Improving Walking in Peripheral Artery Disease Using Specially Designed Assistive Shoes
Phase: NA
Conditions: Peripheral Artery Disease
Sponsor: VA Office of Research and Development

Amendment No 2: June28, 2021 
Improving 
Walking 
in 
Peripheral 
Artery 
Disease 
ClinicalTrials.gov Identifier (NCT Number): NCT05103280 
 
 
 

Amendment No 2: June28, 2021 
VA Tennis Shoes Protocol 
Title: Improving Walking in Peripheral Artery Disease, Using Specially Designed 
Assistive Shoes 
Objective: The objective of this research is to evaluate the ability of different specially 
designed tennis shoes to improve walking performance, muscle oxygenation of patients 
with peripheral artery disease (PAD). 
Hypothesis: We hypothesize that the specially designed tennis shoes will provide 
assistance to the ischemic legs of patients with PAD and will therefore reduce the 
biological contribution and oxygen requirements of the ischemic leg muscles. This will 
acutely increase the walking performance, muscle oxygenation in the patients.  
If our hypothesis is correct, the carbon fiber insole shoes and spring shoes may become 
a new effective conservative intervention for patients with PAD. However, if none of the 
components of our hypothesis are correct, then our study would direct us away from the 
carbon fiber insole shoes and/or spring shoes and toward other therapies. 
We also hypothesize that an intervention with specially designed tennis shoes (spring 
loaded or carbon fiber insole shoes) will increase physical activity, and improve walking 
performance and quality of life. Our preliminary results show promising results in 
increasing the walking distances including initial claudication distances and absolute 
claudication distances during first-time use of the specially designed tennis shoes. 
Subjects will complete a 3month intervention with their preferred specially designed tennis 
shoe based on the initial data collection. They will be tested prior to starting the 
intervention and after 3 months of the intervention. 
Endpoints measured: The patients will walk while wearing their own walking shoes, the 
carbon fiber insole shoes and the spring-loaded shoes (in random order) and we will 
measure the following performance endpoints for both phases: 
1) Initial and maximum claudication distance on our instrumented treadmill 
using the Gardner protocol: Subjects will complete a Gardner treadmill walking. 
Subjects will walk in a dynamic gait and pressure analysis treadmill (FDMT Scifit 
AC500M, Noraxon USA,Inc., Scottsdale Ariz) located at the VA Medical center at 
Omaha. This treadmill collects synchronized pressure measurements allowing for 
gait analysis and the calculation of steps taken during exercise. Participants 
initiated exercise at 2.0 miles per hour at 0.0% incline. With each subsequent 2-
minute stage, the treadmill incline was increased 2.0% to a maximum of 12.0%. 
Time of initial symptoms (claudication onset time [COT] and time at which 
claudication symptoms were prohibitive to further walking [peak walking time] will 
be recorded. Data will be collected using regular shoes and specially designed 
(carbon fiber insole shoes and spring) shoes. They will be allowed to rest for 15 
minutes between tests. Patients will do 3 walks in the treadmill (regular walking 
shoes, carbon fiber insole shoes, and spring shoes). 

Amendment No 2: June28, 2021 
2) Calf muscle saturation at one-minute walking: Bilateral gastrocnemius muscle 
oxygenation (StO2) will be measured using continuous-wave near infrared spectroscopy 
(PortaMon, Artinis Medical System, Netherlands) before, during and after each treadmill 
walking condition (described above). Measurements will be continuously captured during 
the exercise and recovery interval. We will measure resting StO2 and StO2 at 1-minute 
walking.  
3) Vertical ground reaction forces in the first two minutes of walking: Biomechanical 
data will be collected with a dynamic gait and pressure analysis treadmill (FDMT SciFit 
AC5000M, Noraxon USA, Inc.). The parameter measured will be the vertical ground 
reaction force. 
4) We will use the Borg Rating of Perceived Exertion (RPE) questionnaire after each 
condition 
5) Physical Activity: Participants will wear the Actigraph (Actigraph GT3X, Actigraph, 
FL, USA) accelerometer on their hip for seven days (the whole day except when sleeping) 
prior to starting the intervention phase to measure baseline activity level and seven days 
after the intervention phase to measure post-intervention physical activity. Average 
steps/day, maximum cadence, and average peak activity index will be calculated. 
6) Questionnaires: At the end of the study subject will be interviewed and asked to fill 
out survey questionnaires to assess acceptability, demand, implementation, and 
practicability. This interview will be held via phone call. 
Research Design: This study will be a prospective clinical trial. 
Background:                                                                                                                                  Peripheral 
Arterial Disease (PAD) affects approximately 8.5 million of people age 40 and older in the 
United Stated according to the CDC (Benjamin 2019). Intermittent claudication (IC) is the 
most common presentation of PAD. Intermittent claudication presents as cramping pain, 
occurring in the calves, thighs and/or buttocks brought on by physical activity and relieved 
with rest (Myers 2016). This impairment is of major importance primarily because it 
restricts the physical activity of PAD patients, leading to further adverse effects on their 
general health and quality of life (Hernandez 2019). Recently IC has been identified as 
an ambulatory disorder. Previous studies done by our group demonstrate that patients 
with clinically diagnosed femoro-popliteal PAD have significant ankle motion alterations 
with abnormal ankle joint kinematics. Celis et at demonstrate that PAD patients had 
evidence of significant ambulatory abnormalities even when not experiencing any 
claudication pain. The abnormalities contributing to the baseline gait dysfunction are 
complex and include axonal nerves loss (Koopman1996)(Laghi1996) and mitochondrial 
dysfunction (Pipinos2007)(Pipinos2006)(Pipinos2000). Ischemia superimposed to this 
issue would then result in variability worsening gait resulting in an increased work 
requirement and energy cost.  

Amendment No 2: June28, 2021 
Despite the functional limitations present in PAD, only few medical therapies exist for 
improving walking performance and preventing mobility loss in patients with PAD. 
Exercise training has been demonstrated to improve PAD symptoms and is 
recommended as first line therapy for PAD. The carbon fiber insole tennis shoe is 
designed with a full-length, carbon fiber plate underfoot that is supposed to provide a 
propulsive sensation to help to push the pace. Hoogkamer et al reported that this tennis 
shoe lowered the energetic cost of running by 4% on average (Hoogkamer 2018).  The 
spring-loaded shoe has a shock-absorbing springs in the soles that relieve the stress and 
fatigue from athletic activities.  In this study, we want to evaluate the effectiveness of 
these two specially designed tennis shoes and determine if they improve walking 
performance and/or reduce walking work requirement in PAD patients compared to 
regular walking shoes. 
 
Methodology: 
Recruit 30 willing patients with peripheral vascular disease and claudication at the 
vascular surgery clinic at the Nebraska and Western Iowa Veterans Affairs Medical 
Center (VANWIHCS) in Omaha.10 patients will be recruited from the total 30 patients for 
the intervention phase and rest of the 20 patients will only participate in the baseline 
phase . Patients will be evaluated by a Board-Certified Vascular Surgeon to determine if 
they have PAD and whether they are eligible to participate in the study the study. Subject 
will be consented prior to the study. 
1. Inclusion/Exclusion Criteria 
Inclusion criteria: At entry into the study, all subjects must: 
a. Be able to provide written, informed consent 
b. Demonstrate positive history of chronic claudication 
c. Demonstrate exercise-limiting claudication established by history and direct 
observation during a screening walking test administered by the evaluating 
vascular surgeon 
d. Have an ankle/brachial index <0.90 at rest 
e. Have a stable blood pressure regimen, stable lipid regimen, stable diabetes 
regimen, and risk factor control for 6 weeks 
Exclusion criteria: Any potential subjects will be excluded if they have: 
a. Rest pain or tissue loss due to PAD (Fontaine stage III and IV) 
b. Acute lower extremity ischemic event secondary to thromboembolic 
disease or acute trauma 
c. Walking capacity limited by conditions other than claudication, including 
leg and systemic pathology 
2. Patients will perform Gardner protocol on the pressure treadmill at the VA at 
Omaha, NE.  
a. Normal walking shoes 

Amendment No 2: June28, 2021 
b. Carbon fiber insole shoes 
c. Spring loaded shoes 
3. Clinical data to be collected 
a. ABI  
b. Medical conditions/comorbidities  
4. Voluntary Data Repository- If the patient agreed a study and health data will be de-
identified and store in a special VA research drive only available to authorized 
research personnel. Information will be used for future studies about PAD or other 
vascular diseases. If the patient agrees he will be asked to sign a special HIPPA 
form. 
 
Statistical Analysis: The sample size was calculated to detect effect sizes observed in 
pilot data for ankle plantarflexor push off. A sample size of 30 subjects will provide 79% 
power to detect differences of 0.30 standard deviations between walking with control and 
assistive tennis shoes, using a paired t-test for sample size estimation purposes only, and 
a significance level of 0.02 to informally adjust for multiple testing. For statistical analysis, 
a linear (or generalized linear, as appropriate) mixed modeling approach will be used. 
This approach will allow us to detect differences between walking with and without an 
AFO while adjusting for confounding variables. The level of significance will be set at 0.05. 
 Descriptive statistics will be used to summarize results of survey data. We will use counts 
and percents for categorical data and means and standard deviations for quantitative 
data. Associations between walking performance and comfort, fatigue, perceived 
intensity, and feasibility variables will be examined using t-tests for dichotomous variables 
and correlations for continuous variables. Comparisons will be done independently for 
each shoe type. 
We expect differences from a 3-month intervention to be larger than the immediate 
differences shown in Aim 1. A sample size of 30 subjects would provide 80% power to 
detect differences of 0.59 standard deviations between walking with and without assistive 
tennis shoes, using a paired t-test for sample size estimation purposes only, and a 
significance level of 0.025 to adjust for multiple testing. For this pilot study, we plan to 
collect 10 subjects after the intervention and seek additional funding to fully power the 
study.  
For statistical analysis, a linear mixed modeling approach (or generalized linear mixed 
model, as appropriate) will be used. This approach will allow us to detect differences 
within and between groups (different types of assistive shoes), and adjust for confounding 
variables. The main comparison of interest will be changes in walking distances due to 
wearing the assistive shoes. This pilot study will allow us to detect if walking distances 
improve after wearing the assistive shoes for 3-months. To evaluate the relationship 
between improvements in walking performance, physical activity, and quality of life, 
multiple correlations will be used. The level of significance will be set at p=0.05. 

Amendment No 2: June28, 2021 
 
Assumptions for sample size calculations to obtain 80% power. The test statistic is a two-
sided paired t-test with an assumed correlation between mean 1 and mean 2 of 0.30. The 
alpha level is assumed as 0.001 to account for multiple comparisons between the different 
shoe types. Mean 1 is assumed as normal walking the control shoe and mean 2 is walking 
in the best assistive shoe. Choosing the largest sample size across all measures will 
ensure the desired power for all outcome measures*14. 
References: 
1- Benjamin EJ, Muntner P, Alonso A, Bittencourt MS, Callaway CW, Carson AP, et 
al. Heart disease and stroke statistics—2019 update: a report from the American 
Heart Association. Circulation. 2019;139(10):e56–528. 
2- Myers SA, Applequist BC, Huisinga JM, Pipinos II, Johanning JM. Gait kinematics 
and kinetics are affected more by peripheral arterial disease than age. J Rehabil 
Res Dev.2016;53(2):229-238. 
3- Hernandez H, Myers SA, Schieber M, Ha DM, Baker S, Koutakis P, Kim KS, Mietus 
C, Casale GP, Pipinos II. Quantification of Daily Physical Activity and Sedentary 
Behavior of Claudicating Patient. Ann Vasc Surg. 2019 February; 55: 112–121 
4- Celis R, Pipinos II, Scott-Pandorf MM, Myers SA, Sterguio N, Johanning JM. 
Peripheral arterial disease affects kinematics during walking. J Vasc Surg. 
2009;49(1):127-132 
5- Koopman J.P., de Vries A.C., and de Weerd A.W.: Neuromuscular disorders in 
patients with intermittent claudication. Eur J Surg 1996; 162: pp. 443-446 
6- Laghi Pasini F., Pastorelli M., Beermann U., de Candia S., Gallo S., Blardi P., and 
Di Perri T.: Peripheral neuropathy associated with ischemic vascular disease of 
the lower limbs. Angiology 1996; 47: pp. 569-577 
7- Pipinos I.I., Judge A.R., Selsby J.T., Zhu Z., Swanson S.A., Nella A.A., and Dodd 
S.L.: The myopathy of peripheral arterial occlusive disease: part 1. Vasc 
Endovascular Surg 2007; 41: pp. 481-489 
8- Pipinos I.I., Judge A.R., Zhu Z., Selsby J.T., Swanson S.A., Johanning J.M., et al: 
Mitochondrial defects and oxidative damage in patients with peripheral arterial 
disease. Free Radic Biol Med 2006; 41: pp. 262-269 
9- Pipinos I.I., Shepard A.D., Anagnostopoulos P.V., Katsamouris A., and Boska 
M.D.: Phosphorus 31 nuclear magnetic resonance spectroscopy suggests a 
mitochondrial defect in claudicating skeletal muscle. J Vasc Surg 2000; 31: pp. 
944-952 
Outcome measure 
Mean 1 
Mean 2 
Difference 
Standard 
Deviation 
Power 
Required 
Sample 
Size 
Push-off11 
1.4 
1.7 
-0.3 
0.30 
0.79 
29 
Visual 
analog 
scale12 
5.0 
7.0 
-2.0 
2.00 
0.81 
30 
Borg (scenario 2)13  
14.0 
11.0 
3.0 
2.50 
0.81 
23 

Amendment No 2: June28, 2021 
10- Hoogkamer W, Kipp S, Frank JH, Farina EM, Lou G, Kram R. A Comparison of the 
Energetic Cost of Running in Marathon Racing Shoes. Sports Med 2018;48:1009-
1019 
11- Collins SH, Wiggin MB, Sawicki GS. Reducing the energy cost of human walking 
using 
an 
unpowered 
exoskeleton. 
Nature. 
2015;522(7555):212-215. 
doi:10.1038/nature14288. 
12- Nilsson A, Vreede K, Häglund V, Kawamoto H, Sankai Y, Borg J. Gait training early 
after stroke with a new exoskeleton – the hybrid assistive limb: a study of safety 
and feasibility. J Neuroeng Rehabil. 2014;11(1):92. doi:10.1186/1743-0003-11-92. 
13- Miller L, Zimmermann A, Herbert W. Clinical effectiveness and safety of powered 
exoskeleton-assisted walking in patients with spinal cord injury: systematic review 
with 
meta-analysis. 
Med 
Devices 
Evid 
Res. 
2016;9:455-466. 
doi:10.2147/MDER.S103102. 
14- Edwards D, Berry JJ. The Efficiency of Simulation-Based Multiple Comparisons. 
Biometrics. 1987;43(4):913-928. doi:10.2307/2531545.