test Article Storage, Administration, & Accountability .................................................................... 19 
6.6.1 Instructions for Use .......................................................................................................................... 19 
6.6.2 Product Labeling, Packaging, and Storage ..................................................................................... 19 
6.6.3 Treatment Assignment .................................................................................................................... 20 
6.6.4 Procedural Description .................................................................................................................... 20 
6.6.5 Test Article/Supply Accountability ................................................................................................... 22 
7 
Subject Selection ............................................................................................................................. 22 
7.1 
Inclusion Criteria .............................................................................................................................. 22 
7.2 
Exclusion Criteria ............................................................................................................................. 23 
8 
Study Procedures ............................................................................................................................ 24 
8.1 
Center Readiness ............................................................................................................................ 24 
8.2 
Informed Consent Procedures ........................................................................................................ 24 
8.3 
Electronic Case Report Forms ........................................................................................................ 25 
8.4 
Measures and Methods of Assessment .......................................................................................... 25 

 
 
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8.4.1 Demographic information ................................................................................................................ 25 
8.4.2 Index Knee ...................................................................................................................................... 25 
8.4.3 Radiographic Evaluation .................................................................................................................. 25 
8.4.4 Subject Reported Clinical Symptoms of Chronic Knee Pain ........................................................... 25 
8.4.5 Combined Investigator/Subject Reported Outcomes ...................................................................... 26 
8.4.6 Intraoperative Radiographic Assessment ........................................................................................ 26 
8.4.7 Post-Treatment Care ....................................................................................................................... 26 
8.4.8 Subject-Reported Quality of Life Outcome Measures ..................................................................... 26 
9 
Schedule of Assessments ............................................................................................................... 27 
10 
Procedures by Visit .......................................................................................................................... 27 
10.1 
Visit 1- Screening / Randomization ................................................................................................. 27 
10.2 
Visit 2 – Index Treatment (Day 0) .................................................................................................... 28 
10.3 
VISIT 3-6 – FOLLOW-UP ASSESSMENTS .................................................................................... 28 
10.4 
Discontinuation / Early Termination (ET) ......................................................................................... 29 
10.5 
Crossover visit (visit 5a) .................................................................................................................. 30 
11 
Adverse Event Reporting................................................................................................................. 31 
11.1 
Adverse Events (AE) Assessment .................................................................................................. 31 
11.1.1 Definitions and Classification........................................................................................................... 31 
11.2 
Severity of Adverse Events ............................................................................................................. 32 
11.3 
Relationship of Adverse Events ...................................................................................................... 32 
11.4 
Reporting Adverse Events ............................................................................................................... 33 
11.5 
Reporting Serious Adverse Events ................................................................................................. 34 
11.6 
Clinical Safety Monitoring ................................................................................................................ 34 
12 
Statistical Methods and Data Analysis ............................................................................................ 35 
12.1 
Determination of Sample Size ......................................................................................................... 35 
12.1.1 Disposition of Subjects .................................................................................................................... 35 
12.1.2 Protocol Deviations .......................................................................................................................... 36 
12.2 
Dataset Definitions .......................................................................................................................... 36 
12.2.1 Safety Set ........................................................................................................................................ 36 
12.2.2 Full-Analysis Set .............................................................................................................................. 36 
12.2.3 Per-Protocol Set .............................................................................................................................. 36 
12.3 
Effectiveness Parameter ................................................................................................................. 37 
12.3.1 Primary Effectiveness Parameter .................................................................................................... 37 
12.3.2 Secondary Effectiveness Parameters ............................................................................................. 37 
12.3.3 Tertiary Effectiveness Parameter .................................................................................................... 37 
12.3.4 Exploratory Analysis ........................................................................................................................ 37 
12.4 
General Considerations ................................................................................................................... 37 
12.5 
Demographics, Baseline Characteristics, and Concomitant Medications ....................................... 38 

 
 
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12.6 
Effectiveness Analyses .................................................................................................................... 38 
12.6.1 Primary Effectiveness Analysis ....................................................................................................... 38 
12.6.2 Secondary Effectiveness Analysis .................................................................................................. 39 
12.6.3 Tertiary Effectiveness Analysis ....................................................................................................... 39 
12.7 
Safety Analyses ............................................................................................................................... 41 
12.7.1 Safety Parameter ............................................................................................................................. 41 
12.7.2 Method of Analysis .......................................................................................................................... 41 
12.8 
Handling of Missing Data ................................................................................................................. 41 
13 
Ethical, Administrative, and Regulatory Obligations ....................................................................... 41 
13.1 
Independent Ethics Committee (IEC) or Institutional Review Board (IRB) ..................................... 41 
13.2 
Health Insurance Portability and Accountability Act (HIPAA) .......................................................... 41 
14 
Data and Quality Management ........................................................................................................ 42 
15 
Records Retention and Archival ...................................................................................................... 42 
16 
Monitoring and Auditing ................................................................................................................... 42 
17 
Study / Site Termination .................................................................................................................. 43 
18 
publication plan ................................................................................................................................ 43 
18.1 
Generalities ..................................................................................................................................... 43 
18.2 
Steering Committee ......................................................................................................................... 44 
18.3 
Authorship Criteria ........................................................................................................................... 44 
18.4 
Primary Presentations ..................................................................................................................... 44 
19 
References ...................................................................................................................................... 45 
 
 
 

 
 
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3 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
 
Abbreviation 
 
Definition 
AE 
Adverse Event 
SAE 
Serious Adverse Event 
CRF 
Case Report Form 
CRFA 
COOLIEF™ Radiofrequency Ablation 
CFR 
US Code of Federal Regulations 
Cm 
Centimeter 
CTA 
Clinical Trial Agreement 
HA 
Synvisc-One (Hylan G-F 20) 
IRB 
Institutional Review Board 
NRS 
Numeric Rating Scale 
NSAID 
Non-steroidal anti-inflammatory drug 
OA 
Osteoarthritis 
PI 
Principal Investigator 
PDMP 
Prescription Drug Monitoring Program 
QOL 
Quality of Life 
RF 
Radiofrequency 
SOP 
Standard Operating Procedure 
UADE 
Unanticipated Adverse Device Effect 
 
 
 
 

 
 
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4 
INTRODUCTION 
4.1 
BACKGROUND / STUDY POPULATION 
With the population aging in the United States and around the world, chronic knee pain from conditions 
such as osteoarthritis (OA) is becoming a more prominent problem on the medical landscape.  Non-
steroidal anti-inflammatory drugs (NSAIDs) are the first line treatment for OA for the purpose of reducing 
pain and inflammation and allowing for the maintenance of activities.  Physical therapy or other exercise-
based modalities are also considered to be standards of care in the earliest stages of OA to maintain 
patient mobility to the extent possible. 
 
While total joint replacement is a well-established terminal treatment for late stage OA of major joints, 
such as the hip and knee, not all patients are well-suited for this procedure due to issues of age, health, 
or other factors.  In addition, total knee replacement, while generally considered effective, has been 
associated in at least one study with ongoing moderate to significant pain in up to 53% of patients, with 
patients in that study noting a median average pain score of 3 of 10 and worst pain score of 5 of 10.1 
 
Currently, there are a limited number of treatment options available for patients who are not candidates 
for total joint replacement and/or for whom drugs are either ineffective or are interfering with their overall 
quality of life and general health.  Corticosteroid injection provides significant short term improvement as 
far as pain relief 2, but multiple treatments are required and the steroid and analgesic medication may 
actually exacerbate cartilage destruction if used over an extended period of time.3  Viscosupplementation 
(the injection of protein-based gel/fluids into the joint space to improve synovial fluid viscosity) has shown 
some moderate effectiveness in some studies,4 5 but its clinical utility for knee OA has recently been 
called into question by the American Academy of Orthopaedic Surgeons (AAOS).6   
 
COOLIEF™ (CRFA) is a well-established method for delivering lesions into nervous tissue to accomplish 
neurotomy procedures.  Multiple references exist in the literature noting the clinical outcomes of patients 
treated with CRFA cooled radiofrequency for pain managing denervation in other anatomic locations, 
including the sacroiliac joint7,8,9,10 and the lumbar spinal disc.11,12,13  Recent human studies have started to 
demonstrate the effects of CRFA when specifically used for genicular neurotomy procedures in patients 
with chronic knee pain resulting from conditions such as OA14.   
 
Sensory innervation of the knee joint is accomplished by the articular branches of several nerves, 
including the femoral, tibial, saphenous, obturator, and common peroneal nerves.  As a group, these 
nerves have been termed “genicular nerves.”15,16 Radiofrequency-generated lesions of the genicular 
nerves (i.e., genicular neurotomy) using standard, non-cooled radiofrequency ablation has been defined 

 
 
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in the literature. Choi and colleagues17 published a prospective, randomized, double-blind controlled trial 
of genicular neurotomy in a series of 38 elderly OA patients with severe knee pain who had failed 
conservative therapy but responded to a diagnostic block. In this study, the superomedial and 
inferomedial branches of the saphenous nerve and the superolateral branch of the femoral nerve were 
targeted for treatment.  The probe placement is demonstrated in the figure below taken from Choi, et al.   
They showed statistically significant improvements in pain, Oxford Knee Score, and global perceived 
effect when compared to placebo at up to 3 months post treatment.  Ikeuchi and colleagues18 also 
published a prospective randomized study comparing RF neurotomy to diagnostic block alone.  In their 
study, at 12 weeks post treatment, 44% of the RF group rated “good or excellent” compared to only 12% 
of the block group.  The probe placement and lesioning pattern in the Ikeuchi, et al study differed from the 
method of Choi, et al.   
 
 
 
A recent sponsored study was completed which compared CRFA to intraarticular steroid injections (IAS) 
for painful OA of the knee and demonstrated statistically significant improvements in pain, function, and 
global perceived effect of CRFA at 614 and 12 months19. A subset of those patients were followed through 
24 months and it was identified that CRFA has the potential to provide sustained effect through this time 
period. This potential was previously suggested by Ho 2015 where patients reported 24 months of relief 
following CRFA when used to ablate the lateral branches that innervate the sacroiliac joint20 . The nerve 
targets were identical to those utilized in the Choi research.  
 
In 2014, Franco21 et al completed a cadaveric dissection study which confirmed the locations of the 
genicular nerves identified by Choi et al and identified an additional nerve target – the middle branch from 
the vastus intermedius, which will be incorporated as part of the lesioning for this protocol.  
 

 
 
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This protocol outlines a prospective, single arm, multicenter study examining pain relief as well as other 
important clinical efficacy indicators of using CRFA to create lesions of the genicular nerves.  The probe 
placement method and lesioning pattern will include the 3 targets utilized in the Choi et al and Davis et al 
with targeting of the superomedial and inferomedial branches of the saphenous nerve and the 
superolateral branch of the femoral nerve, and will include the additional nerve target identified by Franco 
et al - middle branch from the vastus intermedius. 
4.2 
PRODUCT DESCRIPTIONS AND INTENDED USE 
The following is a summary description of the Study Device. For additional information, please refer to the 
COOLIEF* “Instructions for Use” (Appendix 1).  The COOLIEF™ system components utilized in the study 
are the same in form and function regardless of specific product branding (COOLIEF*, SInergy*, or 
Halyard Health). 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 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 RF 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.  
 
Avanos Medical maintains a list of all model numbers and sizes for the system components. 
 

 
 
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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 OA of the 
knee in patients who have failed to respond adequately to conservative nonpharmacologic therapy 
and simple analgesics, e.g., acetaminophen. 
 
The Synvisc-One® (hylan G-F 20) Instructions For Use is attached as Appendix 2. 
 
4.3 
EXEMPT STUDIES DETERMINATION  
As both products being utilized in this study are commercially available and are being used according to 
their labeled indications, the sponsor has determined that this study meets the criteria for the ‘Exempt 
Studies’ as specified in 21 CFR 812.2 (c)(2) and confirmed in the Information Sheet Guidance For IRBs, 
Clinical Investigators, and Sponsors - Frequently Asked Questions About Medical Devices (January 
2006), which states that “studies of an already cleared medical device in which the device is used or 
investigated in accordance with the indications in the cleared labeling are exempt from Part 812.”
 
 
 
4.4 
SUMMARY OF PRIOR INVESTIGATIONS  
As mentioned above, a recent investigation has been performed in this population using the COOLIEF* 
device for performing genicular neurotomy procedures for managing patients with chronic knee pain due 
to conditions such as osteoarthritis 14. This prospective randomized study compared CRFA against 
intraarticular steroid injections (IAS) and the two treatment groups were homogenous for demographic, 
pain and functional parameters at baseline. Mean Numeric Rating Scale (NRS) at baseline was 7.3 ± 1.2 
(Mean ± SD) for the CRFA group and 7.2 ± 1.0 for the IAS group. One hundred and twenty-six (126) 
patients remained in the study and were evaluated at 6-months post treatment (n = 58 CRFA and n = 68 
IAS). In the CRFA group, 74.1% of patients had ≥ 50% reduction in NRS pain score compared to 16.2% 
in the IAS group at 6 month follow up (p < 0.0001, primary endpoint). At 6 months, the resting mean NRS 
was 2.5 ± 2.3 for the CRFA group and 5.9 ± 2.2 for the IAS group (p < 0.0001), representing a 4.9 point 
drop in NRS for the CRFA group. The mean Oxford Knee Score (measure of function) improved from 
16.7 ± 4.4 at baseline to 35.7 ± 8.8 in the CRFA group at 6 months, compared to 22.4 ± 8.5 in the IAS 
group (p < 0.0001).  At 6 months, 91.4% of subjects in the CRFA group reported improvement in Global 
Perceived Effect (GPE) compared to 23.9% in the IAS group (p < 0.0001). No serious adverse events 

 
 
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related to either procedure were noted, and overall adverse event profiles were similar. The primary 
results noted above are described in Davis et al 2017 14. 
 
These results were sustained at the 12 month time point in that 65.4% of subjects reported ≥ 50% 
reduction in NRS pain score in the CRFA group. In addition, the CRFA patient group’s Oxford Knee Score 
indicated continued functional improvement at 12 months with a mean score of 34.3 ± 11.1. 75% of 
subjects reported being ‘Improved’ on their GPE 12 months after treatment.19 
 
A subset of these subjects were followed through 24 months. Eighteen (18) subjects returned at 24 
months post CRFA procedure and their average NRS score was reported as 3.6 ± 2.7 for these subjects. 
Eleven (11) of the 18 reported pain levels that were ≥ 50% reduced from their baseline values. Functional 
improvements were maintained as well.22  
  
Multiple prior investigations using the CRFA device for delivering radiofrequency lesions into nervous 
tissue have been conducted and published, as described in section 4.1 above. 
 
Information related to clinical experience with the control product (HA) can be found in the Synvisc-One 
Instructions for Use document (Appendix 2).  
4.5 
RATIONALE FOR STUDY 
This prospective, multi-center, randomized, comparison study is examining the effects of the COOLIEF * 
Cooled Radiofrequency Probe used for radiofrequency neurotomy compared to a single injection of 
Hyaluronic Acid (Hylan G-F 20) in subjects to manage knee pain.  The study does not introduce any 
experimental procedures, as both products will be used in a manner that is consistent with their labeled 
indications. The primary rationale for conducting this study is to assist with reimbursement support for the 
product.  
 
The rationale for the long-term extension is to capture data to understand the long term clinical effects of 
utilizing CRFA for the treatment of OA knee pain. 
4.6 
POTENTIAL RISKS & BENEFITS  
The potential benefits of COOLIEF * when used for creating radiofrequency lesions in the genicular 
nerves of knee pain subjects are to provide pain relief, improve function, improve overall quality of life, 
and reduce the need for other modalities to control pain such as prescription opioids. 
 
Avanos Medical follows rigorous Quality Control procedures throughout the life of a product, from the 
business analysis phase through development, market release, and post-market surveillance. The risk 

 
 
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analysis process for COOLIEF* is performed in accordance with industry standards for ‘Risk Management 
for Medical Devices’ and ensures that the level of risk is acceptable prior to starting the clinical study. 
 
The potential risks to subjects in which a radiofrequency neurotomy procedure is performed, regardless of 
the treatment modality, may include the following, all of which are anticipated adverse events that have 
been identified as possible complications of procedures involving lesioning of nervous tissue: 
• 
Infection, 
• 
Damage to collateral nervous tissue, 
• 
Increased pain, 
• 
Visceral injury, 
• 
Failure of technique, 
• 
Superficial burns; 
• 
Damage to collateral tissue (i.e., bruising or hematoma), 
• 
Deafferentation dysesthesiae 
• 
Paralysis, and 
• 
Death 
 
The potential risks specifically associated with the use of COOLIEF* for radiofrequency neurotomy are 
anticipated to be the same as those listed above, with the exception of visceral injury and paralysis, as 
the device will not be used in any anatomic location in this study other than the index knee. 
 
As described in Appendix 2, the potential benefits of single injection of Hyaluronic Acid (Hylan G-F 20) 
include short to medium term pain relief, assistance with therapeutic exercise, and some restoration of 
function. 
 
Hylan injection involves inserting a needle directly into the space inside your knee.  This procedure 
carries certain risks, including: 
• 
Arthralgia 
• 
Arthritis 
• 
Arthropathy 
• 
Gait disturbance 
• 
Injection site pain 
• 
Joint effusion 
• 
Joint stiffness 
• 
Joint swelling 
• 
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There are other Hylan products on the market which have reported the following risks: 
• 
Rash 
• 
Hives 
• 
Itching 
• 
Fever 
• 
Nausea 
• 
Headache 
• 
Dizziness 
• 
Chills 
• 
Muscle cramps 
• 
Paresthesia 
• 
Peripheral edema 
• 
Malaise 
• 
Respiratory difficulties 
• 
Flushing 
• 
Facial swelling 
5 
STUDY OBJECTIVES 
This study is designed to: 
• 
Determine the effectiveness (primarily measured by pain relief) of COOLIEF * when used to 
create radiofrequency lesions of the genicular nerves compared to pain relief following a single 
injection of Hyaluronic Acid (Hylan G-F 20); and 
• 
Confirm the safety of COOLIEF * when used to perform radiofrequency lesions of the genicular 
nerves in subjects to manage knee pain compared to safety of single injection of Hyaluronic Acid 
(Hylan G-F 20). 
• 
To describe the long term clinical effects (such as current level of pain, function, and progression 
of disease through 24 months) for patients who initially randomized to and received CRFA for 
treatment of their OA knee pain. 
6 
INVESTIGATIONAL PLAN 
6.1 
STUDY DESIGN  
This is a prospective, randomized, multicenter comparison study examining the outcomes of subjects with 
OA and knee pain undergoing a procedure to create a radiofrequency lesion of the genicular nerves with 
the CRFA system compared to subjects receiving HA.  A total of approximately 168 subjects will be 
enrolled into this study, with subjects undergoing either CRFA or HA injection in a 1:1 randomization 
scheme.  Follow up will be conducted for a total of 12-months post randomized procedure with the 

 
 
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primary endpoint being completed at month 6.  Subjects randomized to the comparison (HA) group will 
have the option to cross over to the neurotomy group after completing the 6-month endpoint assessment. 
They would then be followed for an additional 6 months.  Pain, overall outcome, quality of life, pain 
medication use, and adverse events will be compared between the two treatment groups in order to 
determine success. Unless they have received an additional procedure on their index knee, subjects who 
were randomized to and received CRFA as their initial treatment will have the option to add 2 additional 
visits at 6-month intervals, representing 18 and 24 months post initial treatment.  
 
CRFA = Genicular Neurotomy using Cooled Radiofrequency Ablation  
HA = Hyaluronic Acid Injection (Synvisc-One 6 mL injection)  
6.2 
ENDPOINTS 
6.2.1 
Primary Endpoints 
Primary Effectiveness Endpoint:  
The proportion of subjects whose knee pain is reduced by ≥ 50% based on the NRS scale at 6 Months. 
 
Primary Safety Endpoint:  
The proportion of subjects experiencing adverse events through final follow up. 
6.2.2 
Secondary Endpoints 
Secondary Effectiveness Endpoints:  
• 
The proportion of subjects whose knee pain is reduced from baseline by ≥ 50% based on the 
NRS at 12 months. 
• 
The change in WOMAC score from baseline to the 6 month visit and 12 month visit.  
6.2.3 
Tertiary Endpoints 
• 
Tertiary effectiveness endpoint 1: The change in measured EQ-5D-5L scale from baseline at the 
6-month visit and 12-month visit. 
• 
Tertiary effectiveness endpoint 2: The measured Global Perceived Effect scale at the 6-month 
visit and 12-month visit. 

 
 
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6.2.4 
Exploratory Analyses 
 
Other variables of interest, which include, but are not limited to, WOMAC subscales (pain, stiffness, 
physical function), change in pain medication usage from baseline as measured by subject self-reported 
average daily dosage, healthcare utilization, and change in weight from baseline, will be summarized at 
various visit intervals. 
 
In addition, the endpoints listed above will also be summarized at 18 and 24 months post treatment. 
 
6.3 
MEASURES TO MINIMIZE/AVOID BIAS 
All subjects presenting to the study centers who report knee pain will be evaluated for eligibility for study 
participation.  Routine evaluations of all site screening logs will be conducted to assure that no subjects 
are excluded based on investigator bias.  Further, the primary endpoint measurements in this study are 
primarily subject generated and are not based on the opinion of the investigator, thus minimizing the 
potential for bias related to the outcome of the procedure.  
 
Independent monitoring, Data Management and Statistics will also be utilized to ensure accuracy of the 
data collected. 
6.4 
DURATION OF SUBJECT PARTICIPATION 
The screening period could take up to 60 days to complete for all subjects. Subjects will participate in the 
study for approximately 13 months from time of randomization treatment visit + 12-month follow up, 
except for subjects who participate in the optional crossover group or the long-term extension.  Crossover 
subjects will be on study for approximately 15 months from randomization (initial treatment + 6-month 
follow-up followed by crossover treatment with an additional 6-month follow up period). 
 
Those who initially received CRFA at Visit 2 will be given the option to return for 2 additional visits, 
representing 18 and 24 months post initial procedure. If they agree, their entire study participation will be 
approximately 25 months.  
 
Enrollment is anticipated to take approximately 8-10 months. 
6.5 
STUDY-STOPPING CRITERIA 
The study may be terminated if the sponsor determines that there is a clinical or other reason to do so.  In 
such cases, subjects already enrolled will be followed according to the protocol and further recruitment 
will be stopped. Potential reasons for early termination may include (but are not limited to): 

 
 
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• 
Withdrawal of IRB/ethics committee approval 
• 
Administrative reasons 
6.6 
TEST ARTICLE STORAGE, ADMINISTRATION, & ACCOUNTABILITY 
6.6.1 
Instructions for Use 
Study products should be maintained according to the manufacturers recommendations as indicated in 
their respective Instructions For Use (IFU) documents. The IFU for the COOLIEF* product is included 
within each kit. A copy is attached as Appendix 1.  
 
The Synvisc-One IFU document is attached as Appendix 2  
6.6.2 
Product Labeling, Packaging, and Storage 
 
As part of this protocol, the sponsor will provide the disposable products needed to manage the 
Treatment Arm procedure (CRFA) and the sites will be responsible for maintaining according to 
manufacturer’s guidelines as outlined in the IFU. The COOLIEF* Kit contains 1 Probe, 3 Introducers, and 
1 Tube Kit. In addition to the kits, a Dispersive Electrode (single use) and an additional Introducer for 
each subject will be supplied to each site. The COOLIEF* Kit and additional introducer are provided 
sterile, having been sterilized by ethylene oxide. The devices should be stored in a cool, dry environment, 
with limited access to the environment.  The Lot numbers and expiration dates of provided supplies will 
be captured for each subject as the kits are utilized. Provided supplies should be maintained in a secure 
location and should be utilized only for eligible study subjects. 
 
The sites will be responsible for securing the post market supplies for the Control Arm (HA) as per their 
standard procedures. Storage should follow instructions provided for the product. The Lot numbers and 
expiration dates of control supplies will be captured for each subject as the kits are utilized. 
Study products may only be used on enrolled study subjects for the procedures as described in this 
protocol. 
6.6.3 
Treatment Assignment  
At visit 1, all subjects who meet the eligibility criteria will be randomly assigned to one of two groups: (A) 
CRFA or (B) HA injection.  Randomly generated treatment assignments (1:1 randomization) have been 
prepared by the study statistician using a computerized randomization program, and will be loaded into 
the electronic data management system being utilized in the study. Upon confirmation that a subject is 
eligible for randomization, sites will log into the system to randomize the subject. Specific instructions will 
be provided. The monitor will confirm that the randomization process is being appropriately followed and 
documentation is being maintained as appropriate. Any deviation from the randomization process must 
be immediately reported to the sponsor and IRB as appropriate and documented appropriately.  

 
 
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6.6.4 
Procedural Description 
For the diagnostic block, a local anesthetic (preferably Marcaine 0.5% or similar) will be injected at each 
target site (with an ideal volume of 0.60 - 0.75 mL at each site). Subjects will be noted as positive 
responders if the participant experiences a decrease in numeric pain scores of at least 50% at least 15 
minutes after the injection. All subjects with a positive response will be eligible for the study. 
 
Subjects randomized to CRFA will be placed in a supine position on a fluoroscopy table with a pillow 
under the popliteal fossa to alleviate discomfort. The true AP fluoroscopic view of the tibiofemoral joint will 
be obtained to show the tibiofemoral joint space with equal width interspaces on both sides. An 
appropriately sized cooled radiofrequency needle will be placed overlying the affected knee joint and 
using fluoroscopic guidance, the needle will be advanced to a bony endpoint on the superiolateral portion 
of the femoral condyle of the affected knee. A second needle will be advanced to a bony endpoint on the 
superiomedial portion of the femoral condyle. A third needle will be advanced to the bony endpoint at the 
inferiomedial portion of the tibial condyle. The final needle will be placed at the midline of the femur about 
2 cm cephalad of the upper patellar border. Lateral x-ray views should be taken to confirm appropriate 
location at 50% depth of the femur and tibia prior to lesioning. Care should be taken to avoid inserting the 
RF probe into the inferolateral area of the knee to avoid the common peroneal nerve and potential foot 
drop. If pooling of blood or fluid is seen in the stylet, aspirate and reposition as necessary.  
  
AP and lateral x-ray views should be taken during the procedure which show all the needles in final 
positioning for maintenance in the source documentation. Motor stimulation must be tested at 2.0 volts 
with no leg movement. Sensory stimulation should be conducted at < 0.5 volts in all four locations with 
concordant pain reproduction. A mixture consisting of lidocaine (1% or 2% preferred) should then be 
slowly injected. Then, radiofrequency ablation of each of the four targeted geniculate nerves will be 
conducted at 60°C for 2 minutes and 30 seconds at each of the 4 anatomic locations.  At the conclusion 
of the procedure, the needles will be removed, the insertion sites will be treated with appropriate closure, 
and the subject will be allowed to properly recover prior to discharge home. Instillation of post-operative 
analgesic pain medication is permissible per institutional standard of care.  
 
Additionally, selected sites will also collect information during the procedure from the generators utilizing 
a sponsor provided laptop computer loaded with the TeraTerm Software package. This open sourced 
software collects blinded information from the generator during the procedure. The laptops should be 
attached to the generator prior to the initiation of the procedure. The reports will be saved utilizing the 
subject number assigned to the study as an identifier, and the data will be sent to the sponsor for 
analysis.  Specific training will be provided for participating sites and details will be described in a 
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Synvisc-One is administered as a single intra-articular and subjects randomized to the HA group will 
receive the dose per the Instructions For Use for the product. The preferred approach is the suprapatellar, 
pending anatomic limitations. Strict aseptic administration technique must be followed and the procedure 
should be performed per the instructions for use for the product. 
• 
Optional: If necessary, using an 18- to 20-gauge needle, remove synovial fluid or effusion 
before injecting Synvisc-One. 
• 
Do not use the same syringe for removing synovial fluid and for injecting Synvisc-One; 
however, the same 18- to 20-gauge needle should be used. 
• 
Twist the tip cap before pulling it off, as this will minimize product leakage. 
• 
To ensure a tight seal and prevent leakage during administration, secure the needle tightly 
while firmly holding the luer hub. 
 
Precaution: Do not over tighten or apply excessive leverage when attaching the needle or removing the 
needle guard, as this may break the syringe tip. 
 
• 
Inject the full 6 mL in one knee only.  
 
If concurrent minor procedures, such as arthrocentesis, are performed on the index knee prior to 
administration of either treatment, volume information should be captured in the subject’s source 
documentation. 
 
Subjects will be encouraged to refrain from strenuous activity for 48 hours following both procedures. 
6.6.5 
Test Article/Supply Accountability 
The investigator must ensure that accurate records of receipt of study devices, dispensing information, 
and the prompt return or destruction of unused supplies are maintained at all times.  A device 
accountability log will be supplied to the site for the purposes of recording study device dispensation and 
will be monitored by periodically sponsor personnel. All provided supplies and unused test articles must 
be returned or destroyed per the sponsor at the end of the study after final accountability has been 
conducted by sponsor personnel. 
7 
SUBJECT SELECTION 
Subjects will include male and non-pregnant females ≥ 21 years of age who present with chronic knee 
pain resulting from osteoarthritis and meet all inclusion and exclusion criteria. 

 
 
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7.1 
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 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 
7.2 
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 
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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 

 
 
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8 
STUDY PROCEDURES  
8.1 
CENTER READINESS 
Prior to initiating study procedures, all applicable regulatory requirements must be fulfilled. Each study 
site must have written documentation of readiness including but not limited to:  
A. 
Investigational Review Board (IRB) approval of the current version of the Clinical 
Investigation Plan (Protocol) and Informed Consent Form (ICF)  
B. 
Signed/dated Curriculum Vitae and current medical licensure for Investigator and Sub-
Investigator(s) 
C. 
Signed/dated Financial Disclosure Forms for Investigator and Sub-Investigator(s) 
D. 
Signed/dated Clinical Trial Agreement / Statement of Investigator  
8.2 
INFORMED CONSENT PROCEDURES 
Prior to undergoing any study procedure or baseline testing, each subject must indicate their consent by 
signing and dating the current IRB-approved Informed Consent Form.  Consent forms must be approved 
by both Avanos Medical and the IRB prior to implementation and must be provided to the subject in their 
primary language complying with the requirements of 21 CFR 50. 
 
The principal investigator or qualified delegate will administer informed consent procedures by providing 
to and reviewing with the potential subject the IRB approved informed consent form (ICF) in accordance 
with 21 CFR 50.  The subject must be allowed adequate time to review the consent document and ask 
any questions.  The subject must indicate their consent by personally signing (or making their legal mark) 
and dating the consent form.  The investigator or qualified delegate must countersign the consent form. 
The subject must receive a copy of the signed/dated consent form for their records.  Information detailing 
the Informed Consent process must be clearly documented in each subject’s medical / study record 
(source document). 
 
Subjects in the treatment group who remain in the study through the 12-month time period will be offered 
the option to continue participation through 24 months. Subjects will need to sign an additional informed 
consent in order to participate in the extension.  Subjects who have received an additional procedure on 
their index knee will not qualify for the extension study.  
  
8.3 
ELECTRONIC CASE REPORT FORMS 
All study data will be entered into an Electronic Case Report Form (eCRF). The investigator is responsible 
for ensuring the accuracy of all data entered on the eCRF.  Each eCRF entry must be supported by 
source documentation in the subject’s medical records. 

 
 
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8.4 
MEASURES AND METHODS OF ASSESSMENT 
The following assessments will be utilized throughout the study in accordance with the assessment 
schedules described in sections 9 and 10. 
8.4.1 
Demographic information 
Age, gender, race, BMI, osteoarthritis diagnosis and treatment history, comorbidities, and concomitant 
medications will be collected for demographic analysis.  
8.4.2 
Index Knee 
The “index” knee is defined as the knee that is being studied and to which the eligibility criteria are 
applied.  This is the knee that will be treated with either CRFA or HA injection.  Subjects may have 
moderate osteoarthritis in the contralateral limb and still be included in the clinical trial; however, only one 
knee may meet eligibility and be entered into the study.   
8.4.3 
Radiographic Evaluation 
All subjects are required to have radiographic confirmation of arthritis (x-ray/MRI/CT) of OA grade of 2 
(mild), 3 (moderate) or 4 (severe) noted within 6 months prior to study enrollment.  OA grade will be 
based on the classification system of Kellgren-Lawrence23 diagnosed by standard x-rays. Radiographic 
evaluations will also be assessed at each subject’s Visit 6 (12 Month Visit) and at 24 months as 
appropriate.  
8.4.4 
Subject Reported Clinical Symptoms of Chronic Knee Pain 
All subjects are required to complete a Numeric Rating Scale24 (NRS) for pain at multiple points during 
the clinical study.  Subjects will be asked to rate their usual pain, worst pain, least pain, and current pain 
in each knee at each time point. An NRS of ≥ 6 (usual daily pain) for their index knee is required for 
entrance in the study.  An accurate assessment of NRS is critical at all points in the study, especially at 
the 6-month visit, as this will be used as the primary endpoint of the study. 
 
8.4.5 
Combined Investigator/Subject Reported Outcomes 
The WOMAC is a disease-specific validated outcomes instrument that is routinely used to evaluate the 
overall condition of subjects with osteoarthritis of the knee25.  This instrument assesses pain, stiffness and 
physical function subscales and requires inputs from both the subject and the investigator.   
 
For study inclusion, WOMAC Knee Score group at baseline of Score of 2 or 3 (0 to 4 scale) on WOMAC 
question A1 (pain while walking on flat surface) and a mean score of 1.5 to 3.5 on all five questions of the 
WOMAC subscale A (pain) are required.  

 
 
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8.4.6 
Intraoperative Radiographic Assessment 
 
An antero-posterior (AP) and lateral fluoroscopic views of the treated knee will be obtained 
intraoperatively to confirm placement of the RF probes.  The images must be captured on archive media 
and maintained as described in section 6.6.4. 
8.4.7 
Post-Treatment Care 
Unless there is an adverse event requiring further medical intervention, subjects will be discharged home 
from the treatment facility on the day of the procedure with strict instructions for a caregiver or other 
individual to drive them home.  Subjects will be encouraged to refrain from strenuous activity for 48 hours 
following both procedures. It is anticipated that subjects will feel some pain and discomfort at the site of 
the procedure for up to 1-2 weeks following the procedure. Subjects will be instructed to use common 
conservative therapy such as ice packs at the procedure site and may be prescribed analgesic 
medication to decrease their discomfort, if needed.  Subjects will be instructed to return to ambulation 
based upon their own pain tolerance and using any modalities such as a cane that was employed prior to 
the RF procedure.   
8.4.8 
Subject-Reported Quality of Life Outcome Measures 
The EQ-5D-5L scale 26, a validated instrument for subject quality of life and overall health status, will be 
obtained at all visits. The EQ-5D-5L allows assessments of impact on healthcare systems to be 
undertaken.  
 
The Global Perceived Effect (GPE) scale27, a validated instrument for subject quality of life outcomes, will 
be used for this study.  The GPE has been validated to measure health transitions in subjects with 
musculoskeletal disorders such as osteoarthritis.  The GPE will be obtained at all follow up visits. 

 
 
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9 
SCHEDULE OF ASSESSMENTS 
Table 1: Schedule of Assessments 
  
 
 
10 
PROCEDURES BY VISIT 
10.1 VISIT 1- Screening / Randomization 
Perform the following assessments: 
(1) Subject Selection / Informed Consent. 
(2) Follow institutional standard protocol for confirming pregnancy status prior to treatment. 
(3) Obtain demographic information and medical history. 
(4) Assess subject radiographs for eligibility. 
(5) Perform Physical Exam (including BMI and vital signs). 
(6) Knee exam 
(7) Obtain baseline Beck’s Depression Index (subject completed questionnaire). 

 
 
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(8) Perform Numeric Rating Scale assessment for pain (subject completed questionnaire).  
(9) Obtain a baseline WOMAC Score (subject completed questionnaire). 
(10) Obtain a baseline EQ-5D-5L Score (subject completed questionnaire). 
(11) Obtain Healthcare Utilization Form 
(12) Assess concomitant medications. 
(13) Verify that diagnostic block procedure was performed and confirm responder status. 
(14) Verify subject eligibility and randomize subject. 
(15) Perform adverse event assessment (if screening visit occurs over more than one day)   
(16) Assess concomitant medications. 
(17) Schedule Treatment visit 
 
The screening procedures/visit can occur on more than one day, but must be concluded (patient should 
be randomized) within 60 days of signing informed consent.  
10.2 Visit 2 – Index Treatment (Day 0) 
It is permissible that Visit 2 can occur on the same day as Visit 1/Randomization date, but it should occur 
within 30 days from the date of randomization. 
Perform the following assessments: 
(1) Verify that subject continues to meet all eligibility criteria. 
(2) Follow institutional standard protocol for confirming pregnancy status prior to treatment (if 
applicable and >30 days since previous one) 
(3) Obtain Healthcare Utilization Form  
(4) Perform CRFA or HA injection procedure per section 6.6.4. 
(5) Perform adverse event assessment. 
(6) Assess for changes to concomitant medications. 
(7) Provide subject with perioperative care and at-home care instructions 
(8) Schedule next clinic visit 
 
It is recommended (but not required) that the first several CRFA procedures at each site should be 
proctored by a Avanos Medical clinical specialist to ensure procedural consistency between sites. 
10.3 VISIT 3-6 – FOLLOW-UP ASSESSMENTS    
Visit 3/1 Month Visit should occur at post-operative day 30 ± 7 days. Visit 4/3 Month Visit should occur at 
post-operative day 90 ± 14 days. Visit 5/6 Month Visit should occur at post-operative day 180 ± 14 days.  
Visit 6 should occur at post-operative day 360 ± 14 days.  
 
 

 
 
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Perform the following assessments: 
(1) Subjects will return at months 1, 3, 6 and 12 after the procedure within the allowable follow-up 
intervals described above. 
(2) Obtain a Numeric Rating Scale for pain (subject completed questionnaire).  
(3) Obtain WOMAC Score (subject completed questionnaire). 
(4) Obtain an EQ-5D-5L Assessment (subject completed questionnaire). 
(5) Obtain a Global Perceived Effect Score (subject completed questionnaire). 
(6) Obtain Healthcare Utilization Form 
(7) Perform Physical Exam including BMI and vital signs (Visits 5 and 6 only). 
(8) Perform Knee Exam (Visits 5 and 6 only). 
(9) Perform adverse event assessment. 
(10) Assess concomitant medications. 
(11) Schedule next clinic visit. 
(12) Collect and assess Radiographs (Visit 6 only). 
10.4 VISIT 7-8 – LONG TERM FOLLOW-UP ASSESSMENTS    
 
These visits are only available to those subjects who originally received CRFA at Visit 2 and who signed 
the informed consent to continue participation in the study. Visit 7/18 Month Visit should occur at post-
operative day 540 ± 14 days and Visit 8/24 Month Visit should occur at post-operative day 720 ± 14 days.  
 
Perform the following assessments: 
(1) Obtain Informed consent (only at Visit 7). 
(2) Obtain a Numeric Rating Scale for pain (subject completed questionnaire).  
(3) Obtain WOMAC Score (subject completed questionnaire). 
(4) Obtain an EQ-5D-5L Assessment (subject completed questionnaire). 
(5) Obtain a Global Perceived Effect Score (subject completed questionnaire). 
(6) Obtain Healthcare Utilization Form. 
(7) Perform Physical Exam including BMI and vital signs. 
(8) Perform Knee Exam. 
(9) Perform adverse event assessment. 
(10) Assess concomitant medications. 
(11) Schedule next clinic visit (only at Visit 7). 
(12) Collect and assess Radiographs (only at Visit 8). 
 

 
 
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10.5 DISCONTINUATION / EARLY TERMINATION (ET)  
Subjects may withdraw from the study at any time for any reason.  Early terminations can occur under the 
following circumstances: 
1. Subject withdraws consent. 
2. Subject receives an additional procedure on their index knee. 
3. Investigator withdraws the subject for any reason following discussion with the sponsor. 
4. Investigator withdraws the subject immediately for emergent safety issues and reverts to 
institutional standards-of-care. 
 
If it becomes necessary to exit the subject from the study early, the following exit procedures should be 
conducted if at all possible: 
(1) Obtain a Numeric Rating Scale for pain (subject completed questionnaire).  
(2) Obtain WOMAC Score (subject completed questionnaire). 
(3) Obtain an EQ-5D-5L Assessment (subject completed questionnaire). 
(4) Obtain a Global Perceived Effect Score (subject completed questionnaire). 
(5) Obtain Healthcare Utilization Form 
(6) Collect and assess Radiographs  
(7) Perform Physical Exam including BMI and vital signs 
(8) Perform Knee Exam 
(9) Perform adverse event assessment. 
(10) Assess concomitant medications. 
 
The study may be terminated by the sponsor at any time for any reason.  If a subject is withdrawn or the 
study is terminated, investigators will revert to institutional standards-of-care. 
10.6 Crossover visit (visit 5a) 
Only subjects initially randomized to the control group (HA injection) who remain in significant pain at 
Visit 5 are eligible to receive crossover. Significant pain is defined as pain substantial enough to warrant 
receipt of a minimally invasive procedure (i.e., CRFA) per the investigators and subject assessment. 
Subjects do not need to formally requalify for the study to receive crossover per the inclusion/exclusion 
criteria; however, confirmation and documentation is needed that subjects remain a medically 
appropriate candidate for the CRFA procedure in order to be eligible.  
 
Prior to receiving the Crossover procedure, the subject should be reminded of the risks of the CRFA 
procedure as described in section 4.6 and should sign the Crossover section of the informed consent 
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If the subject is still receiving relief from the HA injection at the time of this visit and/or is not medically 
appropriate for the CRFA procedure or elects not to Crossover, the subject should not receive crossover 
treatment and should continue to complete Visit 6.   
 
It is anticipated that the Crossover procedure will occur on a different day than the 6 Month visit (Visit 5); 
however, it is allowable to perform the procedure on the same day if the Visit 5 items are completed first. 
Otherwise, the crossover treatment should occur within 30 days of Visit 5. If Visit 5A occurs on the same 
day as Visit 5, overlapping assessments noted below that were completed as part of Visit 5 do not need 
to be re-done (i.e., NRS, WOMAC, Healthcare Utilization, etc.). 
 
If a subject choses crossover, the timing of their follow up visits (5B, 5C and 6) will now be based off their 
Visit 5A treatment date. Visit 5B/1 Month Visit should occur at post-operative day 30 ± 7 days. Visit 5C/3 
Month Visit should occur at post-operative day 90 ± 14 days and the 6 Month Visit/Visit 6 should occur at 
post-operative day 180 ± 14 days.   
 
At the Crossover Visit, the following assessments must be performed. 
(1) Verify Crossover consent was obtained 
(2) Verify and document that the subject remains medically appropriate for the procedure.  
(3) Obtain a Numeric Rating Scale for pain (subject completed questionnaire).  
(4) Obtain WOMAC Score (subject completed questionnaire). 
(5) Obtain an EQ-5D-5L Assessment (subject completed questionnaire). 
(6) Obtain a Global Perceived Effect Score (subject completed questionnaire). 
(7) Obtain Healthcare Utilization Form 
(8) If applicable, follow site standard procedures for confirming pregnancy status prior to treatment. 
(9) Perform CRFA procedure per section 6.6.4. 
(10) Perform adverse event assessment. 
(11) Assess concomitant medications. 
(12) Provide subject with perioperative care and at home care instructions. 
(13) Schedule next clinic visits (1, 3, and 6 months as noted above). 
 
11 
ADVERSE EVENT REPORTING 
11.1 ADVERSE EVENTS (AE) ASSESSMENT 
Subjects should be instructed to contact the Investigator (or designee) immediately if an AE occurs.  At 
each visit, the investigator (or authorized designee) should further query the subject to determine if any 

 
 
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new adverse events have occurred.  Adverse Events will be assessed from the time the subject signs 
consent until study exit.  All adverse events must be reported according to the following procedure. 
 
Sites will be instructed to follow their normal /routine processes for adverse event reporting of post market 
products to the FDA per 803.20 – Individual Adverse Event Reports, however; related events that result in 
death, serious injury or malfunction that could cause death or serious injury will be specifically monitored 
for. As an additional measure of control, the sponsor will periodically review reported events as described 
in section 11.6 looking for items that meet the reporting criteria.  
11.1.1 Definitions and Classification 
Adverse Event (AE):  
Any untoward medical occurrence that occurs in a subject or clinical investigation subject using a study 
device including any unfavorable and unintended sign (including abnormal laboratory finding), symptom, 
or disease temporally associated with the use of the study device, whether or not considered related to 
the device. 
Treatment Emergent Adverse Event (TEAE):   
An AE that begins or worsens in severity after the subject has used at least one study device 
 
Non-Treatment Emergent Adverse Event:  
An AE that begins or worsens in severity between the time that the consent form is signed and 
the first use of the study device 
 
Serious Adverse Event (SAE):  
A Serious Adverse Event is defined as any untoward medical occurrence that falls into one of the 
following categories: 
A. 
Results in death 
B. 
Is life threatening, meaning that the subject is at risk of death at the time of the event; this 
does not mean that the event hypothetically might have caused death if it were more 
severe. 
C. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
D. 
Results in persistent or significant disability or incapacity 
E. 
Is a congenital anomaly or birth defect in a subject’s fetus or baby 
F. 
Is an important medical event that may not be immediately life-threatening or result in 
death or hospitalization, but that may jeopardize the subject or require intervention to 
prevent one of the above outcomes.  Examples of such events are intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias, or 
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Unanticipated Adverse Device Effect (UADE):  
Any serious adverse effect on health or safety or any life-threatening problem or death cause by, or 
associated with, a device, if that effect, problem or death was not previously identified in nature, severity, 
or degree of incidence in the investigational plan or application, or any other unanticipated serious 
problem associated with the device that relates to the rights, safety, or welfare of subjects. 
11.2 SEVERITY OF ADVERSE EVENTS 
The Investigator (or authorized delegate) will assess the severity of each AE based on the following 
definitions:  
 
11.3 RELATIONSHIP OF ADVERSE EVENTS 
 
For each AE, the Investigator (or qualified delegate) will assess the causality/relationship to the 
investigational device according to the following criteria: 
 
Relatedness 
Definition 
Unrelated 
A clearly evident relationship to other etiologies, such as concomitant medications 
or conditions or subject’s known clinical state 
Unlikely 
Based upon available information regarding subject history or disease process, 
relationship of adverse event to test article(s) is unlikely 
Possible 
The association of the AE with the test article is unknown; other etiologies are also 
possible 
Severity 
Definition 
Mild 
An AE in which the subject is aware of signs or symptoms, but which does not interfere with 
the subject’s usual activities of daily living, or is transient and resolves without treatment or 
sequelae 
Moderate 
A sign or symptom which interferes with the subject’s usual activities of daily living or 
requires treatment 
Severe 
An AE that results in incapacity with inability to do work or do usual activities of daily living. 
Severe AEs require treatment or medical intervention to resolve 

 
 
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Probable 
A reasonable temporal sequence of the AE with test article administration exists 
and based upon the medical professional’s clinical experience, the association of 
the AE with the test article seems likely 
Definite 
A causal relationship exists between the test article and the AE, and other 
conditions (e.g., concomitant illness, progression or expression of the disease state, 
reaction to concomitant medications) do not appear to explain the AE 
 
For AE’s, the most likely cause (e.g., disease under treatment, concomitant disease, concomitant 
medication, other) will be indicated on the eCRF with details of the concomitant disease or medication or 
other cause. 
11.4 REPORTING ADVERSE EVENTS 
A. 
All AEs must be recorded in the subject’s medical record and the appropriate eCRF.  The 
description of the AE will identify the date of onset, date of remission, severity, causal 
relationship to the study product, action taken along with the results of any diagnostic 
procedures or laboratory tests, all treatments that were required and the outcome of the 
event. 
B. 
The Investigator will follow all study device related AEs until there is a return to baseline or 
until a clinically satisfactory resolution is achieved. 
11.5 REPORTING SERIOUS ADVERSE EVENTS 
The Investigator must report any SAE to the Sponsor within 24 hours of becoming aware of the event.  All 
deaths, whether or not considered study-related, must be reported immediately to the Sponsor with a 
copy of the autopsy report and death certificate provided when and if available. 
 
SERIOUS ADVERSE EVENT REPORTING INSTRUCTIONS 
 Dr. Hilton Kaplan, MBBCh FCSSA PhD 
Medical Monitor 
Telephone Number: 646-499-0132 
Email:  Hilton.Kaplan@avanos.com 
 
Fax/Scan the Serious Adverse Event form and supporting documentation to 
(678) 669-2791 within 24 hours of becoming aware of a Serious Adverse Event. 
 

 
 
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The Investigator and the Sponsor will review each SAE report to evaluate the seriousness and the causal 
relationship of the event to study device.  In addition, the Sponsor will determine if that effect, problem, or 
death was not previously identified in nature, severity, or degree of incidence in the investigational plan.  
Based on the Investigator and Sponsor’s assessment of the event, a decision will be made concerning 
the need for further action. 
 
All SAEs will be captured from signing of informed consent throughout the study. The Investigator must 
notify the IRB in writing of all SAEs in accordance with IRB requirements. 
11.6 CLINICAL SAFETY MONITORING 
Avanos Medical’s Medical Director will conduct periodic safety monitoring and oversight throughout the 
course of the study by reviewing all Serious Adverse Event reports, conducting Adverse Event listing 
reviews, and monitoring post-market surveillance reports.   
 
Upon receipt of any Serious Adverse Event (SAE) report at Avanos Medical, the medical monitor will 
review the SAE report for completeness and when necessary, will request clarification and/or additional 
information from the investigator. The designated medical monitor is responsible for reviewing the 
investigator’s assessment and classification of each event. If the designated medical monitor disagrees 
with the investigator’s classification of the event, the rationale will be provided to the investigator. If the 
investigator agrees with the designated medical monitor, the subject’s Adverse Event Report Form will be 
updated accordingly. If the investigator does not agree with the designated medical monitor classification, 
both determinations will be documented within the study report. However, the Avanos Medical 
determination will be used for analysis purposes. 
 
Given the ‘Exempt’ status of this study, Avanos Medical has determined that a Data Monitoring 
Committee (or DSMB) is not required based on the FDA guidance document, “Establishment and 
Operation of Clinical Trial Data Monitoring Committees”.   
12 
STATISTICAL METHODS AND DATA ANALYSIS 
Prior to initiation of the analysis, a stand-alone Statistical Analysis Plan (SAP) will be prepared, which will 
provide detailed methods for the analyses outlined below. Any deviations from the planned analyses will 
be described and justified in the final integrated study report. 
 
The primary analysis is planned when the last enrolled subject completes the 6-month follow-up visit. The 
subjects will continue to be followed through 12 months, and a final analysis is planned at the conclusion 
of the study after the last subject completes the 12-month follow-up visit. 
 

 
 
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An additional analysis will be conducted once the last subject completes the extension study to analyze 
data collected at 18 and 24 months. 
 
12.1  
DETERMINATION OF SAMPLE SIZE  
A non-inferiority approach on response rate was used to estimate the sample size for this study, with 
“response” defined as ≥ 50% reduction in pain on the NRS scale from baseline.  The upper bound of a 2-
sided 95% CI will be calculated for the rate difference between treatments (Standard minus Test). If the 
upper bound is less than (δ), then “non-inferiority” is achieved for the test treatment relative to standard 
treatment, as described in the table below: 
 
Success Rate of CRFA 
(based on 50% Pain 
Score Reduction in VAS)  
Success Rate of 
Standard (Based on 
30% Pain Score 
Reduction in VAS) 
Non-Inferiority 
Margin (δ) 
Sample Size 
5% Level of Significance 
(2-sided) 
90% Statistical Power 
62%* 
40%** 
5% 
134 
* - 14 Davis, et al, RAPM 2017, In Press /FDA clearance K163461 
** - 5 Chevalier, X et al. “Single, intra-articular treatment with 6 ml Hylan G-F 20 in patients with symptomatic primary 
osteoarthritis of the knee: a randomized, multi-center, double-blind, placebo controlled trial” Ann Rheum Dis 2010 69: 113-119.  
 
Assuming an attrition rate of 20%, 168 subjects enrolled into the study will yield 134 completers.   
12.1.1 Disposition of Subjects 
The number and percentage of subjects entering the study will be presented.  Reasons for any screen 
failures and/or early terminations will be summarized.  A flow chart will present the aggregate disposition 
of subjects from Visit 1 (Screening Visit) through the final 24-month visit, including all subjects who cross 
over from the viscosupplementation injection group to the CRFA denervation group. 
12.1.2 Protocol Deviations 
Deviations from the protocol, including violations of inclusion/exclusion criteria, will be assessed as 
“minor” or “major” by the sponsor prior to database lock and analysis.  Major deviations from the protocol 
will lead to the exclusion of a subject from the Per-Protocol Set.   
 
Certain clinical situations may require waivers for the safety of the subjects enrolled, integrity of the data 
or scheduling conflicts. Any waiver request will be reviewed on an independent basis and must be 
documented in writing prior to the event occurrence.  Clinical decisions will be made by the medical 
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12.2 DATASET DEFINITIONS 
12.2.1 Safety Set 
All randomized subjects who receive CRFA or HA injection treatment will be included in the safety 
analyses. 
12.2.2 Full-Analysis Set 
All randomized subjects will be analyzed following the principle of intention-to-treat (ITT) provided they 
received CRFA or HA injection treatment and had at least one effectiveness observation.   
12.2.3 Per-Protocol Set 
All randomized subjects who are compliant with the study protocol (i.e., who do not experience any major 
protocol deviations) and who receive CRFA or HA injection treatment and have at least one effectiveness 
observation will be included in the Per-protocol Set.  
 
The primary effectiveness endpoint analysis will be based on the Full Analysis Set, although a secondary 
analysis will also be performed based upon the Per-Protocol Set (if there are differences), to assess the 
sensitivity of the analysis to the choice of analysis population. The analyses of all other endpoints will be 
based upon the Full Analysis Set only unless otherwise stated in the SAP.  All safety analyses will be 
based upon the Safety Set. 
 
Crossover subjects that continue to meet all Inclusion/Exclusion criteria will be included in the Per-
protocol Set, and may be combined with CRFA randomized subjects for purposes of overall assessment 
of the CRFA procedure. 
 
12.3 EFFECTIVENESS PARAMETER  
12.3.1 Primary Effectiveness Parameter 
The primary effectiveness parameter is defined as the proportion of subjects whose knee pain is reduced 
from baseline by ≥ 50% based on the Numeric Rating Scale (NRS) at the 6-month visit. 
 
12.3.2 Secondary Effectiveness Parameters 
Secondary Effectiveness Endpoint 1:  The proportion of subjects whose knee pain is reduced from 
baseline by ≥ 50% based on the Numeric Rating Scale (NRS) at the 12-month visit. 
 
Secondary Effectiveness Endpoint 2: The change in the WOMAC Score from baseline to the 6 month visit 
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12.3.3 Tertiary Effectiveness Parameter 
Tertiary effectiveness endpoint 1: The change in measured EQ-5D-5L scale from baseline at the 6-month 
visit and 12-month visit. 
 
Tertiary effectiveness endpoint 2: The measured Global Perceived Effect scale at the 6-month visit and 
12-month visit. 
12.3.4 Exploratory Analysis  
Other variables of interest, which include, but are not limited to, WOMAC subscale analysis (pain, 
stiffness, physical function), change in pain medication usage from baseline as measured by subject self-
reported average daily dosage, healthcare utilization, and change in weight from baseline, will be 
summarized at various visit intervals as discussed below in section 12.5. 
 
In addition, the endpoints listed above will also be summarized at 18 and 24 months post treatment.  
 
12.4 GENERAL CONSIDERATIONS 
 
All statistical tests will be two-sided and will be performed at the 5% level of significance, unless otherwise 
stated in the statistical analysis plan (SAP).  Continuous data will be summarized by randomized device 
assignment and other subset (center, age, etc.) groupings using descriptive statistics (number, mean, 
median, standard deviation [SD], minimum, and maximum).  Categorical data will be summarized by 
randomized device assignment and other subset groupings using frequency tables (frequencies, 
percentages, confidence intervals). The natural log transformation will be applied to variables which are 
highly skewed.  If the model assumptions for the ANOVA are not met, transformation of the data or non-
parametric analysis may be implemented. 
 
12.5 DEMOGRAPHICS, BASELINE CHARACTERISTICS, AND CONCOMITANT 
MEDICATIONS 
Demographic data, medical history, and concomitant medications will be summarized by means of 
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12.6 EFFECTIVENESS ANALYSES 
12.6.1 Primary Effectiveness Analysis 
The primary efficacy parameter is the response rate which is defined as the proportion of subjects whose 
knee pain is reduced from baseline by ≥ 50% based on the NRS scale at 6 months after treatment.  
Each subject’s response to the treatment will be treated as an independent binomial event: 
 
Ho: πC - πT ≥ 0.05 
Ha: πC - πT < 0.05 
 
Where: 
 
ΠT: proportion of subjects with ≥ 50% decrease from baseline in NRS pain score from baseline at the 6 
months post randomization in the CRFA group 
ΠC: proportion of subjects with ≥ than 50% decrease from baseline in NRS score from Screening at the 6 
months post randomization in the HA injection group 
 
The non-inferiority margin is set at 5% for the primary efficacy parameter expressed as proportion. The 
difference of proportions between treatment groups will be calculated and a two sided 95% confidence 
interval will be constructed using Wald asymptotic confidence limits approach or exact binomial limits 
approach. If the upper bound is less than 0.05, then ‘Non-inferiority’ is established for the CRFA group 
relative to the HA injection group. If, in addition, the upper bound of the confidence interval is below zero, 
the CRFA group can be determined to be ‘Superior’ to the HA injection group.  
 
Treatment by study center interaction may be examined graphically across study center to determine the 
association between treatment and response rate is in the same direction or using logistic regression with 
response rate at 6 months as the response variable, and the study center, treatment group, study center 
by treatment group interaction as predictor variables in the model. 
 
12.6.2 Secondary Effectiveness Analysis  
 
If the null hypothesis is rejected for the primary endpoint, i.e., CRFA is concluded to be either non-inferior 
or superior to the HA injection, the secondary endpoints will be compared between treatment groups as 
detailed below.  
12.6.2.1 
Knee Pain Reduction 

 
 
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The proportion of subjects whose knee pain is reduced from baseline by ≥ 50% based on the Numeric 
Rating Scale (NRS) at the 12 month will be calculated and compared between the two treatment groups 
and within each group as described in section 12.7.1 for the primary endpoint. The method for controlling 
the secondary endpoint familywise error rate will be detailed in the SAP. 
 
12.6.2.2 
WOMAC 
The change in the WOMAC Score from baseline to the 6 month and 12 month visits will be calculated and 
compared between the two treatment groups: 
 
Ho: µ1 = µ2  
Ha: µ1 ≠ µ2 
 
Where: 
µ1: mean of WOMAC Score change between the Baseline and the Follow-Up at 6 months and 12 months 
for the CRFA group 
µ2: mean of WOMAC Score change between the Baseline and the Follow-Up at 6 months and 12 months 
for the HA injection group 
 
Analysis of variance (ANOVA) with treatment as fixed effect and study center as block effect on changes 
in the WOMAC between the Baseline and the Follow-Up at 6 months and 12 months separately will be 
performed for the comparison of the CRFA with the HA injection groups. 
 
Treatment by study center interaction may be examined using analysis of variance (ANOVA) with 
treatment, study center and treatment by study center interaction effects on changes in the WOMAC 
between the baseline and the Follow-Up at 6 months and 12 months in the model. 
 
 
12.6.3 Tertiary Effectiveness Analysis 
The change in the EQ-5D-5L Score from baseline to the 6 month and 12 month visits will be calculated 
and compared between the two treatment groups: 
 
Ho: µ1 = µ2  
Ha: µ1 ≠ µ2 
 
Where: 

 
 
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µ1: mean of EQ-5D-5L Score change between the Baseline and the Follow-Up at 6 months and 12 
months for the CRFA group 
µ2: mean of EQ-5D-5L Score change between the Baseline and the Follow-Up at 6 months and 12 
months for the HA injection group 
 
Analysis of variance (ANOVA) with treatment as fixed effect and study center as block effect on changes 
in the EQ-5D-5L Score between the Baseline and the Follow-Up at 6 months and 12 months separately 
will be performed for the comparison of the CRFA with the HA injection groups. 
 
Treatment by study center interaction may be examined using analysis of variance (ANOVA) with 
treatment, study center and treatment by study center interaction effects on changes in the EQ-5D-5L 
Score between the baseline and the Follow-Up at 6 months and 12 months in the model.  
 
The GPE scale at the 6 month and 12 month visit will be calculated and compared between the two 
treatment groups: 
 
Ho: µ1 = µ2  
Ha: µ1 ≠ µ2 
 
Where: 
µ1: mean of GPE score at 6 months and 12 month for CRFA group 
µ2: mean of GPE score at 6 months and 12 month for the HA injection group 
 
Analysis of variance (ANOVA) with treatment as fixed effect and center as block effect on the GPE score 
at 6 months and 12 months separately will be performed for the comparison of the CRFA with the HA 
injection groups. 
 
Treatment by study center interaction may be examined using analysis of variance (ANOVA) with 
treatment, study center and treatment by study center interaction on the GPE score at the Follow-Up at 6 
months and 12 months in the model. 
 
12.7 SAFETY ANALYSES 
12.7.1 Safety Parameter 
All adverse events that occur during the study will be recorded per the protocol definitions.  An overall 
adverse event rate will be summarized for both treatment groups.  

 
 
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12.7.2 Method of Analysis 
Adverse events occurring during the study will be tabulated by body system, severity, and Investigator 
reported relationship to the study device.  Any deaths or serious device associated AEs will be 
summarized. From enrollment to follow up visit at 6 months, adverse events will be stratified by subjects 
randomization assignment. After follow up visit at 6 months to follow up visit at 12 months (end of study), 
adverse events will be stratified among subject status between CRFA, HA and Crossover.   
12.8 HANDLING OF MISSING DATA 
For the primary outcomes using the full analysis set, last observation carried forward (LOCF) procedures 
may be used to impute missing data.  A sensitivity analysis will be performed to evaluate the effect of 
assumption of imputation.  For the secondary outcomes and safety analysis, missing data will not be 
imputed. 
13 
ETHICAL, ADMINISTRATIVE, AND REGULATORY OBLIGATIONS 
13.1 INDEPENDENT ETHICS COMMITTEE (IEC) OR INSTITUTIONAL REVIEW 
BOARD (IRB) 
The study protocol, ICF document(s), subject recruitment materials, and any amendments must be 
submitted to and approved by the IRB/IEC prior to enrolling subjects.  The IRB must be operating in 
compliance with 21CFR Part 56.  
13.2 HEALTH INSURANCE PORTABILITY AND ACCOUNTABILITY ACT (HIPAA) 
In accordance with the Health Insurance Portability and Accountability Act (HIPAA) of 1996, the 
Investigator must obtain authorization from the subject to use and/or disclose protected health information 
(PHI).  HIPAA authorization may be obtained as part of the ICF or in a separate document. HIPAA 
authorization must include: 
A. 
Identification of the parties that can use and disclose the PHI 
B. 
Identification of the parties to whom the PHI may be disclosed 
C. 
A meaningful description of the PHI 
D. 
A description of each purpose for the use and disclosure 
E. 
Information about the subject’s rights related to the authorization 
F. 
Information about the expiration of the authorization 
G. 
Instructions on how to revoke the authorization 
H. 
A statement about what may happen if the authorization is not signed 
I. 
A warning that once information has been released, it may be released again without further 
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DATA AND QUALITY MANAGEMENT 
All data obtained during this study will be entered into a 21 CFR 11 compliant Electronic Data Capture 
(EDC) system.  All eCRF data must be supported by source documentation in the subject’s 
medical/research record.   
The sponsor will designate a qualified Monitor (CRA) to verify that study data are supported by adequate 
source documentation and are complete, accurate, and verifiable. Instances of inconsistent, missing or 
illogical data will be communicated to the Investigator or study coordinator and queried for resolution. 
Site personnel will enter all data into the EDC system.  The specific procedures for using the EDC 
system, including, but not limited to, entering and editing eCRF data and reviewing and resolving queries 
will be provided to investigative sites during training sessions and a training manual. 
A Data Management Plan prepared by the sponsor will document the specifications for consistency and 
plausibility checks.  Queries/corrections will be managed within the EDC system via the ‘query process.’   
Prior to database lock, the Principal Investigator must electronically sign each eCRF.  
15 
RECORDS RETENTION AND ARCHIVAL 
Study records must be maintained for a period of 2 years after the later of the following two dates:  The 
date on which the investigation is terminated or completed, or the date that the records are no longer 
required for purposes of supporting a premarket approval application or a notice of completion of a 
product development protocol.  Prior approval by the study sponsor is required before destroying or 
moving any study records off site. 
 
After database lock, a CD or other electronic media containing a copy of the eCRF data will be provided 
to the investigator and must be maintained in the Trial Master File. 
 
All source worksheets/documents, records, and reports must be retained by the study site in accordance 
with 21 CFR 812.140.  All primary data or copies thereof (e.g., laboratory records, source documents, 
data sheets, correspondence, photographs, and computer records), which are a result of the original 
study observations, and are necessary for the reconstruction and evaluation of any study report, must be 
retained at the study site until otherwise notified by the Sponsor.  Please contact Avanos Medical before 
archiving / destroying any study records. 
16 
MONITORING AND AUDITING 
Avanos Medical will assign a qualified Monitor (CRA) to each site.  The Monitor will visit the site at regular 
intervals throughout the study and at study completion to assess: 
A. Compliance with applicable regulations and Good Clinical Practices  

 
 
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B. Adherence to the study protocol 
C. Adequacy and accuracy of record keeping and source documentation 
D. Acceptability of storage of clinical trial materials and accountability of test articles 
E. Accuracy of eCRF data 
Medical records for all subjects participating in the trial, eCRFs and study related documents (IRB 
approval, Instructions for use, correspondence pertaining to the trial, etc.) must be made available to 
monitor at each visit and upon request. The sponsor will create a Monitoring plan that outlines the 
anticipated schedule, processes, and expectations.  
 
Avanos Medical, the IRB or regulatory authorities may also audit the study center to evaluate the conduct 
of the study. The clinical Investigator(s)/institutions(s) shall allow trial related monitoring, audits, IRB 
review and regulatory inspections by providing direct access to source worksheets/documents.   
17 
STUDY / SITE TERMINATION 
Avanos Medical reserves the right to terminate the study or a study site at any time. Acceptable reasons 
for termination may include but are not limited to: 
• 
Non-compliance with the Investigational Plan, Protocol, Regulatory Obligations, etc. 
• 
Administrative Reasons 
18 
PUBLICATION PLAN 
Avanos Medical will devise a plan for communications and publications regarding the study (primary, 
secondary, and extension objectives, sub analysis) and sub studies. 
18.1 
GENERALITIES 
The publication policy described below applies for all publications related to this study. 
• 
The agreement of Avanos Medical is mandatory before any submission made before the 
publication of any paper.  
• 
Sub-investigators participating in the study may be listed on the paper at the discretion of the 
Steering Committee.   
• 
Co-authors’ order in the Authorship list will be submitted to each journal per journal-specific 
requirements; journal guidelines on the number of allowable authors will be followed. 
• 
Avanos Medical must be cited in all publications where appropriate. 
 
18.2 STEERING COMMITTEE 
A Steering Committee will be established and will be responsible for assisting and guiding publication(s) 
of study results. The steering committee should consist of one or more clinicians qualified by experience. 

 
 
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The chair of the steering committee is the study Principal Investigator. If the study Principal Investigator 
leaves that role during the study, the steering committee will decide upon a replacement. A minimum of 
one Avanos Medical employee will facilitate the steering committee interaction. Members may be added 
or removed from the steering committee at any time as needs change or previously agreed to timelines 
get missed.  
 
18.3 AUTHORSHIP CRITERIA 
Authors for all publications should be qualified by experience and have participated in the clinical trial as 
an enrolling investigator or be a consultant responsible for key elements of the study process (e.g. 
protocol design, results interpretation, clinical strategy, etc.). 
 
Lead Principal Investigator will be listed as the lead author, the Steering Committee will be represented, 
then authorship order will be determined by enrollment ranking pending journal allowances. Enrollment is 
defined as the number of patients who successfully reached the primary objective taking into account 
major data quality issues. A Working Group will be created which may allow for inclusion of participating 
investigators or referring sub-investigators who provided significant scientific contribution leading to the 
successful conduct of the trial. 
 
18.4 PRIMARY PRESENTATIONS 
 
Study presentations occurring at a public conference or meeting. Author affiliation with the associated 
society will be taken into account as part of the decision-making process for choosing presenters.  
 
• 
Primary speaker:  Principal investigator of the study shall have first right of refusal.  
 
• 
Secondary speaker or back-up speaker: if more than one speaker is necessary or the 
principal investigator of the study is not available, the principal investigator of the highest 
enrolling center will be given the next priority, and so on. If neither of the first two options are 
available or interested, a steering committee member will be chosen. 
 
Speakers for subsequent presentations can be any of the authors noted and should be confirmed by the 
steering committee. 
 
19 
REFERENCES 

 
 
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1 Liu SS, Buvanendran A, Rathmell JP, et al.  A cross-sectional survey on prevalence and risk factors for 
persistent postsurgical pain 1 year after total hip and knee replacement.  Reg Anesth Pain Med. 2012 
Jul-Aug; 37(4):415-22. 
2 Arroll B, Goodyear-Smith F.  Corticosteroid injections for osteoarthritis of the knee: meta-analysis.  BMJ. 
2004 Apr 10; 328(7444):869. Epub 2004 Mar 23. 
3 Raunauld J, Buckland-Wright C, et al.  Safety and efficacy of long-term intra-articular steroid injections 
in osteoarthritis of the knee.  Arth Rheum 2003; 48:370-7. 
4 Conrozier T, Jerosch J, Beks P, et al.  Prospective, multi-centre, randomized evaluation of the safety 
and efficacy of five dosing regimens of viscosupplementation with hylan GF-20 in patients with 
symptomatic tibio-femoral osteoarthritis: a pilot study.  Arch Orthop Trauma Surg 2009; 129:417-423. 
5 Chevalier, X et al. Single, intra-articular treatment with 6 ml hylan G-F 20 in patients with symptomatic 
primary osteoarthritis of the knee: a randomized, multi-center, double-blind, placebo controlled trial. 
Ann Rheum Dis 2010 69: 113-119 
6 http://www.aaos.org/Research/guidelines/TreatmentofOsteoarthritisoftheKneeGuideline.pdf , 
Recommendation #9. 
7 Kapural L, Stojanovic M, Bensitel T, et al.  Cooled Radiofrequency (RF) of L5 Dorsal Ramus for RF 
Denervation of the Sacroiliac Joint: Technical Report.  Pain Medicine 2010; 11(1): 53–57 
8 Patel N, Gross A, et al. A randomized, placebo controlled study to assess the efficacy of lateral branch 
denervation for chronic sacroiliac joint pain. Pain Med 2012 Mar; 13(3):383-98. 
9 Stelzer W, Aiglesberger M, Stelzer D, et al.  Use of Cooled Radiofrequency Lateral Branch Neurotomy 
for the Treatment of Sacroiliac Joint-Mediated Low Back Pain: A Large Case Series.  Pain Medicine 
2013 Jan: 14(1):29-35. 
10 Ho, KY, Hadi MA, Pasutharnchat K, et al.  Cooled radiofrequency denervation for treatment of 
sacroiliac joint pain: two-year results from 20 cases.  J Pain Research 2013; 6(2):505–511. 
11 Kapural L, Mekhail N.  Novel intradiscal biacuplasty (IDB) for the treatment of lumbar discogenic pain.  
Pain Pract 2007 Jun; 7(2):130-4. 
12 Karaman H, Tufek A, Kavak GO, et al.  6-month results of TransDiscal Biacuplasty on patients with 
discogenic low back pain: preliminary findings.  Int J Med Sci 2010 Dec 14; 8(1):1-8. 
13 Kapural L, Vrooman B, Sarwar S, et al.  A randomized, placebo-controlled trial of transdiscal 
radiofrequency biacuplasty for treatment of discogenic lower back pain.  Pain Med. 2013 Mar; 
14(3):362-73. 
14 Davis, et al, Prospective, Multicenter, Randomized, Crossover Clinical Trial Comparing the Safety and 
Effectiveness of Cooled Radiofrequency Ablation With Corticosteroid Injection in the Management of 
Knee Pain From Osteoarthritis. Reg Anesth Pain Med. 2017 Nov 1. [Epub ahead of print] 
                                                     
 

 
 
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15 Hirasawa Y, Okajima S, Ohta M, Tokioka T. Nerve distribution to the human knee joint: anatomical and 
immunohistochemical study. Int Orthop 2000; 24:1–4. 
16 Gardner E.  The innervation of the knee joint.  Anat Rec 1948 May; 101(1):109-30. 
17 Choi WJ, Hwang SJ, et al.  Radiofrequency treatment relieves chronic knee osteoarthritis pain: A 
double-blind randomized controlled trial.  PAIN 152 (2011) 481–487. 
18 Ikeuchi M, Ushida T, et al.  Percutaneous Radiofrequency Treatment for Refractory Anteromedial Pain 
of Osteoarthritic Knees.  Pain Medicine 2011; 12: 546–551 
19 Davis, et al. Twelve-month analgesia and rescue, by cooled radiofrequency ablation treatment of 
osteoarthritic knee pain: results from a prospective, multicenter, randomized, cross-over trial. Davis T, et 
al. Reg Anesth Pain Med 2019;0:1–8. [epub ahead of print] 
 
20 Ho, Kok-Yuen, et al. Cooled Radiofrequency Denervation for Treatment of Sacroiliac Joint Pain: Two-
Year Results from 20 Cases. Journal of Pain Research 2013:6, 505-511. 
21 Franco CD, et al. Innervation of the Anterior Capsule of the Human Knee: Implications for 
Radiofrequency Ablation. Regional Anesthesia and Pain Medicine 2015;40:363-368 
 
22 DePalma, M, et al. Cooled Radiofrequency Ablation Treatment of Osteoarthritic Knee Pain: 24 Month 
Results. ASRA, 17th Annual Pain Medicine Meeting, poster presentation. Nov 15-17, 2018.  
23 Kellgren JH, Lawrence JS.  Radiological assessment of osteoarthrosis.  Ann Rheum Dis 1957; 16:494-
501. 
24 Farrar JT, Young JP, et al.  Clinical importance of changes in chronic pain intensity measured on an 
11-point numerical pain rating scale.  Pain 2001; 94(1):149-158. 
25 Bellamy, et al. Validation of WOMAC. The Journal of Rheumatology, 1988 Dec;15(12):1833-40 
26 The EuroQol Group (1990). EuroQol-a new facility for the measurement of health-related quality of life. 
Health Policy 16(3):199-208 
27 Kamper SJ, Ostelo RW, et al.  Global Perceived Effect scales provided reliable assessments of health 
transition in people with musculoskeletal disorders, but ratings are strongly influenced by current 
status.  J Clin Epidemiol. 2010 Jul; 63(7):760-766.e1. doi: 10.1016/j.jclinepi.2009.09.009. Epub 2010 
Jan 8. 
 
 
 
 
 
 

 
 
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APPENDIX 1 – COOLIEF* INSTRUCTIONS FOR USE 

 
 
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APPENDIX 2 – SYNVISC-ONE INSTRUCTIONS FOR USE 
 

 
 
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