Effects of an Electrical Stimulation Program on Strength, Functional Capacity, Pain, and Gait in Individuals With Knee Osteoarthritis
Phase: NA
Conditions: Osteoarthritis, Osteoarthritis, Knee
Sponsor: Cionic, Inc.

 
 
 
 
 
 
 
 
 
 
 
 
 
Effects of an Electrical Stimulation Program on Strength, Functional 
Capacity, Pain, and Gait in Individuals With Knee Osteoarthritis 
 
NCT05765435 
 
February 21, 2023 
 
 
 

 
 
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Introduction ..................................................................................................................................... 4 
Significance..................................................................................................................................... 6 
Research Objectives ........................................................................................................................ 7 
Hypotheses ...................................................................................................................................... 8 
Specific Aims .................................................................................................................................. 8 
Aim 1 – Validate FES for disuse atrophy in KOA ..................................................................... 8 
Aim 2 - Provide statistically significant evidence ...................................................................... 9 
Participation Selection and Randomization .................................................................................... 9 
Inclusion Criteria .................................................................................................................. 10 
Exclusion Criteria ................................................................................................................. 10 
Methodology ................................................................................................................................. 11 
Overview of Study .................................................................................................................... 11 
Participant Identification, Recruitment & Informed Consent ....................................................... 14 
Participant Capacity and Comprehension ................................................................................. 15 
Lab Visits .................................................................................................................................. 16 
Exercise and Walking Program .................................................................................................... 17 
Exercise Program .................................................................................................................. 17 
Walking Program .................................................................................................................. 18 
Electrical Stimulation System ............................................................................................... 18 
Study Removal and Device Returns ......................................................................................... 19 
Primary Outcome Measures .......................................................................................................... 19 
Quadriceps Strength .............................................................................................................. 19 
Perceived Functional Capacity ............................................................................................. 20 
Pain ....................................................................................................................................... 20 
Walking Performance ........................................................................................................... 21 
Secondary Measures ..................................................................................................................... 22 
Adherence to Program .......................................................................................................... 22 
Thigh Muscle Volume .......................................................................................................... 22 
Functional Ability of the Lower Limb .................................................................................. 23 
Quality of Life....................................................................................................................... 23 
Data Analysis/Statistical Analysis ................................................................................................ 24 

 
 
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Organizational Relationships ........................................................................................................ 24 
Risk & Benefit Assessment .......................................................................................................... 25 
Risk Mitigation Strategies......................................................................................................... 25 
Benefits ..................................................................................................................................... 27 
Study Withdrawal ..................................................................................................................... 28 
Data Storage and Contact for Future Studies ............................................................................ 30 
Debriefing Procedures .............................................................................................................. 30 
Costs to Participants .................................................................................................................. 30 
Compensation for Participation ................................................................................................ 31 
REFERENCES ............................................................................................................................. 32 
Appendix A: Power Analysis........................................................................................................ 40 
Appendix B: Exercise Handout and Calendar .............................................................................. 41 
Appendix C: Encouragement During 6-Minute Walk Test .......................................................... 45 
Appendix D: Quadriceps Strength Testing ................................................................................... 46 
Appendix E: Western Ontario/McMaster Universities Osteoarthritic Index (Physical Function) 47 
Appendix F: Western Ontario/McMaster Universities Osteoarthritis Index (Pain) ..................... 48 
Appendix G: 10-Meter Walk Test ................................................................................................ 49 
Appendix H: 6-Minute Walk Test ................................................................................................ 50 
Appendix I: Five Times Sit to Stand Test ..................................................................................... 51 
Appendix J: Short Form-36 .......................................................................................................... 52 
 
 
 

 
 
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Introduction 
 
Knee osteoarthritis (KOA) is a degenerative joint disease that affects the knee and loss of 
cartilage1, resulting in pain; quadriceps weakness; and swelling, locking, and giving way of the 
knee2. The severity of KOA based on radiologic findings can be graded using the Kellgren & 
Lawrence (K&L) scale, a measure that ranges from 0 to 4, with 0 being none and 4 being 
severe3. Depending on the severity of the disease, symptoms of KOA may be managed by non-
surgical or surgical interventions, such that non-surgical management is recommended to delay 
the need for invasive joint replacement procedures4, and surgical treatment is most beneficial for 
those at the severe stage who have exhausted conservative measures2. Despite these means, the 
extent of patients with KOA who engage in interventions to delay disease progression and 
operative procedures is low. 
 
Conservative treatment of KOA includes exercise4 to alleviate pain, improve strength5, 
and improve quality of life and physical function6. However, exercise interventions involve a 
physical capacity that may be challenging for the KOA community7. In fact, adults with 
radiographic KOA spend an average of 67% of their daily waking hours in sedentary behavior8. 
This proportion of sedentary time may lead to disuse atrophy, or atrophy of muscle fibers due to 
prolonged unloading9, which may reduce muscle mass and strength, impair mobility, and hasten 
the need for surgery10. Additionally, physical inactivity may have a detrimental effect on quality 
of life for persons with KOA11, further contributing to the disease burden12. Given the limited 
options to maintain muscle mass or strength if patients with KOA are unwilling or unable to 
exercise, alternative therapies, such as electrotherapy, have been proposed. 

 
 
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Electrotherapy, or electrical stimulation delivered to target muscles using an external 
stimulator connected to electrodes and surface hydrogel pads, has been widely used for 
treatment, rehabilitation, and training purposes. Electrotherapy interventions, such as 
neuromuscular electrical stimulation (NMES) and functional electrical stimulation (FES), have 
resulted in improvements in gait performance13,14 and increased quadriceps strength15,16 to 
counteract muscle decline. This is reasonable as NMES produces muscular contractions38, and 
FES provides stimulation with a targeted movement, such as walking, to mimic normal voluntary 
kinematics39. On the contrary, there are studies that do not support NMES for pain management17 
and objective measures of function18. However, those studies explored the application of NMES 
alone and excluded studies combining electrical stimulation interventions with exercise. 
Additionally, there are limited studies exploring FES in the KOA population despite its positive 
effects in walking speed40, 41, lower limb kinematics41, and muscle mass and strength42 in the 
stroke and multiple sclerosis communities. Pairing electrical stimulation with exercise has been 
employed to improve muscle activation in the affected leg of hemiplegic patients19 and provide a 
greater stimulus for muscle hypertrophy than stimulation or exercise alone when voluntary 
activation deficit is present20, thereby confirming the value of combined electrotherapy for those 
with impaired limbs. This combined intervention was also supported as an effective alternative to 
relieve pain, increase quadriceps strength, improve physical function and functional performance 
in patients with KOA who have difficulty performing an exercise program21. Although there are 
inconsistencies regarding electrotherapy for the KOA community, there should be a recognition 

 
 
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and utilization of electrotherapy combined with activities to promote physical activity and better 
manage some symptoms associated with the disease.  
 
Acknowledging the benefits of combined electrotherapy and KOA as a progressive and 
degenerative condition with unlikely regression or restoration of damaged structures, the study 
aims to investigate the effects of stimulation assisted activities to delay the disease progression 
and muscle atrophy in those with KOA. Thus, the purpose of this research is to investigate if 
stimulation assisted (NMES and FES) activities can combat disuse atrophy for individuals 
diagnosed with KOA. This study will use a home-based medical device (Cionic Neural Sleeve 
NS-100, K213622, CIONIC, San Francisco, CA) to administer electrical stimulation and 
measure its effect on outcomes that include quadriceps strength, perceived functional capacity, 
pain, and walking performance. 
Significance 
Adults with KOA spend most of their day engaging in sedentary behavior and report worse 
physical function8, which may lead to progression of the condition, increased functional 
dependence and decreased quality of life22. Existing literature shows that NMES assisted 
exercise may counter disuse atrophy in sedentary individuals23, but because there has been 
minimal research investigating the effects of FES in the KOA community, exploration of this 
study is warranted.  
 
 

 
 
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Figure 1: Cionic Neural Sleeve system 
Note: Left: Cionic Neural Sleeve showing the configuration of the FES and electromyographic 
(EMG) electrode arrays. Center: Cionic mobile application interface for setting FES parameters 
(frequency, pulse width, intensity) and current field steering. Right: Cionic Neural Sleeve on 
body.  
 
Research Objectives 
1. Analyze the effects of electrical stimulation assisted interventions versus a conventional 
exercise program on muscle strength, perceived function, and pain in KOA. 
2. Compare the effects of unassisted walking and stimulation assisted walking on walking 
performance in KOA. 
3. Measure the compliance of electrical stimulation assisted interventions to a conventional 
exercise program on the effects of pain and perceived function in KOA. 

 
 
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Hypotheses 
It was hypothesized that combined electrotherapy groups will show larger muscle mass and 
strength improvements; improved gait kinematics, pain and perceived function; and a high 
compliance to the assigned program compared to the unstimulated group. 
Specific Aims 
This protocol describes a study intended to evaluate the Cionic Neural Sleeve for subjects 
diagnosed with KOA. CIONIC will use this study as an opportunity to validate FES for disuse 
atrophy in KOA. CIONIC will use lab visits (Table 1) to record participants’ strength, kinematic 
gait metrics, walking performance, self-reported functional capacity and pain.  
 
The Cionic Neural Sleeve has been evaluated for safe use in a simulated at-home environment 
under prior studies (CIONIC-02-001 and CIONIC-03-001). 
 
There are two specific aims with this study: 
Aim 1 – Validate FES for disuse atrophy in KOA 
The study intends to obtain evidence to support the use of the FES for disuse atrophy in the KOA 
community. Standard clinical assessments will be collected at meaningful endpoints in the study 
to allow CIONIC to measure subjects’ performance over time.  
 

 
 
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Aim 2 - Provide statistically significant evidence  
The study design is a randomized controlled trial, where CIONIC will collect spatial and 
kinematic metrics to track participants’ mobility and gait patterns. Some examples of these 
metrics may include: gait speed, total steps, step variability, and foot-floor angle at heel strike. 
 
Table 1: Schedule of events  
Initial visit  
● Verify consent 
● Gather demographic information and anthropometric 
measurements 
● Measure strength, walking performance, thigh muscle volume, 
functional ability of the lower limb 
● Distribute questionnaires on perceived functional capacity, pain, 
and quality of life  
● Prescribe exercise and walking program  
● Random assignment of groups 
● Distribute the Cionic Neural Sleeve and provide Instructions for 
Use 
6 week study 
midpoint 
● Measure strength, walking performance, thigh muscle volume, 
functional ability of the lower limb 
● Distribute questionnaires on perceived functional capacity, pain, 
and quality of life 
End of study   
● Measure strength, walking performance, thigh muscle volume, 
functional ability of the lower limb 
● Distribute questionnaires on perceived functional capacity, pain, 
and quality of life  
● Collect equipment 
Participation Selection and Randomization 
A sample size of 32 participants was calculated to be sufficient for a two-tailed significance level 
of 5% and a power of 80% (Appendix A). This was adjusted to 45 participants with knee 
osteoarthritis to allow for dropouts. Recruitment for this study will be conducted using a 
recruitment flyer and through the CIONIC website. Recruitment will be based on a first come 

 
 
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basis. Interested participants will complete a questionnaire to be reviewed according to the 
inclusion and exclusion criteria. Responses will then be reviewed, and prospective participants 
will be invited to schedule a virtual meeting with a study staff member who will screen the 
prospective subject for an understanding of the study and for their voluntary participation. All 
participants will be assigned a unique number using a computer random number generator and 
randomly assigned to a group by a researcher. All participants will receive their assigned 
intervention at their first lab visit. 
Inclusion Criteria 
● Persons with knee osteoarthritis between the ages of 22 and 75 
● Ability to walk a duration of 30 minutes per walking session (with or without an assistive 
device), for three days per week 
● Able to tolerate the device for up to 1 hour per lab session  
● No recent change in medication or exacerbation of symptoms over the last 60 days 
● Radiographic KOA K&L grade 2 or 3 or physician diagnosed mild or moderate KOA if 
radiographic imaging is not available 
● No hyaluronic acid or cortisone injection into knees in previous 12 months 
 
Exclusion Criteria 
● Lower motor neuron disease or injury (e.g. peripheral neuropathy) that may impair 
response to stimulation 
● Absent sensation in the impacted or more impacted leg 

 
 
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● Inadequate response to stimulation, as defined as inability to achieve muscle contraction 
or tolerate stimulation 
● Inability to ambulate with the sleeve in place of an ankle foot orthosis (AFO)/knee ankle 
foot orthosis (KAFO) if utilized 
● Use of FES devices in the past year 
● Demand-type cardiac pacemaker or defibrillator 
● Malignant tumor in the impacted or more impacted leg 
● Existing thrombosis in the impacted or more impacted leg 
● Fracture or dislocation in the impacted or more impacted leg that could be adversely 
affected by motion from stimulation 
● History of knee surgery 
● History of other types of arthritis  
● History of neurological disease 
● History of seizures or diagnosed with epilepsy/seizures 
● Current pregnancy 
Methodology 
 
Overview of Study  
This study is a randomized controlled trial. Figure 2 depicts a flow diagram of the study design. 
Participants will be screened for eligibility through a questionnaire, and after study details are 
explained and consent is obtained, they will be invited to the study site. Assessments will be 
conducted at CIONIC Inc., and involve approximately 45 patients for a 12 week study period. 

 
 
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All subjects will be assigned an electrical stimulation system to wear on the most impacted leg 
and be prescribed a home-based exercise and walking program. Subjects will be randomly 
assigned into three groups: (a) control; (b) NMES+; (c) NMES+FES. The control group will not 
receive stimulation for the exercise and walking program, whereas subjects in NMES+ will 
receive stimulation during exercises, and subjects in the NMES+FES group will receive 
stimulation during exercises and walking. Outcome measures will be assessed at baseline, 6 
weeks after baseline, and end of study (Table 2). Equipment and additional feedback will be 
collected at the end of study. These three groups will be analyzed using several outcome 
measures. Primary outcome measures of the study are quadriceps strength, perceived functional 
capacity, self-reported pain, and walking performance. Secondary interest will be adherence to 
program, thigh muscle volume, functional ability of the lower limb, and quality of life. The 
CIONIC system will be used to track adherence (duration of sessions, frequency of use).  

 
 
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Figure 2: Study flow 
 
 
 

 
 
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Table 2: Study overview  
Comparison Groups Treatment Schedule 
Timing and Outcome Measures 
Control (unstimulated 
exercise and walking) 
 
NMES+ 
(NMES+exercise and 
unstimulated 
walking) 
 
NMES+FES 
(NMES+exercise and 
FES+walking) 
Exercise: 
5x/week for 12 weeks 
Progression every 3 
weeks 
 
Walking: 
10 min, 3x/week for 12 
weeks 
Progression up to 30 
min by end of study 
 
 
At baseline, midpoint and end of study: 
Quadriceps strength 
Perceived functional capacity 
Self-reported pain 
Walking performance 
Thigh muscle volume 
Functional ability of lower limb 
Quality of life 
EMG activity 
 
Weekly: 
Adherence to program 
Participant Identification, Recruitment & Informed Consent  
CIONIC researchers will follow a recruitment plan (Figure 3). CIONIC will post a recruitment 
flyer on their website and interested participants may send an email directly to 
trials@cionic.com. CIONIC may also recruit directly from physical therapy providers and 
osteoarthritis advocacy groups through a recruitment flyer with their permission. The study staff 
will email interested candidates a screening questionnaire to assess for study eligibility. CIONIC 
researchers will then contact qualified candidates to set up a Zoom meeting to explain study 
details, address risks and benefits, and answer questions. Those who opt to participate in the 
study will receive an electronic consent form via DocuSign for their review and electronic 
signature. A member of the CIONIC team will guide the participant through the informed 
consent document, and answer concerns. Participants who sign the informed consent document 
will receive a copy for their records and proceed with the study. All forms will be stored on a 
secure server. After consent is obtained, the CIONIC researchers will schedule the subject to 
report to the study site for initial assessment.  

 
 
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Figure 3: Recruitment plan 
 
Participant Capacity and Comprehension  
The study’s inclusion criteria and recruitment plan may include individuals with decision making 
impairments and/or language and communication impairments. To mitigate this, the video 
conference call will further screen and determine if the severity of their impairments will require 
additional safeguards or if the interested party will need to be excluded from the study.  
 

 
 
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Lab Visits  
The study will be explained to the participants and written informed consent will be obtained 
before the initial lab visit. Physical measurements, performance tests, and questionnaire 
responses will be collected at three lab visits: initial, study midpoint (6 weeks), and end of study 
(12 weeks). Physical measurements will include height, weight, and thigh circumference of the 
impacted leg. If subjects report bilateral compromised legs, the most impacted/painful leg will be 
measured. Participants will be asked to complete four performance tests (maximal voluntary 
isometric contraction of the quadriceps, Five Times Sit to Stand Test (FTSST), 10-meter Walk 
Test (10mWT), and the 6-Minute Walk Test (6MWT)) and three questionnaires (Western 
Ontario/McMaster Universities Osteoarthritis Index physical function (WOMAC-PF) subscale, 
WOMAC-pain, and the Short Form-36). Order of the tasks at the lab visits are as follows: 
maximal voluntary isometric contraction of the quadriceps, FTSST, 10mWT, WOMAC-PF, 
10mWT, WOMAC-pain, 6MWT, Short Form-36, and 6MWT. Instruction will be provided to the 
participants before beginning a new task, and the researchers will periodically gauge the subjects 
for a need for a break and understanding of the task. For the walking tests, subjects will be fitted 
with the electrical stimulation system to collect EMG/kinematic data, and depending on the 
subject’s group assignment, stimulation may or may not be enabled. All subjects will be 
provided with and instructed to wear the electrical stimulation system for the subsequent 12 
weeks. All subjects will be taught how to navigate the supporting app and receive a user manual 
on how to operate/care for the system. Subjects assigned to receive stimulation will be taught 
how to adjust parameters of the device using the supporting app. All participants will receive a 
handout explaining the exercise, and a calendar for the exercise and walking program (Appendix 

 
 
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B). Subjects will be informed to perform the exercise and walking program in an area free from 
obstacles. Lab visits may be up to 90 minutes in duration.   
 
Exercise and Walking Program 
The participants will wear the device during the 12-week exercise and walking program. This 
may range from 1 minute to 35 minutes per day (Appendix B).  
 
Exercise Program 
All participants will be prescribed the same exercise program and instructed to adhere to the 
program for 5 days per week for 12 weeks, for a total of 60 exercise sessions. This program 
requires isometric quadriceps contractions in a supine position with a rolled-up towel placed 
behind the knee. For this study, subjects will contract their thigh muscle to straighten their knee 
for three seconds and relax for three seconds for a repetition, as prompted by the supporting app. 
Participants in this study will be instructed to perform sets of 10 repetitions, with a progression 
every 3 weeks (Table 3). For exercise sessions requiring more than 1 set, the sets should be 
separated by 30-second rest intervals.  
 
Table 3: Exercise Program 
Exercise 
Frequency 
Progression 
Isometric quadriceps contraction 
 5 days per 
week 
Weeks 1-3: 1 set of 10 
Weeks 4-6: 2 sets of 10 
Weeks 7-9: 3 sets of 10 
Weeks 10-12: 2 sets of 10, twice per day 
 

 
 
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Walking Program 
All participants will be prescribed the same walking program, where subjects will be instructed 
to walk 3 days per week for 12 weeks, for a total of 36 walking sessions. At the start of the study, 
participants will walk for 10 minutes and then gradually increase walking time up to 30 minutes 
per walking session by the end of the study.  
 
Electrical Stimulation System 
Electrical stimulation will be given using the Cionic Neural Sleeve, a wearable single channel 
stimulator with a monophasic rectangular pulse. The Cionic Neural Sleeve system consists of a 
Nylon/Lycra garment equipped with small metal electrodes covered by reusable 1.75” x 1.75” 
electrode pads that adhere to the skin’s surface and a Control Unit. Small wires are routed 
through the interior of the sleeve from each metal electrode and electrode pad to a handheld 
removable Control Unit that houses the central computing module and battery. There are flaps on 
the upper and lower leg that are secured in place with Velcro, and an upper thigh pocket to hold 
the Control Unit. The Control Unit connects to the sleeve via a short connector located in the 
upper thigh pocket and communicates with a smartphone via the CIONIC application using 
Bluetooth™ Low Energy (BLE). The device is a Food and Drug Administration (FDA)-cleared 
Class 2 medical device. 
 

 
 
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Study Removal and Device Returns  
If participants have questions during the study, they may call, text (cell phone number 925-788-
6649), or email the primary investigator (PI) directly (rebecca@cionic.com) at any time. If a 
participant loses or damages the system (Control Unit or the Cionic Neural Sleeve), the 
equipment will be replaced via next day freight or by in-person pickup from the lab site. Broken 
or damaged equipment may be returned to the lab in person or CIONIC will mail a return 
shipping label and box. Under no circumstances will the participant be financially responsible for 
any damaged devices or associated shipping costs. If a participant chooses to withdraw from the 
study, they may return the equipment to the lab in person or CIONIC will mail them a return 
shipping label and box. Participants who lose or irreparably damage two sleeves or Control Units 
may be asked to withdraw from the study early but will be compensated for their time.  
Primary Outcome Measures 
Quadriceps Strength 
Quadriceps strength, as measured by maximal voluntary isometric contraction (N), will be 
assessed using a handheld dynamometer according to a testing protocol24 for both limbs. To 
assess maximal voluntary isometric contraction of the quadriceps, participants will be seated 
with the back erect and legs hanging over the edge of the treatment table. The researchers will 
visually ensure that the subjects are sitting upright before administering the test, but if the 
subjects are not seated upright, the researchers may give them a tactile cue for posture if needed. 
With the handheld dynamometer placed distally on the affected leg with the knee in 90 degrees 
flexion, participants will push against the dynamometer for 5 seconds. Subjects will get two 

 
 
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warm-up trials separated by a 1-minute rest period. The first warm up will be at 50% maximal 
effort, and second trial at 70% maximal effort, with contractions to be held for 5 seconds. 
Subjects will then perform 3 repetitions of maximal effort, separated by two minutes of rest 
between each. The test will be repeated on the other leg. The average of the 3 repetitions will be 
recorded as the subjects’ 1 repetition maximum, the gold standard for evaluating dynamic 
strength in non-laboratory conditions25.  
 
Perceived Functional Capacity 
The WOMAC-PF is a 17-item questionnaire that measures the impact of KOA on daily physical 
activities in the past 48 hours26. Scores on the WOMAC-PF range from 0 to 68, with high scores 
indicative of worse functional limitations26. The minimal clinically important difference (MCID) 
for improvement of 14.4827 will be used as a benchmark.  
 
Pain 
The WOMAC-Pain is a 5-item survey that prompts the respondent to reflect on the quality of 
pain in 5 activities during the last 48 hours26. Scores range from 0 to 20, with high scores 
indicative of worse pain26, and the MCID of 8.7427 will be used as an indicator of improvement 
in our study.  
 

 
 
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Walking Performance 
Walking performance will be evaluated by gait speed and walking endurance. All subjects will 
wear the Cionic Neural Sleeve during the walking tests, and all subjects will perform the same 
number of tests. The control group will perform the walking tests in unstimulated conditions. 
Unstimulated conditions require subjects to wear the Cionic Neural Sleeve as they traverse to 
collect EMG/kinematic data, but stimulation will not be enabled. Subjects assigned to receive the 
stimulation intervention will perform the walking tests in unstimulated conditions before 
traversing in stimulated conditions. Stimulated conditions require subjects to wear the Cionic 
Neural Sleeve and receive stimulation assistance while walking. 
 
Gait speed (m/s) will be measured using the 10mWT on a 10-meter walkway with brightly 
colored tape to indicate boundaries, two chairs, a stopwatch/timer, and the subject’s usual 
walking aid. During this performance test, the subject will walk with the Cionic Neural Sleeve 
for 10 meters, and time will be measured for the intermediate 6 meters. Two trials will be 
administered at the subject’s comfortable walking speed, followed by two trials at fast walking 
speed. Rests will be provided between each trial. The trials for each speed and stimulation 
condition will be averaged. Acceleration and deceleration will occur outside of the timed portion 
to allow for a more accurate assessment28. Prior literature reported an improvement of 0.12 m/s 
in patients with unilateral KOA post-surgery29,30, and this will be used as a point of comparison 
in our study.   
 

 
 
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Walking endurance (m) will be measured using the 6MWT using the same walkway utilized for 
the 10mWT. Participants will wear the Cionic Neural Sleeve during the two 6MWTs. For the 
6MWT, the subject will be instructed to walk as far as possible for 6 minutes, up and down the 
pathway, and pivoting to turn at the end of each lap31. Timing will begin when the participant 
steps over the start line, and distance traveled will be recorded. Encouragement outlined in the 
guideline (Appendix C) will be given to the subjects after each minute, and participants will be 
instructed to stop at 6 minutes or prior, if they are unable to complete 6 minutes. Use of a 
walking aid and standing rests will be permitted. Normative values of people aged 40-80 years 
will be used as reference values32. 
 
Secondary Measures  
Adherence to Program  
Adherence to the program will be measured by the usage log of the Cionic Neural Sleeve. The 
data collected from the Cionic Neural Sleeve worn on the affected limb/most affected limb will 
be recorded to monitor compliance to the program in number of repetitions and duration of 
walking.  
 
Thigh Muscle Volume  
Thigh muscle volume will be estimated using a measurement tape for thigh circumference and a 
prediction model. Thigh circumference (cm) will be measured from a point 15 cm proximal to 
the superior pole of the patella. The prediction model is as follows: Muscle volume (cm3) 

 
 
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=4226.3 - 42.5×age(year) - 955.7× gender(male=1, female=2) + 45.9×body weight(kg) + 
60.0×thigh circumference(cm)33. It was selected for this study for its correlation (r2 = 0.745) to 
magnetic resonance imaging, the gold standard of measuring muscle volume37.  
 
Functional Ability of the Lower Limb  
To measure functional ability of the lower limb, subjects will be asked to perform the FTSST. 
The FTSST requires participants to sit in a chair with their arms crossed over the chest and then 
to stand up/sit down for five times, as fast as possible34. Subjects will be timed from the initial 
sitting position to the final standing position. Cut-off points of 10.8 and 12.8 seconds will be 
used as references for intermediate and poor function, respectively35.  
 
Quality of Life 
The Short Form 36 (SF-36) is a generic measure of health status that measures self-reported 
functional health and well-being in the past four weeks in eight domains or two summary scores. 
Scores range from 0 to 100, with 0 representing extreme interference, and 100 representing no 
interference36.  
 
Other information to be collected include date of birth, gender, ethnicity, height, weight, duration 
of condition, and type and dosage of medication.  

 
 
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Data Analysis/Statistical Analysis 
For each of the primary and secondary measures, we will perform a Shapiro-Wilk test for 
normality to assess the assumption of normality. If the outcome variable is approximately 
normally distributed, a paired t-test will be used to statistically compare outcome metrics before 
and after the intervention within a condition. If the normality assumption is not met, the 
Wilcoxon signed rank test will be used as an alternative to the paired t-test for this statistical 
comparison. Bonferroni multiple hypothesis correction will be utilized for a corrected 
significance level. 
To compare across conditions, an analysis of variance (ANOVA) test will be performed if the 
outcome variable is normally distributed. If the normality assumption is not met, the Kruskal 
Wallis test will be used as the non-parametric version of ANOVA. We may also employ a 
repeated measures ANOVA test for inclusion of all three timepoints.  
Organizational Relationships 
CIONIC works closely with Edge Analytics, a consulting firm who has been contracting for 
CIONIC for over two years. The firm is primarily responsible for algorithm development and 
statistical analyses of kinematic and EMG data. Ren Gibbons, Lauren Goodman, PhD, and 
Brinnae Bent, PhD are employees of Edge Analytics who have been working closely with 
Cionic. Brinnae Bent is a sub-investigator on this study.  
 

 
 
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Risk & Benefit Assessment 
The Cionic Neural Sleeve has been tested extensively in previous studies. Across these prior 
studies, the Cionic Neural Sleeve has been evaluated for walking and exercise mode, approved 
for FDA 510k submission and its intended use in a simulated home environment, and for home 
usability with no adverse events.  
 
However, any study of this kind comes with some known risks, that although rare, are associated 
with participation:  
● Discomfort from the electrical stimulation  
● Minor skin irritation at the sites of sensor/electrode pad placement   
● Muscle fatigue from prolonged device use  
● Anxiousness due to the anticipation of receiving an electrical stimulation  
● Injury caused by unintended falls while using the Cionic Neural Sleeve 
● Exposure to coronavirus disease 2019 (COVID-19) or other communicable disease  
 
It is not always possible to know all the risks associated with a study such as this one. If any new 
risks are reported for this study, a member of the study team will inform the participant so that 
they can decide whether they would like to continue in the study.  
 
Risk Mitigation Strategies  
CIONIC has taken the following actions to reduce the risks to participants: 

 
 
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1. Evaluated the Cionic Neural Sleeve across 42 mobility-impacted adult participants for 
formative and summative Human Factors testing required for FDA 510k submission 
(CIONIC-02). 
2. Extensively tested (more than 2 hours) the Cionic Neural Sleeve during walking and 
exercise mode on 32 mobility-impacted candidates in a lab setting (CIONIC-01) and on 
17 subjects in their home environment (CIONIC-03) with no adverse events.  
3. Modified system design to improve usability and increase safety. 
4. Comprehension of the study tasks will be discussed with the participant prior, and their 
comfort will be monitored throughout the study. 
5. A clinician (PT) is included in the study team and will be present at the initial visit, as 
well as advising for the home use instructions.  
6. The testing area will be safe, well-lit and clear of all obstacles. 
7. The CIONIC team is trained to strictly follow the study protocols. 
8. Participants are provided with access to the Cionic Neural Sleeve Instructions for Use. 
9. Participants are provided with instructional videos within the CIONIC app.  
10. Participants will be provided CIONIC’s contact information to answer questions and 
provide technical support throughout the study.  
11. Participants will manage their walking speed and control the electrical stimulation 
intensity at their own comfort.  
12. The research team will wear masks upon request by the participant to minimize exposure 
to communicable diseases. 

 
 
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13. The research team will instruct subjects to wear the Cionic Neural Sleeve in an area of 
their home environment that is free from obstacles.  
14. A Use/Application Hazard Analysis was performed during the development of the Cionic 
Neural Sleeve, and risks related to stimulation were considered and evaluated. Use-
related errors related to these risks were validated in human factors study. 
 
Benefits  
Participants in this study will be early adopters of the Cionic Neural Sleeve system and may 
benefit from the product in a few distinct ways:  
1. Performing routine exercise (with or without stimulated assistance) has been shown to 
improve general health, strength, and pain. 
2. Walking with a stimulation device may facilitate neural retraining which could result in 
improved motor control, pain, and walking performance. Although this has been 
anecdotally reported in previous studies, CIONIC hopes to establish this with clinical 
endpoints in this study.  
3. If requested, CIONIC will provide the participant with a copy of their data, which the 
participant may choose to share with members of their clinical team to support their care. 
CIONIC is not a medically licensed company and cannot and will not provide medical 
advice; however, CIONIC will explain the data in more detail to the participant if 
requested. 
 

 
 
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Study Withdrawal  
During the consent process, participants will be informed that they may withdraw from the study 
at any time. The study team member responsible for reviewing informed consent will confirm 
that they understand that they have this option. Participants will be entitled to financial 
compensation for each lab visit. The investigators or sponsors may stop the study or take 
participants out of the study at any time should they judge that it is in their best interest, if 
subjects experience a study-related injury, if subjects need additional or different 
medication/treatment, or if they do not comply with the study plan. The researchers may remove 
participants from the study for various administrative and medical reasons. Participants will not 
be compensated for lab visits that they cancel or miss. 
 
Data Storage, Monitoring and HIPAA  
This study involves the collection of data from sensors on the Cionic Neural Sleeve system, and 
possibly external kinematic data collection systems for validation. Data collected will not include 
personally identifiable information. The devices comprising the system connect wirelessly via 
BLE to an application running on a smartphone or iPad.  
 
CIONIC’s smartphone or iPad’s camera will also record video of the lower body at the lab visits. 
The participant’s face and voice will not be recorded. The content of the data will be uploaded to 
a secure server. Each set of data will be organized using a unique numerical identifier that does 
not include protected health information (PHI) (e.g., initials) will be stored in our Health 
Insurance Portability and Accountability Act (HIPAA) compliant database with access limited to 

 
 
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CIONIC employees who will administer the study. This unique identifier (date of testing and 
study session) will be recorded separately in a participant tracking file which will include 
demographic data such as gender, age, diagnosis, and duration of diagnosis. Adverse events 
(AEs) and protocol deviations will be recorded for each participant. This data will also be stored 
on a secure server.  
 
The PI, Rebecca Webster, will be responsible for ensuring participants’ safety on a daily basis. 
Data collected from this study will be reviewed on a weekly basis by the PI and sponsor for each 
week there are study participants. All data will be collected and stored on a secure server. There 
is no Data and Safety Monitoring Board for this study.  
 
All AEs will be reviewed by the PI within one business day of occurrence. AEs determined to be 
Serious adverse events related to subject safety will be reported to Salus Institutional Review 
Board within one business day of review by the PI. AEs and unanticipated problems will be 
reviewed on a monthly basis in order to ensure good practice and identify any emerging issues of 
concern. The PI will determine whether the study should be modified based on these findings.  
 
Quality assurance activities include following written and consistent procedures. Data collection 
pages will be reviewed monthly to ensure the quality of the data collection, management, and 
analysis.  
 

 
 
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The study sponsors recognize the requirement to adhere to HIPAA. As stated, all participant PHI 
will be stored in our HIPAA compliant database with access limited to CIONIC study staff. 
Additionally, individual data will not be publicly disclosed. In the future, aggregate data from the 
study (mean, variance, demographic data) may be used to disseminate the results. 
 
Data Storage and Contact for Future Studies  
In the informed consent document, participants will indicate whether they would like their 
information to be saved for future studies. If they select “Yes”, their information will be saved. If 
they select “No,” their information will be destroyed from all databases. Study records and study 
data will be kept indefinitely or until users request they be deleted.  
 
Debriefing Procedures  
At the beginning of each lab visit, there will be a debriefing with the participants, where they 
will be informed of assessments to complete. At the end of the lab visits, subjects may provide 
feedback about the Cionic Neural Sleeve system.  
 
Costs to Participants  
Participants will not be charged and will not incur any costs for participating in the study.  
 

 
 
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Compensation for Participation  
Participants will be given a $50.00 Amazon gift card at the end of the study. If the participant 
does not complete the entirety of the study, the subject will not receive a $50.00 Amazon gift 
card. 
 
Reimbursement for Travel Expenses  
Transportation logistics (including parking, ride scheduling, and directions) will be 
communicated by the PI prior to the lab visits. Transportation costs will be reimbursed. If 
needed, parking cost will be reimbursed by cash or Venmo at the end of the session. 
Documentation of transportations costs may be requested.  
 
 
 
 
 

 
 
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3. Kellgren, J. H., & Lawrence, J. S. (1957). Radiological Assessment of Osteo-Arthrosis. 
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Improving Gait Parameters in Multiple Sclerosis and Stroke. PM&R, 9(4), 339-347.e1. 
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Appendix A: Power Analysis 
 
Power and Significance Level 
These are set to standard, 
Power = 0.8 
Significance Level (alpha) = 0.05 
 
Metric 
Effect Size used in 
calculation 
Required sample size 
when comparing 
participants’ sessions 
(paired sample) 
Required sample size 
when comparing 
group A to group B 
WOMAC - Function 
bivariate 
0.7127 
18 
32 
WOMAC - Pain 
bivariate 
0.4127 
49 
94 
WOMAC - Function 
Standing/Walking 
bivariate 
0.4527 
41 
78 
 
 

 
 
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Appendix B: Exercise Handout and Calendar 
 
 

 
 
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WEEK 1 
MON 
TUE 
WED 
THURS 
FRI 
SAT 
 Quad 
exercise: 1 set 
of 10 reps 
 Walk: 10 
min 
 Quad 
exercise: 1 set 
of 10 reps 
 
 Quad 
exercise: 1 set 
of 10 reps 
 Walk: 10 
min 
 Quad 
exercise: 1 set 
of 10 reps 
 
 Quad 
exercise: 1 set 
of 10 reps 
 Walk: 10 
min 
REST 
 
WEEK 2 
MON 
TUE 
WED 
THURS 
FRI 
SAT 
 Quad 
exercise: 1 set 
of 10 reps 
 Walk: 10 
min 
 Quad 
exercise: 1 set 
of 10 reps 
 
 Quad 
exercise: 1 set 
of 10 reps 
 Walk: 15 
min 
 Quad 
exercise: 1 set 
of 10 reps 
 
 Quad 
exercise: 1 set 
of 10 reps 
 Walk: 15 
min 
REST 
 
WEEK 3 
MON 
TUE 
WED 
THURS 
FRI 
SAT 
 Quad 
exercise: 1 set 
of 10 reps 
 Walk: 15 
min 
 Quad 
exercise: 1 set 
of 10 reps 
 
 Quad 
exercise: 1 set 
of 10 reps 
 Walk: 15 
min 
 Quad 
exercise: 1 set 
of 10 reps 
 
 Quad 
exercise: 1 set 
of 10 reps 
 Walk: 15 
min 
REST 
 
WEEK 4 
MON 
TUE 
WED 
THURS 
FRI 
SAT 
 Quad 
exercise: 2 sets 
of 10 reps 
 Walk: 15 
min 
 Quad 
exercise: 2 sets 
of 10 reps 
 Quad 
exercise: 2 sets 
of 10 reps 
 Walk: 15 
min 
 Quad 
exercise: 2 sets 
of 10 reps 
 Quad 
exercise: 2 sets 
of 10 reps 
 Walk: 15 
min 
REST 
 
 
 

 
 
CIONC FOR ORTHOPEDICS 
 
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WEEK 5 
SUN 
MON 
TUE 
WED 
THURS 
FRI 
SAT 
REST  Quad 
exercise: 2 
sets of 10 reps 
 Walk: 15 
min 
 Quad 
exercise: 2 
sets of 10 reps 
 Quad 
exercise: 2 
sets of 10 reps 
 Walk: 15 
min 
 Quad 
exercise: 2 
sets of 10 reps 
 Quad 
exercise: 2 
sets of 10 reps 
 Walk: 20 
min 
REST 
 
WEEK 6 
SUN 
MON 
TUE 
WED 
THURS 
FRI 
SAT 
REST  Quad 
exercise: 2 
sets of 10 reps 
 Walk: 20 
min 
 Quad 
exercise: 2 
sets of 10 reps 
 Quad 
exercise: 2 
sets of 10 reps 
 Walk: 20 
min 
 Quad 
exercise: 2 
sets of 10 reps 
 Quad 
exercise: 2 
sets of 10 reps 
 Walk: 20 
min 
REST 
 
WEEK 7 
SUN 
MON 
TUE 
WED 
THURS 
FRI 
SAT 
REST  Quad 
exercise: 3 
sets of 10 reps 
 Walk: 20 
min 
 Quad 
exercise: 3 
sets of 10 reps 
 Quad 
exercise: 3 
sets of 10 reps 
 Walk: 20 
min 
 Quad 
exercise: 3 
sets of 10 reps 
 Quad 
exercise: 3 
sets of 10 reps 
 Walk: 20 
min 
REST 
 
WEEK 8 
SUN 
MON 
TUE 
WED 
THURS 
FRI 
SAT 
REST  Quad 
exercise: 3 
sets of 10 reps 
 Walk: 25 
min 
 Quad 
exercise: 3 
sets of 10 reps 
 Quad 
exercise: 3 
sets of 10 reps 
 Walk: 25 
min 
 Quad 
exercise: 3 
sets of 10 reps 
 Quad 
exercise: 3 
sets of 10 reps 
 Walk: 25 
min 
REST 
 
 
 

 
 
CIONC FOR ORTHOPEDICS 
 
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WEEK 9 
SUN 
MON 
TUE 
WED 
THURS 
FRI 
SAT 
REST  Quad 
exercise: 3 
sets of 10 reps 
 Walk: 25 
min 
 Quad 
exercise: 3 
sets of 10 reps 
 Quad 
exercise: 3 
sets of 10 reps 
 Walk: 25 
min 
 Quad 
exercise: 3 
sets of 10 reps 
 Quad 
exercise: 3 
sets of 10 reps 
 Walk: 25 
min 
REST 
 
WEEK 10 
SUN 
MON 
TUE 
WED 
THURS 
FRI 
SAT 
REST  Quad 
exercise: 2 
sets of 10 
reps, 2x/day 
 Walk: 25 
min 
 Quad 
exercise: 2 
sets of 10 
reps, 2x/day 
 Quad 
exercise: 2 
sets of 10 
reps, 2x/day
 Walk: 30 
min 
 Quad 
exercise: 2 
sets of 10 
reps, 2x/day 
 Quad 
exercise: 2 
sets of 10 
reps, 2x/day
 Walk: 30 
min 
REST 
 
WEEK 11 
SUN 
MON 
TUE 
WED 
THURS 
FRI 
SAT 
REST  Quad 
exercise: 2 
sets of 10 
reps, 2x/day 
 Walk: 30 
min 
 Quad 
exercise: 2 
sets of 10 
reps, 2x/day 
 Quad 
exercise: 2 
sets of 10 
reps, 2x/day
 Walk: 30 
min 
 Quad 
exercise: 2 
sets of 10 
reps, 2x/day 
 Quad 
exercise: 2 
sets of 10 
reps, 2x/day
 Walk: 30 
min 
REST 
 
WEEK 12 
SUN 
MON 
TUE 
WED 
THURS 
FRI 
SAT 
REST  Quad 
exercise: 2 
sets of 10 
reps, 2x/day 
 Walk: 30 
min 
 Quad 
exercise: 2 
sets of 10 
reps, 2x/day 
 Quad 
exercise: 2 
sets of 10 
reps, 2x/day
 Walk: 30 
min 
 Quad 
exercise: 2 
sets of 10 
reps, 2x/day 
 Quad 
exercise: 2 
sets of 10 
reps, 2x/day
 Walk: 30 
min 
REST 
 
 

 
 
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Appendix C: Encouragement During 6-Minute Walk Test 
 
After the first minute, tell the patient the following (in even tones): “You are doing well. You 
have 5 minutes to go.”  
 
When the timer shows 4 minutes remaining, tell the patient the following: “Keep up the good 
work. You have 4 minutes to go.”  
 
When the timer shows 3 minutes remaining, tell the patient the following: “You are doing well. 
You are halfway done.”  
 
When the timer shows 2 minutes remaining, tell the patient the following: “Keep up the good 
work. You have only 2 minutes left.”  
 
When the timer shows only 1 minute remaining, tell the patient: “You are doing well. You have 
only 1 minute to go.”  
 
Do not use other words of encouragement (or body language to speed up). 
 
 

 
 
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Appendix D: Quadriceps Strength Testing 
 
1. With the handheld dynamometer placed distally on the affected leg with the knee in 90 
degrees flexion, participants will push against the dynamometer for 5 seconds.  
2. Subjects will get two warm-up trials separated by a 1-minute rest period.  
3. The first warm up will be 10 repetitions at 50% maximal effort, with contractions to be 
held for 5 seconds.  
4. The second warn up will be 5 repetitions at 70% maximal effort, with contractions to be 
held for 5 seconds.  
5. Subjects will then perform 3 repetitions of maximal effort, separated by two minutes of 
rest between each.  
6. The test will be repeated on the other leg. 
 
 

 
 
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Appendix E: Western Ontario/McMaster Universities Osteoarthritic Index (Physical 
Function) 
 
Think about the difficulty you had in doing the following daily physical activities due to your 
knee during the last 48 hours. By this, we mean your ability to move around and look after 
yourself. 
 
Question: What degree of difficulty do you have? 
 
None Mild Moderate Severe Extreme 
Descending stairs 
Ascending stairs 
Rising from sitting 
Standing 
Bending to the floor 
Walking on flat surfaces 
Getting in and out of a car, or on or off a bus 
Going shopping 
Putting on your socks or stockings 
Rising from the bed 
Taking off your socks or stockings 
Lying in bed 
Getting in or out of the bath 
Sitting 
Getting on or off the toilet 
Performing heavy domestic duties 
Performing light domestic duties 
 
 
 
 
 

 
 
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Appendix F: Western Ontario/McMaster Universities Osteoarthritis Index (Pain) 
 
Think about the pain you felt in your knee during the last 48 hours. 
 
Question: How much pain do you have?  
 
 
None Mild Moderate Severe Extreme 
Walking on a flat surface 
Going up and down stairs 
At night while in bed, pain disturbs your sleep 
Sitting or lying 
Standing upright 
 
 

 
 
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Appendix G: 10-Meter Walk Test 
 
 
 
1. Subjects will walk with/without assistance for 10 meters.  
2. Time will be measured for the intermediate 6 meters to allow for acceleration and 
deceleration. 
3. Timing will start when the toes of the leading foot crosses the 2-meter mark. 
4. Timing will stop when the toes of the leading foot crosses the 8-meter mark. 
5. Assistive devices can be used but should be kept consistent and documented from test to test.  
6. Collect two trials at the subject’s comfortable walking speed, followed by two trials at their 
fast-walking speed.  
7. Trials for each speed will be averaged.  
 
 

 
 
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Appendix H: 6-Minute Walk Test 
 
1. A “warm-up” period before the test should not be performed.  
2. The patient should sit at rest in a chair, located near the starting position, for at least 10 
minutes before the test starts. 
3. During this time, check for contraindications, and make sure that clothing and shoes are 
appropriate. 
4. Instruct the subject as follows: 
“The object of this test is to walk as far as possible for 6 minutes. You will walk 
back and forth in this hallway. Six minutes is a long time to walk, so you will be 
exerting yourself. You will probably get out of breath or become exhausted. You 
are permitted to slow down, to stop, and to rest as necessary. You may lean 
against the wall while resting, but resume walking as soon as you are able.  
 
You will be walking back and forth around the cones. You should pivot briskly 
around the cones and continue back the other way without hesitation. Now I’m 
going to show you. Please watch the way I turn without hesitation.” 
 
Demonstrate by walking one lap yourself. Walk and pivot around a cone briskly.  
 
“Are you ready to do that? I am going to use this counter to keep track of the 
number of laps you complete. I will click it each time you turn around at this 
starting line. Remember that the object is to walk AS FAR AS POSSIBLE for 6 
minutes, but don’t run or jog.  
 
Start now, or whenever you are ready.” 
5. Position the patient at the starting line. You should also stand near the starting line during the 
test. Do not walk with the patient. As soon as the patient starts to walk, start the timer.  
6. Do not talk to anyone during the walk. Use an even tone of voice when using the standard 
phrases of encouragement. Watch the patient. Do not get distracted and lose count of the 
laps. Each time the participant returns to the starting line, click the lap counter once (or mark 
the lap on the worksheet). Let the participant see you do it. Exaggerate the click using body 
language, like using a stopwatch at a race. 
7. Record the number of laps from the counter.  
8. Record the additional distance covered (the number of meters in the final partial lap) using 
the markers on the wall as distance guides. Calculate the total distance worked, rounding to 
the nearest meter.  
9. Congratulate the patient on good effort and offer a drink of water.  
 

 
 
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Appendix I: Five Times Sit to Stand Test 
 
1. To perform the test, the person must sit in a chair, with arms crossed over their chest with 
their back resting on the back of the chair. 
2. The chair should have a straight back, and it is recommended it have a height between 
43-46 cm.  
3. When ordered, the subject should stand up completely and then return to the sitting 
position during 5 repetitions, performing this activity as fast as possible.  
4. Subjects will be timed from the initial sitting position to the final standing position.  
 
 

 
 
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Appendix J: Short Form-36 
 
 

 
 
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