Cryoneurolysis for Improvements in Pain, Activities of Daily Living and Quality of Life in Patients With Ankle Osteoarthritis
Phase: NA
Conditions: Ankle Osteoarthritis
Sponsor: University of Kansas Medical Center

 
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University of Kansas Medical Center  
RESEARCH PROTOCOL INVOLVING HUMAN SUBJECTS  
TEMPLATE WITH GUIDANCE 
 
Version date: April 25, 2019 
Principal Investigator: Neil Segal, MD, MS 
Study Title: An open label trial of cryoneurolysis for improvements in pain, activities of daily living and 
quality of life in patients with ankle osteoarthritis. 
 
 
I. 
Purpose, Background and Rationale 
A. Aim and Hypotheses  
 
This will be an open-label trial to describe the effects of cryoneurolysis with iovera on symptom 
relief in patients with painful Kellgren-Lawrence (KL) grade 2–4 ankle osteoarthritis (OA). The 
Foot and Ankle Outcome Score (FAOS) subscales will be used to assess outcomes at 6, 12 and 24 
weeks after treatment. 
The aim of this study is to assess clinically significant long-term symptomatic relief with 
cryoneurolysis in people with unilateral ankle osteoarthritis (OA).  
Depending on the location of pain, we will treat either 1) the Superficial Fibular Nerve (SFN), Sural 
Nerve (SN) and Saphenous Nerve or 2) the deep fibular nerve with cryoneurolysis using the iovera 
device. The primary study endpoint, clinically significant improvement in pain 12 weeks after each 
treatment, will be assessed using the FAOS-Pain subscale. 
The secondary outcomes will be improvement in quality of life (FAOS-QoL), activities of daily living 
(FAOS-ADL) and Numerical Rating Scale (NRS) for pain. 
The tertiary outcome will be improvement in physical performance measures (40m fast-paced 
walking test, Standing Balance Test). 
We hypothesize that people with painful ankle OA will experience significant improvement in pain, 
activities of daily living, quality of life and physical performance for at least 12 weeks following 
treatment. Based on research done using iovera in patients with knee osteoarthritis, we anticipate 
that it will have a greater magnitude and duration of analgesic effect along with significantly fewer 
adverse events compared with the rates reported for standard of care therapy (i.e. corticosteroid 
injection).1,2 
 
Specific Aim 1: To determine the extent of pain relief after cryoneurolysis of nerves innervating 
the ankle joint in patients with ankle osteoarthritis. 
Primary Hypothesis 1: Cryoneurolysis of nerves innervating the ankle joint in patients with 
ankle OA results in reduction in ankle pain (FAOS-Pain) detectable at the following post-treatment 
time points:  
a) 6 weeks 
b) 12 weeks (primary outcome) 
c) 24 weeks 
 

 
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Specific Aim 2: To determine the extent of improvement in activities of daily living (ADL) and 
quality of life (QOL) after cryoneurolysis of nerves innervating the ankle joint in patients with 
ankle osteoarthritis.  
Hypothesis 2a: Cryoneurolysis of nerves innervating the ankle joint in patients with ankle OA 
results in improved ADL (FAOS-ADL) detectable at the following post-treatment time points:  
a) 6 weeks 
b) 12 weeks  
c) 24-weeks 
Hypothesis 2b: Cryoneurolysis of nerves innervating the ankle joint in patients with ankle OA 
results in improved QOL (FAOS-QOL) detectable at the following post-treatment time points:  
a) 6 weeks 
b) 12 weeks  
c) 24-weeks  
 
Specific Aim 3: To determine the extent of improvement in physical performance measures (40m 
fast-paced walking test and Standing Balance Test) after cryoneurolysis of nerves innervating the 
ankle joint in patients with ankle osteoarthritis.  
 
Hypothesis 3a: Each cryoneurolysis treatment results in improved physical performance 
detectable at the following post-treatment time points: 
a) 6 weeks 
b) 12 weeks  
c) 24-weeks  
 
B. Background and Significance 
 
Approximately 15% of the world’s adult population is affected by joint pain and disability 
resulting from osteoarthritis (OA), and approximately 1% have OA of the ankle. There has 
been substantial clinical and basic science research related to hip and knee OA. However, 
research related to ankle OA is sparse.3 Although the hip and knee joints are most commonly 
affected by primary OA, at the ankle, OA is most commonly post-traumatic. Traumatic ankle 
injuries that may result in OA include fractures of the malleoli, tibial plafond, talus, isolated 
osteochondral damage of the talar dome, and ankle ligament injuries. 
 
OA of the ankle (tibiotalar) joint progresses from early damage to diffuse and severe 
degeneration and deformity of the joint. The leading causes include trauma, ischemia, 
abnormal ossification, and genetic predisposition. Although trauma is probably the most 
common cause of injury and degeneration of the ankle (70% of reported cases), repetitive 
microtrauma could also be a contributing factor. Despite the high prevalence of ankle trauma 
and related chondral lesions, the rate of symptomatic and disabling OA is lower than that of 
the hip and knee, due to the different biologic and biomechanical characteristic of the cartilage 
and subchondral bone at the ankle4. 
 
Pharmacologic and surgical therapeutic options for ankle osteoarthritis are limited. Treatments 
have traditionally consisted of temporizing measures such as physical therapy and topical, oral 
and intra-articular pharmaceutical therapies until operative treatment with either arthrodesis 

 
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or arthroplasty is required. Cryoneurolysis is a specialized technique for providing long-term 
pain relief in interventional pain management settings5. Treated nerves are temporarily 
blocked from transmitting pain signals, followed by functional recovery after a time period.  
 
Using cryoneurolysis in patients with ankle OA could potentially provide immediate 
symptomatic relief with a greater duration of analgesia and a lower rate of side effects than 
other non-operative treatments. These potential benefits could reduce the need for both clinic 
and injection visits when compared to other treatment modalities, thereby reducing patient 
and provider burden and health care expenditures. 
 
The iovera° device is 510(k)-cleared (K133453 and K161835) and is used to destroy tissue 
during surgical procedures by forming a precisely controlled, sub-dermal cold zone. It can also 
be used to produce lesions in peripheral nervous tissue by forming a precise cold zone of -20 
to -88.5 degrees Celsius to temporarily disrupt peripheral nerve function, ultimately blocking 
pain.1 It is also indicated for the relief of pain and symptoms associated with osteoarthritis of 
the knee for up to 90 days. The iovera° system is not indicated for treatment of central nervous 
system tissue. 
 
The iovera° device uses liquid nitrous oxide (N2O) that is contained within the handpiece. This 
pressurized liquid travels from the hand-piece to the closed-end needles of the smart tip, 
where it undergoes a phase change, forming a precise cold zone. The gaseous nitrous oxide is 
expelled out of the hand-piece, leaving nothing behind in the body. This treatment causes a 
temporary nerve block based on a process called Wallerian degeneration or 2nd -degree nerve 
injury. This degeneration affects the axon and myelin sheath while leaving the surrounding 
nerve components intact such as the endoneurium, perineurium or epineurium Figure 1. When 
sensory nerves are treated, their ability to convey sensory signals, such as pain, is immediately 
interrupted.  
 
 
 
Figure 1 

 
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Post-treatment, the axon regenerates until it re-innervates to the sensory receptor for  
predictable restoration of nerve function. The effect on the nerve is temporary. The duration 
of the pain relief depends on the individual and the location of the nerve being treated. In 
general, nerves regenerate at a rate of approximately 1.0-1.5mm per day.6 Therefore, we 
hypothesize a duration of relief of ankle pain of approximately 90 days. 
 
Preliminary Data: A recent randomized, double-blind, sham-controlled, multicenter trial (17 
sites) with a 6-month follow-up was conducted in 180 patients with mild-to-moderate knee 
OA. This study demonstrated that a single treatment of the infrapatellar branches of the 
saphenous nerve with iovera° resulted in a reduction in the pain and symptoms for at least 90 
days.1 Compared to the sham group, patients who received iovera° treatment had a 
statistically significant greater change from baseline in the WOMAC pain subscale score at Day 
30 (p=0.0004), Day 60 (p=0.0176), and Day 90 (p=0.0061) post-treatment. Patients deemed 
WOMAC pain responders at Day 120 continued to experience a statistically significant 
treatment effect at Day 150.  Most expected side effects were mild in severity and 
resolved within 30 days. The incidence of device- or procedure-related adverse events were 
similar in the two treatment groups with no occurrence of serious or unanticipated adverse 
device effects (ADE). 
 
This clinical trial will be the first to systematically evaluate the symptomatic and functional 
benefits of cryoneurolysis for patients suffering from painful ankle OA. Patients are more likely 
to seek medical care when they are experiencing symptoms, have reduced activity and/or 
functional limitation. Therefore, finding that an affordable, safe treatment could alleviate 
symptoms and improve activities of daily living while avoiding the side effects of 
pharmacological and surgical therapies, holds promise to improve quality of life and reduce 
health care expenditures.  
 
iovera° Device and Treatment Procedure 
 
The iovera° device consists of a reusable, portable hand-piece, along with a single-patient use 
sterile smart tip, or cryoprobe, and disposable nitrous oxide (N2O) cartridges. The smart tip 
contains embedded software that manages procedure parameters and provides physician 
feedback throughout all stages of device preparation, treatment and post-treatment via 
communication with the hand-piece.  The hand-piece is battery powered and is stored and 
recharged via the charging dock. 
 
The cryogen is provided in a nitrous oxide cylinder attached to a custom filter, known as the 
cartridge.  To remove contaminants that may be present in the cylinder, a custom filter is 
added to the cylinder to filter the liquid nitrous oxide before it enters the hand-piece.  This 
ensures optimal performance of the device. 
 
There are 2 types of smart tips (including their respective variants) that we will be utilizing 
with this study, depending on the depth of the nerves being treated. The shorter smart tip 
comes in 2 variants - composed of either three 6.9 mm or three 8.9 mm, 27-gauge needles. 
It has an attached skin warmer to prevent damage to the underlying skin from sub-zero 
temperatures. The longer smart tip also comes in 2 variants - composed of a 22-gauge single 
needle measuring 55 mm or a 20G single needle measuring 90 mm and it will be used to treat 
nerves not accessible by the shorter smart tip. The iovera° device produces the desired effect 
through the initiation of a cooling cycle that lasts for 60 seconds. Each cooling cycle is initiated 
by fully inserting the smart tip into the selected procedure site and activating the cryogen flow. 
As the cryogen gas travels through the length of the needle, an ice ball develops around the 
needle causing the surrounding tissue to be frozen. Operation instructions and further details 
on the device are in the User Guide provided by Myoscience.  
 

 
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C. Rationale 
The cryoneurolysis mechanism of action is well-understood and established in prior studies.5 
Results of a recent study demonstrate that cryoneurolysis can alleviate the pain and symptoms 
of knee OA for up to 90 days1.  Pharmacologic and surgical options for ankle OA are limited. 
Using cryoneurolysis in patients with ankle OA could potentially provide immediate 
symptomatic relief with a greater duration of analgesia and a lower rate of side effects. These 
potential benefits could reduce the need for both clinic and injection visits when compared to 
other available treatment modalities, thereby reducing patient and provider burden and health 
care expenditures. 
 
II. 
Research Plan and Design 
 
A. Study Objectives: The goal of this study is to evaluate the efficacy of cryoneurolysis for 
improving ankle symptoms and function. Specifically, this study will measure changes in 
pain, activities of daily living, quality of life and physical performance at 6, 12 and 24 weeks 
after each superficial and deep treatment.   
B. Study Type and Design:  
This is a single-site, open-label study of participants with painful ankle OA assigned to undergo 
cryoneurolysis of either the Superficial Fibular Nerve (SFN), Sural Nerve (SN) and Saphenous 
Nerve, or the Deep Fibular Nerve (DFN) using ultrasound-guided cryoneurolysis. Subjects will 
initially undergo diagnostic nerve blocks using 1% lidocaine with epinephrine for either the 
superficial nerves or the DFN to confirm analgesia prior to the cryoneurolysis procedure.  
 
We will evaluate responder status with NRS at clinic visits 6 weeks, 12 weeks and 24 weeks 
following treatment as well as NRS via web-form or phone calls (per subject preference) at 3, 
9 and 18 weeks. “Non-responders” being defined as anyone reporting less than 20% pain relief 
with respect to their baseline NRS scores. For subjects who become non-responders, we will 
treat the other nerve group with iovera at their next clinic visit (e.g. if a subject becomes a 
non-responder 9 weeks after superficial nerves are treated, then at 12 week follow-up, the 
participant will be offered treatment of the deep fibular nerve). 
 
Figure 2 depicts the flow of how participants will be treated and potentially offered an 
alternative treatment if their initial treatment fails to provide durable benefit. 
 
FAOS (Pain, ADL, QoL), NRS for pain and physical performance tests (40 m fast paced walking 
test and, Standing Balance Test) will be assessed at baseline and 6, 12, and 24 weeks post-
treatment. Phone calls at 3, 9 and 18 weeks post-treatment will monitor subjects using the 
NRS pain scale.7 Electronic data capture will be used for this study. Adverse events will be 
monitored at each telephone call and follow-up visit. There will be a grace period of 21 days 
between the screening and treatment visit. There is a +/- 3-day window for follow-up visits. 
During the time period of March to May, 2020(depending on duration of suspension of non-
essential research), we are modifying the protocol to conduct virtual study visits to address 
the COVID-19 pandemic. The following data points will be or will not be collected during this 
time as per the individual circumstance: 40mFPWT or Standing Balance test at 6 week, 12 
week, and 24 week. In order to ensure subject safety and welfare we will conduct the 6 week, 
12 week and 24 week f/u visit remotely for each treatment arm as per KU essential research 
guidelines. We will also offer participants masks, gloves, and complete the f/u visit at the 

 
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earliest to limit any potential exposure to people in the hospital.  In order to address data 
integrity issues, we will try to conduct the 12 week f/u visits in person.  
 
Figure 2 – Protocol flowchart depicting criteria for responders and non-responders at each follow 
up time point. 
 
 

 
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C. Sample size and power calculation 
In this open-label study, participants will undergo cryoneurolysis using iovera. FAOS (Pain, 
ADL, QoL), NRS for pain and physical performance tests (40m fast-paced walking test and 
Standing Balance Test) data will be collected at baseline and 6, 12 and 24 weeks post-
treatment. A 24-week follow-up duration was selected to detect meaningful differences from 
standard of care and long-term effects. A control group will not be included in this initial pilot 
study. Differences between each of the three follow-up time points and baseline will be 
assessed using one-sample t-tests or repeated measures analyses, as appropriate, controlling 
for study-wide alpha level to account for multiple comparisons as well as 6-week and 24-week 
analyses. 
 
A FAOS validation study, completed by S.B.Mani et al., confirmed that some FAOS sub-scales 
(i.e. pain, activities of daily living and quality of life) are valid for independent use. According 
to the study, the effect size for FAOS pain and quality of life is 1.06, whereas for activities of 
daily living there is an effect size of 0.65. At an effect size of 0.65 and a single-sized alpha of 
0.025, a sample size of 32 would provide a power of 90%. While 80% power is customary, it 
would be desirable to plan for 90% to reduce the probability of missing an effect if one is 
present and to provide sufficient power for comparisons at 2-time points. Assuming up to 20% 
dropout, we plan to recruit 40 participants. This should be more than sufficient, considering 
that the effect size for the other 2 outcomes has been reported to be 1.06.9 
 
 
D. Subject Criteria (See Vulnerable Populations appendix, if applicable):  
Enrollment will be comprised of 40 subjects, age 18 and over with symptomatic ankle OA. 
There will be no exclusions based on sex or ethnic group. Potential subjects will be identified 
through hospital records, referrals from physicians in the surrounding community, and mass 
mailings, or advertisements posted in area clinics and businesses.  
 
1. Inclusion criteria 
 
• 
Participation in an institutional review board-approved informed consent process, 
culminating in providing written consent. 
• 
Willingness and ability to comply with the study procedures, visit schedules and 
ability to follow verbal and written instructions. 
• 
Male or female over 18 years of age. 
• 
Currently Kellgren-Lawrence (KL) Grade 2, 3 or 4 in the ankle based on an X-ray. 
(weight-bearing mortise views with 20° internal rotation)10 
• 
Limited by unilateral ankle pain, rated on a Numerical Rating Scale for pain severity 
as !5 on most days over the last month. 
• 
Foot and ankle outcome score (FAOS) of < 75 in at least 1 category. 
• 
Body mass index (BMI) " 50 kg/m2      
• 
Ambulatory.       
• 
Willingness to abstain from the use of protocol-restricted medications during the 
study and also willing to abstain from using analgesics other than acetaminophen 1 
week prior to the beginning of the study. 
• 
Has undergone at least one prior conservative osteoarthritis treatment (e.g. 
physical therapy, analgesics).    
 
2. Exclusion criteria:  

 
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• 
Baseline knee, hip, spine or other limitations that affect the walking ability to a 
greater extent than their ankle. 
• 
Cryoglobulinemia, paroxysmal cold hemoglobinuria, Raynaud’s disease, cold 
urticaria. 
• 
Clinical signs or symptoms of active or recurrent infection in the index ankle joint 
or overlying skin. 
• 
IA corticosteroid (investigational or marketed) within 3 months of screening.                    
• 
Oral corticosteroids (investigational or marketed) within 2 weeks of screening 
(unless on a chronic stable dose for ≥3 months prior to enrollment). 
• 
Women who are pregnant (due to potential for the change in body mass and 
distribution to alter ankle symptoms over the period of follow-up). 
• 
Any condition other than OA of the ankle joint which, in the opinion of the 
investigators, affects their ability to ambulate to a sufficient degree or interferes 
with the assessment of the safety and treatment effects of the study injection.  
• 
Arthroscopy or open surgery of the ankle joint within 6 months of screening. 
• 
Planned/anticipated surgery of the index ankle joint during the 6-month study 
period. 
• 
Any clinically significant degree of cognitive impairment or other condition, finding, 
or psychiatric illness at screening which, in the opinion of the investigator, could 
compromise patient safety or interfere with the assessment of the safety and 
treatment effects of the study injection.  
• 
Skin breakdown at the ankle joint where the injection is planned to take place.  
• 
Participated in any investigational drug or device trial within 30 days prior to 
screening or concurrent participation in another research study that could 
complicate interpretation of the findings of either study. 
• 
Current consumption of more than 14 alcoholic drinks per week  
• 
Patients with diffuse pain conditions (Complex pain - diffuse or confounding pain, 
fibromyalgia, etc). 
• 
Known altered nerve anatomy or physiology (e.g. neuropathy) at the target, such 
as due to a congenital, traumatic, medical or surgical cause. 
 
3. Withdrawal/Termination criteria:  
 
Subjects may discontinue the study at any time. The investigator may discontinue a subject 
at any time for subject safety or noncompliance. Subjects who are discontinued for safety will 
be referred to their primary care physician for follow-up. 
 
The Investigator/Coordinator will complete a study exit form in the CRF for any subject who 
prematurely discontinues from the study. If discontinuation was the result of an AE, the AE 
will also be recorded in the CRF. 
 

 
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4.  Allowable Medications/Nonpharmacological Therapies  
 
The following medications and nonpharmacological therapies may be taken or used throughout 
the study:  
• 
Aspirin for cardio-protection at a maximum stable dose of 100 mg per day provided the 
dose was stabilized over 3 months prior to study entry. 
• 
Physical therapy/bracing for the ankle joint if the program was initiated and consistent 
prior to study entry. 
• 
Acetaminophen as an occasional rescue medication. Concomitant treatment for OA will 
be standardized to oral acetaminophen (e.g. Tylenol) for all subjects during the study. 
During the screening period (i.e., prior to the procedure visit), subjects may take 
acetaminophen as needed to a maximum of 3000 mg per day. Use of acetaminophen 
must be discontinued 48 hours prior to the procedure visit and each subsequent 
scheduled visit.  
• 
The use of acetaminophen for other types of pain or illness during the study (e.g., 
toothache, headache, fever) should also be recorded.  
 
5. Restricted Medications/Nonpharmacological Therapies  
 
Patients will be asked to abstain from certain medications and therapies. The following 
medications and nonpharmacological therapies should not be taken or used beginning 
immediately upon enrollment (after signing informed consent) until the subject reaches the 
end of the study:  
• 
Oral non-steroidal anti-inflammatory drugs (NSAIDs) (unless on a chronic stable dose 
for ≥3 months prior to enrollment). 
• 
Topical analgesics applied to the skin over the index ankle (e.g., NSAID’s, capsaicin, 
lidocaine, heat patches).  
• 
Orally administered systemic corticosteroids (unless on a chronic stable dose for ≥3 
months prior to enrollment). 
• 
Intra-articular injection into the ankle or subtalar joints. 
• 
Centrally acting pain medications (unless on a chronic stable dose for ≥3 months prior 
to enrollment). 
• 
Opioid medications (unless on a chronic stable dose for ≥3 months prior to enrollment) 
 
E.  Specific methods and techniques used throughout the study  
 
Primary Outcome  
The Foot and Ankle Outcome Score (FAOS), derived from the validated Knee Injury and 
Osteoarthritis Outcome Score (KOOS). It is a region-specific questionnaire that has been well 
described and validated.9 11 
 
It has been found to be satisfactory in the measurement of many foot and ankle pathologies. 
The largest study of the FAOS to date is a registry-based study that found high internal 
consistency across the entire instrument, and high test-retest reliability in three of its five sub 
scales. It has been specifically evaluated for the assessment of OA in another study. The 
purpose of this study was to verify the content validity, construct validity and responsiveness 
of the FAOS in patients with ankle OA. 
 

 
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The FAOS covers pain, other symptoms, activities of daily living (ADL), recreational function 
and quality of life. This outcome measure comprises of forty-two questions covering pain, 
disability, self-care and psychological factors. The minimum possible total score for each 
subscale is 0 points, whereas the score of 100 points represents the maximum score.   
                    
The primary endpoint of this study is the FAOS-Pain score compared to baseline at 12 weeks 
post-treatment. 
 
FAOS - Pain 
PAIN = 100 - (Total score P1-P9 x 100/ 36) 
FAOS-Pain is a subscale of the Foot and ankle outcome score (FAOS) which is a self-reported 
outcome score. In our study, it will be the primary outcome measure. It comprises of the 
following questionnaire.  The FAOS-Pain will be completed by the subject and will take 
approximately 3 minutes to complete.  The study coordinator or designee will enter the data 
into the CRF. 
 
P1. How often do you experience foot/ankle pain? 
Never Monthly 
 Weekly 
 Daily 
Always 
 
What amount of foot/ankle pain have you experienced the last week during the following 
activities? 
P2. Twisting/pivoting on your foot/ankle 
None  Mild  Moderate  Severe  Extreme 
      
P3. Straightening foot/ankle fully 
None  Mild  Moderate  Severe  Extreme 
      
P4. Bending foot/ankle fully 
None  Mild  Moderate  Severe  Extreme 
      
P5. Walking on flat surface 
None  Mild  Moderate  Severe  Extreme 
      
P6. Going up or down stairs 
None  Mild  Moderate  Severe  Extreme 
      
P7. At night while in bed 
None  Mild  Moderate  Severe  Extreme 
 
P8. Sitting or lying 
None  Mild  Moderate  Severe  Extreme 
 
P9. Standing upright 
None  Mild  Moderate  Severe  Extreme 
           
Secondary Outcomes                                                                                                                  
FAOS - ADL 

 
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ADL = 100 - (Total score A1-A17 x 100/ 68) 
FAOS-ADL is another subscale of the Foot and ankle outcome score (FAOS) which is a self-
reported outcome score. It is similar to the KOOS-ADL components and it comprises of the 
following questionnaire. The FAOS-ADL will be completed by the subject and will take 
approximately 4 minutes to complete.  The study coordinator or designee will enter the data 
into the CRF. 
 
A1. Descending stairs 
None Mild Moderate Severe Extreme   
 
A2. Ascending stairs 
None Mild Moderate Severe Extreme 
 
For each of the following activities please indicate the degree of difficulty you have experienced 
in the last week due to your foot/ankle. 
A3. Rising from sitting 
None Mild Moderate Severe Extreme 
 
A4. Standing 
None Mild Moderate Severe Extreme 
 
A5. Bending to floor/pick up an object 
None Mild Moderate Severe Extreme 
 
A6. Walking on flat surface 
None Mild Moderate Severe Extreme      
 
A7. Getting in/out of car 
None Mild Moderate Severe Extreme 
 
A8. Going shopping 
None Mild Moderate Severe Extreme 
 
A9. Putting on socks/stockings 
None Mild Moderate Severe Extreme 
 
A10. Rising from bed 
None Mild Moderate Severe Extreme 
 
A11. Taking off socks/stockings 
None Mild Moderate Severe Extreme 
 
A12. Lying in bed (turning over, maintaining foot/ankle position) 
None Mild Moderate Severe Extreme 
 
A13. Getting in/out of bath 
None Mild Moderate Severe Extreme  

 
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A14. Sitting 
None Mild Moderate Severe Extreme 
 
A15. Getting on/off toilet 
None Mild Moderate Severe Extreme 
      
For each of the following activities please indicate the degree of difficulty you have experienced 
in the last week due to your foot/ankle. 
A16. Heavy domestic duties (moving heavy boxes, scrubbing floors, etc.) 
None Mild Moderate Severe Extreme 
 
A17. Light domestic duties (cooking, dusting, etc.)  
None Mild Moderate Severe Extreme 
      
Quality of Life 
FAOS - QoL 
FAOS-QoL is another subscale of the Foot and Ankle Outcome Score (FAOS) which is a self-
reported outcome score. It is similar to the KOOS - QoL components and it comprises of the 
following questionnaire.  The FAOS-QoL will be completed by the Subject and will take 
approximately 2 minutes to complete.  The study coordinator or designee will enter the data 
into the CRF. 
 
Q1. How often are you aware of your foot/ankle problem? 
Never Monthly Weekly Daily Constantly 
      
Q2. Have you modified your life style to avoid potentially damaging activities to your 
foot/ankle? 
Not at all Mildly Moderately Severely Totally 
      
Q3. How much are you troubled with lack of confidence in your foot/ankle? 
Not at all Mildly Moderately Severely Extremely 
      
Q4. In general, how much difficulty do you have with your foot/ankle? 
None Mild Moderate Severe Extreme 
 
Numerical Rating Scale (NRS) for Pain 
The Numerical Rating Scale for Pain (NRS for Pain) is a measure of pain intensity. The 
investigator or designee conducts the 11-point scale verbally with the research subject about 
the index ankle.  The investigator or designee will ask the following questions: 
 
• 
 “On a scale of 0 to 10, with 0 being no pain at all and 10 being the worst pain imaginable, 
how would you rate your ankle pain IN THE PAST 7 DAYS?” 
• 
“On a scale of 0 to 10, with 0 being no pain at all and 10 being the worst pain imaginable, 
how would you rate your ankle pain RIGHT NOW?”   
 

 
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The subject will respond verbally and the study coordinator or designee will record the 
response. 
 
The NRS for Pain will be completed by the subject and will take approximately 1 minute to 
complete.  The study coordinator or designee will enter the data into the eCRF. 
 
Tertiary Outcomes  
40m fast paced walking test (40m fpwt) 
The 40-meter fast paced walking test is one of the three OARSI (Osteoarthritis Research 
Society International) recommended minimal core set of performance-based outcome 
measures in OA research and clinical practice.12 These tests are complementary to patient 
reported measures. They are recommended for use prospectively as outcome measures in 
research, and also in clinical practice to make treatment decisions based on the results. The 
40m FPWT will take approximately 2 minutes for each subject to complete.  The study 
coordinator or designee will enter the data into the eCRF. 
 
Standing Balance Test 
The Standing Balance Test outcome is measured with the feet side by side, then in semi-
tandem stance (heel of one foot in front and beside the big toe of the other foot), and then 
in tandem stance (heel of one foot directly in front of the other foot); each stance was held 
for up to 10s. These test results are converted to scores (range 0-4). Higher scores 
represent better function and a score of 0 represents the inability to complete the test. 
Subjects are given a score of 1 if they can hold a side-by-side standing position for 10 s but 
are unable to hold a semi-tandem position for 10s, a score of 2 if they can hold a semi-
tandem position for 10s but are unable to hold a full tandem position for more than 2s, a 
score of 3 if they can stand in the full tandem position for 3-9s, and a score of 4 if they can 
stand in the full tandem position for 10s.13  The Standing Balance Test will be completed by 
the Subject and will take approximately 2 minutes to complete.  The study coordinator or 
designee will enter the data into the eCRF. 
 
The tables below depict the schedule of study assessments, or procedures, for each visit for 
the intervention(s) offered (superficial and/or deep). 
 
 
 
Assessment 
Visit 1 / Screening 
Visit 2 / iovera° 
Treatment -1 
Telephonic 3 Week 
Follow-up 
Visit 3 / 6 Week 
Follow-up 
Telephonic 9 Week 
Follow-up 
Visit 4 / 12 Week 
Follow-up 
Telephonic - 18 
Week Follow-up 
Visit 5 / 24 Week 
Follow-up  
Informed 
Consent 
X 
  
  
  
  
  
  
 
Eligibility 
X 
X 
  
  
  
  
  
 

 
KUMC – HRPP- 03/12/2015 
 
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Radiograph or 
SCT (if not 
previously done) 
X 
 
 
 
 
 
 
 
Medical history 
X 
X 
  
  
  
  
  
 
Concomitant 
medications 
X 
X 
  
X 
  
X 
  
X 
Prior/Concurrent 
Therapy 
X 
  
  
  
  
  
  
  
Study 
Treatment 
  
X 
  
  
  
  
  
 
Physical Exam 
X 
X 
  
  
  
  
  
 
FAOS 
Questionnaire 
X 
 
  
X 
  
X 
  
X 
NRS for Pain 
X 
X 
X 
X 
X 
X 
X 
X 
Physical 
Performance 
Measures 
X 
  
  
X 
  
X 
  
X 
AE/SAE 
Assessment 
  
X 
X  
X 
X  
X 
X  
X 
*Each follow up visit will have a window of +/- 3 days as per the schedule 
 
Assessment 
iovera° Treatment -
2 
Telephonic 3 Week 
Follow-up 
6 Week Follow-up 
Telephonic 9 Week 
Follow-up 
 12 Week Follow-up 
Telephonic - 18 
Week Follow-up 
 24 Week Follow-up 
Informed 
Consent 
 X 
  
  
  
  
  
 
Eligibility 
X 
  
  
  
  
  
 
Radiograph or 
SCT (if not 
previously done) 
 
 
 
 
 
 
 
Medical history 
X 
  
  
  
  
  
 
Concomitant 
medications 
X 
  
X 
  
X 
  
X 
Prior/Concurrent 
Therapy 
  
  
  
  
  
  
  
Study 
Treatment 
X 
  
  
  
  
  
 
Physical Exam 
X 
  
  
  
  
  
 

 
KUMC – HRPP- 03/12/2015 
 
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FAOS 
Questionnaire 
X 
  
X 
  
X 
  
X 
NRS for Pain 
X 
X 
X 
X 
X 
X 
X 
Physical 
Performance 
Measures 
 X 
  
X 
  
X 
  
X 
AE/SAE 
Assessment 
X 
X  
X 
X  
X 
X  
X 
*Each follow up visit will have a window of +/- 3 days as per the schedule 
 
 
F. Risk/benefit assessment:   
1. Physical risk:  
The iovera° device involves percutaneous access to subcutaneous tissue using a needle 
and use of dermal anesthesia. Passage of a needle into the skin, cooling of subcutaneous 
soft tissue and delivery of local anesthesia are known to be associated with the following 
risks 1: 
• 
Bruising (ecchymosis)  
• 
Swelling (edema)  
• 
Inflammation and/or redness (erythema) 
• 
Pain or skin hardening along the treatment line. 
• 
Tenderness on palpation. 
• 
Altered sensation (localized anesthesia or dysesthesia such as burning) 
 
Proper use of the device as described in the iovera° User Guide can help reduce or 
prevent the following complications:  
• 
Injury to the skin related to application of cold or heat 
• 
Hyper- or hypo-pigmentation at the treatment site 
• 
Skin dimpling at the treatment site  
• 
Loss of motor function outside the target area 
 
2. Psychological risk: N/A 
3. Social risk: N/A 
4. Economic risk:  N/A 
5. Potential benefit of participating in the study: 
Participation in this study may produce possible benefits for the individual subject.  
Possible benefits include improved pain, stiffness or function in your ankle.   
G. Location where study will be performed: The study will be performed at the University 
of Kansas Medical Center.  All data forms and records will be kept on site at the University of 
Kansas Medical Center in locked drawers and password-protected computers in a locked 
office. Only the research team will have access to the data. 
H. Collaboration (with another institution, if applicable): N/A 
I. Single IRB Review for a Multi-site study (if applicable):  N/A 
 
J. Community-Based Participatory Research (if applicable): N/A 

 
KUMC – HRPP- 03/12/2015 
 
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K. Personnel who will conduct the study, including: 
1. Indicate, by title, who will be present during study procedure(s):  
a. Dr. Neil Segal, Principal Investigator 
b. Dr. Mayank Kothari, Research Assistant 
c. Jennifer Bedard, Research Coordinator 
2. Primary responsibility for the following activities, for example:  
a. Determining eligibility: Segal/Kothari/Bedard/Wapp 
b. Obtaining informed consent: Segal/Bedard 
c. Providing on-going information to the study sponsor and the IRB: Bedard/Segal 
d. Maintaining participant's research records: Kothari/Bedard/Segal 
e. Completing physical examination: Segal 
f. Measuring height, weight: Segal/Bedard/Kothari 
g. Drawing / collecting laboratory specimens: N/A 
h. Performing / conducting tests, procedures, interventions, questionnaires: 
Segal/Kothari/Bedard 
i. Completing study data forms: Segal/Bedard/Kothari 
j. Managing study database: Bedard/Kothari 
 
L. Assessment of Subject Safety and Development of a Data and Safety Monitoring 
Plan 
 
Compliance reports will be reviewed by the Principal Investigator on a weekly basis. 
 
Reports containing the proportion of subjects completing the intervention or prematurely 
terminating participation will be generated monthly. 
Adverse event information will be collected during all contacts with subjects.  If an adverse 
event is reported to study staff, data including the type of event, onset/end dates, duration, 
severity, and outcome will be collected and reported to the Principal Investigator, who will 
determine severity of the event using CTCAE guidelines.  Post-treatment expected symptoms 
include numbness of the skin over the ankle and foot and possibly redness, swelling, bruising 
or pain at the site of insertion.   
 
An event that is serious must be recorded on the AE worksheet and requires expeditious 
handling to comply with regulatory requirements.  Any adverse events classified as 
“serious” by the Investigator must be reported to the IRB within 24 hours of becoming 
aware of its occurrence. 
 
 
III. 
Subject Participation 
 
A. Recruitment: 

 
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Potential study participants will be recruited from a HERON generated list, the clinics of the 
participating investigators, as well as local advertising. Any study-related advertisements will 
be approved by the governing IRB prior to use. Subjects will be recruited based upon inclusion 
and exclusion criteria detailed above. Participants will be compensated for their time and 
effort at follow-up visits.  
 
Each subject will participate for up to 24 weeks following either deep or superficial nerve 
treatment. Enrollment is expected to take up to 6-12 months following (superficial or deep 
nerve) treatment. Total study duration is expected to be up to 18 months. 
 
B. Screening Interview/questionnaire: Potential subjects who express interest in the study 
will be screened by telephone. A script will be used to determine eligibility for the first 
screening clinic visit by study staff. Please see Appendix II. 
C. Informed consent process and timing of obtaining of consent 
Subjects who pass the initial screening criteria (telephone screen) will be asked to schedule 
a screening visit to provide written consent and possibly undergo screening procedures during 
a screening visit. Subjects will be informed that the study is voluntary and choosing not to 
participate will not affect their current treatment. They may request the opportunity to review 
the consent form with their physician and/or family members.  Moreover, they will be fully 
informed of the purpose of the study and of the possible risks involved before providing their 
consent. Written, informed consent will be obtained and documented by an investigator or a 
study coordinator prior to initiation of study procedures.  All subjects will be provided with a 
copy of the signed consent form.  
 
D. Alternatives to Participation: The alternative to study participation is choosing not to 
participate and continue with their current treatment plan. 
E. Costs to Subjects: There will be no cost to subjects to participate in the study and no 
insurance will be billed as a part of the study procedures. 
F. How new information will be conveyed to the study subject and how it will be 
documented: If any new information is to be provided to the study subject the informed 
consent form (ICF) will be amended and approved by the IRB.  Each subject will then be 
reconsented using the newest revision of the ICF. 
G. Payment, including a prorated plan for payment:  
Subjects would be provided $25 at each visit that they attend (up to $200 per participant) as 
compensation for their time. They additionally will be provided with parking validation for in-
person visits. Moreover, participants will be provided with encouragement during the study 
period, especially prior to and after each study visit through letting them know that their 
contributions are appreciated.  
 
H. Payment for a research-related injury:  
If the subject is injured because of study participation, there will be no compensation for 
physical or non-physical injuries. will be available for any extra expenses that may be the 
result of Research-related physical injuries include additional hospital bills, lost wages, travel 

 
KUMC – HRPP- 03/12/2015 
 
Page 18 of 19
 
 
 
expenses, etc.  No compensation will be available for any non-physical injuries that may 
occur because of research participation, such as legal problems, problems with your finances 
or job, or damage to your reputation. 
 
IV. 
Data Collection and Protection 
A. Data Management and Security:  
FAOS (Pain, ADL, QoL), NRS for pain and physical performance test (40 m fast paced walking 
test, Standing Balance Test) data will be collected at baseline and 6, 12 and 24 weeks after 
cryoneurolysis. All data collected will remain confidential and only accessible to the research 
team 
Data regarding subject demographic, standing ankle radiographs or cone-beam CT,, FAOS 
subscale responses will be obtained directly from subjects.  All data will be coded, with no 
patient identifiers.  A master list with patient information and assigned study IDs will be stored 
in a separate password-protected file on a password-protected research drive available to the 
study team. Analyses will be performed on coded files.  Physical files (e.g. questionnaires) will 
be stored in locked file cabinets in the research office.   
 
B. Sample / Specimen Collection: N/A 
C. Tissue Banking Considerations: N/A  
D. Procedures to protect subject confidentiality:  
Data regarding subjects’ demographic, ankle radiographs or cone-beam CT, FAOS responses 
will be obtained directly from subjects.  All data will be coded, with no information that could 
identify a subject.  A master list with patient information and assigned study IDs will be stored 
in a separate password-protected file on a password-protected research drive available to the 
study team. Analyses will be performed on coded files. Physical files (e.g. questionnaires) will 
be stored in locked file cabinets in the research office. 
 
E. Quality Assurance / Monitoring 
Study staff will have proper qualifications for data entry and will receive training in data entry 
procedures to insure data entered is of highest quality research staff. Data will be entered into 
two separate databases by two separate members of study staff.  The two databases will be 
reconciled by the database manager and the outcome reported to the Principal Investigator.  
Data will be backed-up daily. 
 
V.Data Analysis and Reporting 
A. Statistical and Data Analysis:   
All participants will be assigned to undergo cryoneurolysis using iovera. FAOS (Pain, ADL, QoL), 
NRS for pain and physical performance test (40 m fast paced walking test, standing balance 
test) data will be collected at baseline, 6 weeks, 12 weeks and 24 weeks. A 24-week follow-
up duration was selected to detect meaningful differences from standard of care and long-
term effects, while minimizing the variability that may occur further out from baseline. 
Differences between each of the three follow-up time points for each of the interventions 
(superficial and deep) and baseline will be assessed using one-sample t-tests or repeated 
measures analyses, as appropriate. This will control for study-wide alpha level to account for 
multiple comparisons as well as 6-week and 24-week analyses. A soft-lock of the database will 
occur after the 6- and 12-week time-points.    

 
KUMC – HRPP- 03/12/2015 
 
Page 19 of 19
 
 
 
 
B. Outcome: We expect statistically significant and clinically meaningful improvement in pain, 
activities of daily living, quality of life and physical performance with iovera° in people with 
ankle OA at 12 weeks post-treatment.  
C. Study results to participants: The study will be registered on www.clinicaltrials.gov and 
results posted upon completion of the study. 
D. Publication Plan: Results will be submitted for presentation at an appropriate conference 
and for publication in an appropriate journal for the topic of study. 
 
VI. 
Bibliography / References / Literature Cited  
1. 
Radnovich R, Scott D, Patel AT, et al. Cryoneurolysis to treat the pain and symptoms of knee 
osteoarthritis: a multicenter, randomized, double-blind, sham-controlled trial. Osteoarthritis 
Cartilage 2017;25:1247-56. 
2. 
Ward ST, Williams PL, Purkayastha S. Intra-articular corticosteroid injections in the foot and ankle: 
a prospective 1-year follow-up investigation. J Foot Ankle Surg 2008;47:138-44. 
3. 
Valderrabano V, Horisberger M, Russell I, Dougall H, Hintermann B. Etiology of ankle 
osteoarthritis. Clin Orthop Relat Res 2009;467:1800-6. 
4. 
Repetto I, Biti B, Cerruti P, Trentini R, Felli L. Conservative Treatment of Ankle Osteoarthritis: Can 
Platelet-Rich Plasma Effectively Postpone Surgery? J Foot Ankle Surg 2017;56:362-5. 
5. 
Trescot AM. Cryoanalgesia in interventional pain management. Pain Physician 2003;6:345-60. 
6. 
Evans PJ, Lloyd JW, Green CJ. Cryoanalgesia: the response to alterations in freeze cycle and 
temperature. Br J Anaesth 1981;53:1121-7. 
7. 
Golightly YM, Devellis RF, Nelson AE, et al. Psychometric properties of the foot and ankle outcome 
score in a community-based study of adults with and without osteoarthritis. Arthritis Care Res 
(Hoboken) 2014;66:395-403. 
8. 
Mohammed KM Ali ST, CA Mbah, D Sunderamoorthy. Steroid intra-articular injections for foot and 
ankle conditions: How effective are they? Foot and Ankle Online Journal 2016; 9 (2): 7. 
9. 
Mani SB, Do H, Vulcano E, et al. Evaluation of the foot and ankle outcome score in patients with 
osteoarthritis of the ankle. Bone Joint J 2015;97-B:662-7. 
10. 
Holzer N, Salvo D, Marijnissen AC, et al. Radiographic evaluation of posttraumatic osteoarthritis 
of the ankle: the Kellgren-Lawrence scale is reliable and correlates with clinical symptoms. 
Osteoarthritis Cartilage 2015;23:363-9. 
11. 
Hunt KJ, Hurwit D. Use of patient-reported outcome measures in foot and ankle research. J Bone 
Joint Surg Am 2013;95:e118(1-9). 
12. 
Dobson F, Hinman RS, Roos EM, et al. OARSI recommended performance-based tests to assess 
physical function in people diagnosed with hip or knee osteoarthritis. Osteoarthritis Cartilage 
2013;21:1042-52. 
13. 
McDaniel G, Renner JB, Sloane R, Kraus VB. Association of knee and ankle osteoarthritis with 
physical performance. Osteoarthritis Cartilage 2011;19:634-8. 
 
APPENDIX I: VULNERABLE POPULATIONS 
 
I.     N/A 
II.     Cognitively or decisionally impaired individuals: N/A 
III.     Children: N/A 
IV.     Pregnant women: N/A 
V.     Prisoners: N/A 
VI.     Students and/or Employees: N/A