Leg Thermotherapy for Intermittent Claudication
Phase: NA
Conditions: Peripheral Artery Disease
Sponsor: Indiana University

Study #1601589496 
Version Date:  03/30/2018 
 
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Leg thermotherapy for intermittent claudication 
 
 
NCT02770547 
 
 
Document Version: 12/11/2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Study #1601589496 
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Leg thermotherapy for intermittent 
claudication 
 
 
Principal Investigator: 
 
Dr. Raghu L Motaganahalli MD FRCS FACS 
Assistant Professor -Program Director 
Division of Vascular Surgery 
Indiana University School of Medicine 
Indianapolis 
Ph: 317-962-2300  
Fax: 317-962-0289 
 
Co-investigator 
 
Bruno Tesini Roseguini 
Assistant Professor 
Department of Health and Kinesiology 
Purdue University 
800 W. Stadium Ave.  
West Lafayette, IN – 47907 
Ph: 765-496-2612 
 
 
 
 
 
 
 
 

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Table of Contents: 
 
Study Schema 
1.0 
Background 
2.0 
Rationale and Specific Aims 
3.0 
Inclusion/Exclusion Criteria 
4.0 
Enrollment/Randomization 
5.0 
Study Procedures 
6.0 
Reporting of Adverse Events or Unanticipated Problems involving Risk 
to Participants or Others 
7.0 
Study Withdrawal/Discontinuation 
8.0 
Statistical Considerations 
9.0 
Privacy/Confidentiality Issues 
10.0 Follow-up and Record Retention 
 
 

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1.0 
Background 
 
Peripheral arterial disease (PAD) is characterized by atherosclerotic obstruction of 
the arteries in the lower extremities and affects approximately 10% of individuals older 
than 65 years. The most common clinical presentation of PAD is intermittent claudication 
(IC), defined as leg pain caused by insufficient blood flow during walking. Individuals 
with IC have severe exercise intolerance and markedly reduced levels of daily 
ambulatory activity. It is estimated that up to 40 million people worldwide suffer from 
IC. Despite the increasing prevalence of this condition, few medical therapies improve 
mobility and exercise tolerance in these patients. Cilostazol is the only effective 
medication available to treat IC. Unfortunately, this drug has multiple side effects, and 
the overall improvement in walking performance after long-term treatment is small. 
Supervised treadmill exercise is the best single treatment for IC, but the need for frequent 
visits to a clinical facility over an extended time period makes this option challenging for 
the vast majority of patients. Endovascular and surgical interventions are also effective 
alternatives for patients that do not respond sufficiently to medical therapy; however, 
these procedures are costly, only applicable to patients with certain lesion types and are 
associated with a high risk of restenosis. An urgent need remains for the development of 
novel, non-invasive strategies that are more widely accessible and eliminate the need for 
supervision and frequent traveling to a clinical facility. 
 
2.0 
Rationale and Specific Aims 
 
We propose to evaluate the potential of leg thermotherapy (TT) as a non-pharmacological 
intervention that could improve the mobility and exercise tolerance of patients with IC.  
Thermotherapy (TT) is a simple, easily applicable therapy that enhances exercise 
tolerance in patients with chronic heart failure (CHF) by improving peripheral vascular 
endothelial function. Indeed, recent studies of both healthy individuals and patients with 
CHF have demonstrated that TT promotes a blood flow-dependent improvement in 
vascular endothelial function in the microcirculation and in conduit arteries. In a 
preclinical model of IC, TT accelerates blood flow recovery and increases vascularization 
in the ischemic muscles. This compelling evidence predicts that TT could have 
significant benefits for patients with IC. Indeed, since this intervention is non-
pharmacological, there is high potential for this work to rapidly translate into clinical 
practice and improve patients’ lives. In preliminary studies (IRB Protocol #1409063619), 
we have demonstrated application of TT for 90 min increased leg skin temperature by 
~7ºC, core body temperature by ~0.6°C and evoked a marked reduction in systolic (~12 
mmHg) and diastolic (~6 mmHg) blood pressure when compared to the control 
intervention (Figure 1). In addition, leg TT application induced a marked increase in leg 
blood flow in these patients. Based on these compelling preliminary findings, our goal is 
to evaluate the impact of 6 weeks (3 sessions/week) of TT treatment on vascular function 
and walking tolerance in patients with IC. We hypothesize that treatment with TT will 
enhance walking tolerance in patients with IC by improving endothelial function and 
therefore increasing leg oxygenation during exercise. Thermotherapy will be applied 
using water-circulating ‘pants’ connected to a water pump. These garments are made of a 
tight-fitting elastic fabric, with an extensive network of medical grade polyvinyl chloride 

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tubing sewn onto the fabric, and a portable pump that circulates hot water throughout the 
garment. This is the same system we employed in our initial study in 16 patients with IC 
(IRB Protocol #1409063619). We have shown that this system is safe and well tolerated 
by patients with IC. Before and after the treatment, we will examine the following 
outcomes: 1) cutaneous microvascular function (Laser Doppler flowmetry), 2) reactive 
hyperemia in the popliteal artery (phase-contrast magnetic resonance imaging of the 
popliteal artery, 3) calf muscle oxygenation during exercise (near-infrared spectroscopy) 
and 4) walking distance (6-min walking test). 
 
Figure 1: Physiological responses to acute thermotherapy application in patients with 
intermittent claudication (n=16, IRB# 1409063619). Patients underwent a single 90-min 
session of TT or a control treatment and physiological variables were measured before, 
during and for 2 hours after the intervention. 
 
3.0 
Inclusion/Exclusion Criteria 
 
Inclusion criteria 
 
- 
Men and women with a stable symptomatic claudication for ≥6 months 
- 
Ankle brachial index <0.9 

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Exclusion criteria 
 
- 
Uncontrolled Diabetes (HbA1C > 8.5 measured within 3 months prior to date of 
consent)  
- 
Heart Failure 
- 
COPD 
- 
Critical limb ischemia (ischemic rest pain or ischemia-related non healing wounds 
or tissue loss 
- 
Prior amputation 
- 
Exercise-limiting comorbidity (i.e., angina, chronic lung disease, or arthritis) 
- 
Recent (<3 months) infrainguinal revascularization (surgery or endovascular 
revascularization) or revascularization planned during study period. 
- 
Plans to change medical therapy during the duration of the study 
- 
Active cancer 
- 
Chronic kidney disease (eGFR <30 by MDRD or Mayo or Cockcroft-Gault 
formula). 
- 
HIV positive, active HBV or HCV disease. 
- 
Presence of any clinical condition that in the opinion of the principal investigator 
makes the patient not suitable to participate in the trial. 
- 
Peripheral neuropathy, numbness, or paresthesia in the legs. 
- 
Morbid obesity BMI > 36 or unable to fit into water-circulating pants. 
- 
Open wounds or ulcers on the extremity. 
 
As this study involves MR imaging, patients that have contraindications to MRI will 
be included in the study but will not be allowed to participate in the MRI procedure. 
Information about biomedical devices that may pose a risk to patients undergoing MRI is 
available on the Internet at www.MRIsafety.com. These exclusions include: 
 
- 
Cardiac pacemaker 
- 
Implanted cardiac defibrillator 
- 
Aneurysm clips 
- 
Carotid artery vascular clamp 
- 
Neurostimulator 
- 
Insulin or infusion pump 
- 
Implanted drug infusion device 
- 
Bone growth/fusion stimulator 
- 
Cochlear, otologic, or ear implant 
- 
 History of claustrophobia or who are unable to lie flat or who do not fit inside the 
bore of the scanner  
 
4.0 
Enrollment/Randomization 
 
Patients that fulfill the inclusion criteria and are interested in participating in the 
protocol will receive detailed instructions about the experimental set-up and 

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measurements and will be given a consent form. Once deemed eligible, patients will be 
asked to complete the baseline assessment. After the initial testing is complete, patients 
will be randomly allocated into one of two groups: low-heat therapy (control) and high-
heat therapy. Medical devices and alternative therapies, such massage and thermal-
treatments have shown to be associated with high placebo responses (1). In order to 
control for this important psychological response, it is imperative to incorporate an 
appropriate placebo/sham intervention (1). In the present study, we will adopt strategies 
to minimize the potential confounding effect of psychological and perceptual responses 
to heat therapy. First, participants will be informed that the purpose of the study is to 
compare two ‘intensities’ of heat treatment. In the low-heat group, water at 33ºC will be 
circulated through the garment during the treatment sessions. In our initial study (IRB 
Protocol #1409063619) we observed that this strategy evokes a small increase (~0.9ºC) 
in leg skin temperature. In the high-heat group, hot water will be circulated through the 
garment during the treatment sessions with the goal of increasing skin temperature to 
40ºC, as observed in our initial study. A random allocation software (Research 
Randomizer, Social Psychology Network, http://www.randomizer.org/) will be used to 
perform the randomization. 
 
5.0 
Study Procedures 
 
After enrollment, subjects will be asked 
to complete two experimental sessions for 
baseline testing. The procedures involved in 
each visit, location and estimated duration are 
listed on Table 1. On visit 1, demographic and 
anthropometric 
characteristics 
from 
participants will be initially recorded. Subjects 
will then be asked about comorbid conditions, 
claudication history, and current medications 
and will fill out two questionnaires to assess 
generic (36-item Short-Form Health Survey) 
and disease-specific (Walking Impairment 
Questionnaire) quality of life. Next, subjects 
will be escorted to the examination room and will be asked to rest quietly for 15 min in 
the supine position. During this time, four NIRS (near infrared spectroscopy) sensors 
(Figure 2) will be attached to subjects’ two fingertips and two toes (left and right). These 
sensors are the same as the pulse oximeters used regularly in the hospital. We will 
monitor the blood flow during these 15 minutes while subjects are resting. After this rest 
period, systolic blood pressure will be measured in the arms (brachial artery) and ankles 
(posterior tibial and dorsalis pedis arteries) for the determination of the ankle brachial 
index. Subjects will then be familiarized with the 6-min walking test. A near-infrared 
spectroscopy (NIRS) system will be placed on the calf of the most symptomatic leg for 
monitoring leg oxygenation during the test. This exercise test consists of walking back 
and forth along a 100-ft corridor for 6 min. This session will be performed at the CTSI’s 
Clinical Research Center on the 5th floor of Goodman Hall and is expected to last 
approximately 2 hours. 
Figure 2: Multichannel NIRS used 
to monitor the blood flow at two 
toes and two fingertips. 

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Visit 2 will involve the assessment of the primary study outcomes, including 
vascular function and exercise tolerance. This session is expected to last approximately 4 
hrs. Subjects will be asked to fast overnight prior to attending this session but will be 
permitted to take their usual morning medication regimen. The first exam will be the 
assessment of leg blood flow responses to circulatory occlusion (reactive hyperemia) 
using magnetic resonance imaging. This test will be performed at the Imaging Research 
Facilities in the basement of Goodman Hall. Next, subjects will be escorted to the CTSI’s 
Clinical Research Center on the 5th floor. Subjects will initially be asked to lay supine 
and a nurse will place a catheter in one antecubital vein in the arm for venous blood 
sampling. After 10 min of rest, systolic blood pressures in the arms and in the ankles will 
be measured for the determination of the ankle-brachial index. Once the measurements 
are complete, a blood sample (20 ml) will be taken and the catheter will be removed. 
Next, subjects will be instrumented with laser Doppler probes placed inside local heaters 
for the assessment of cutaneous vascular reactivity. Two probes will be placed on the 
front portion of the most symptomatic leg and secured in place with tape. The sites where 
the probes are placed will be marked with a pen to allow for consistent placement in the 
second and third outcome measurement visits. The protocol consists of heating a site in 
the skin and measuring the changes in cutaneous red blood cell flux in response to the 
thermal challenge. Blood pressure and heart rate will be monitored during the test. This 
procedure will last approximately one hour. Next, the patients will perform the 6-min 
walking test. A near-infrared spectroscopy system, which measures skeletal muscle 
oxygenation, will be placed on the calf of the most symptomatic leg, secured in place 
with tape and covered with aluminum foil and a black Velcro strap. Similar to the laser 
Doppler probes, pen marks will be used identify the location of the probe. Subjects will 
be asked to walk back and forth along a 100-ft corridor for 6 min and report when the 
pain first appears. After the test is completed, subjects will be asked to grade the severity 
of the pain in the most symptomatic leg using the Borg-scale. 
 
Visit # 
Procedures 
Location 
Duration  
1 
1) Medical 
History 
and 
Physical 
Examination 
2) Quality of life assessment 
3) Measurement of ankle-brachial index 
4) Familiarization 
with 
the 
6-min 
walking test 
CTSI’s 
Clinical 
Research Center at 
Goodman Hall 
2 hrs 
2 
1) Leg MRI (reactive hyperemia) 
2) Catheter placement and venous blood 
draw 
3) Measurement of ankle-brachial index 
4) Assessment of cutaneous vascular 
function 
5) 6-min walking test 
Imaging Research 
Facilities 
and 
CTSI’s 
Clinical 
Research Center at 
Goodman Hall 
4 hrs 
Table 1: Procedures involved, location and estimated duration of visits 1 and 2. 
 
 
After the baseline assessment is complete, subjects will be randomly allocated to 
one of two groups using a random allocation software. Participants will be asked to 

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attend 3 treatments sessions/week for 6 consecutive weeks. These sessions will be 
conducted at the CTSI’s Clinical Research Center at Goodman Hall and will last 
approximately 110 min. A research 
coordinator will supervise the patients during 
the sessions. On each session, subjects will 
initially have their body weight and blood 
pressure measured and recorded. Next, 
patients will be asked to change into the 
water-circulating pants (Figure 3) and lay in 
a 
semi-recumbent position. The garments will 
be connected to the water pump and the 
treatment will be applied for 90 min. In the 
high-heat group, hot water will be circulated 
through the garment with the goal of 
increasing skin temperature to 40ºC, while 
thermoneutral water (33ºC) will be used in 
the low-heat group. Subjects will be allowed to drink water ad libitum during the sessions 
but will not be allowed to consume food. At the end of the session, body weight and 
blood pressure will once again be recorded. The research coordinator will measure 
temperature (sublingual measurements) and blood pressure every 15 minutes during the 
treatment and will also inspect the skin in the legs to look for potential signs of injury or 
adverse reactions to the treatment.  The subject will be asked to complete a heat sensation 
scale every 15 minutes during the treatment.  The research coordinator will clean the 
garment after each use using a hospital-grade disinfectant spray. The garment will also be 
washed in a washing machine every week. 
 
 
Outcome measurements will be repeated after 9 sessions (3 weeks) and at the end 
of the treatment period (18 sessions). The protocol for these visits will be similar to visit 
2, with the addition of quality of life assessment. The procedures involved are detailed on 
table 2. This visit is expected to last approximately 4.5 hrs. Subjects will be asked to fast 
overnight prior to attending this session but will be permitted to take their usual morning 
medication regimen. 
 
Visit # 
Procedures 
Location 
Duration  
3 and 
4 
1) Leg MRI (reactive hyperemia) 
2) Catheter placement and venous blood 
draw 
3) Measurement of ankle-brachial index 
4) Quality of life assessment 
5) Assessment of cutaneous vascular 
function 
6) 6-min walking test 
Imaging Research 
Facilities 
and 
CTSI’s 
Clinical 
Research Center at 
Goodman Hall 
4.5 hrs 
Table 2: Procedures involved, location and estimated duration of visits 3 and 4. 
 
Outcome Measures: 
 
 
Figure 3: Water-circulating garment 
system for thermotherapy application 

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Reactive Hyperemia in the Popliteal Artery: Blood flow in the popliteal artery of the most 
symptomatic leg will be measured using MRI. We employed this technique in our initial 
study (IRB Protocol #1409063619). After the knee coil and the occlusion cuff are 
positioned on the most symptomatic leg, participants will be allowed to rest quietly for 15 
min. Resting leg blood flow measurements and brachial systolic blood pressures will be 
completed every 5 min during this period. Next, a blood pressure cuff firmly wrapped 
around the lower thigh will be inflated to 75 mmHg above systolic blood pressure, or 250 
mmHg, whichever is lower, for 5 min (8). Hyperemic flow will be measured for 10 min 
after cuff deflation. Flow reserve will be defined as the absolute difference between 
maximum hyperemic flow after cuff release and resting flow (9). 
 
Cutaneous Microvascular Function: Laser-Doppler flowmetry probes, seated in the 
center of local skin heaters (Moor Instruments, UK), will be used to measure red blood 
cell flux, an index of skin blood flow (SkBF). Baseline SkBF will be recorded for 10 min 
after which local skin temperature will be increased to 39°C (0.1°C/s) and maintained at 
this level until a plateau is achieved (~40 min). Next, the local skin temperature will be 
elevated to 43°C, to induce maximal vasodilation. Cutaneous vascular conductance 
(CVC) will be calculated as laser-Doppler flux divided by mean arterial pressure (MAP), 
measured throughout the study via brachial artery oscillation, and normalized to maximal 
vasodilation (%CVCmax) (10, 11). 
 
6-min Walking Test.: Participants will receive standardized instructions and will be asked 
to walk the greatest distance possible by walking back and forth along a 100-ft corridor 
for 6 min (4). 
 
Measurement of Muscle Oxygenation: The microvascular oxygenation status of the 
gastrocnemius muscle of the most symptomatic leg will be monitored with near-infrared 
spectroscopy (NIRS), as described recently by our group (7). The optode holder of a 
portable NIRS system (The PortaMon Mk II, Artinis Medical Systems, Netherlands) will 
be placed on the medial gastrocnemius, and the concentration of deoxygenated 
hemoglobin + myoglobin [deoxy-Hb+Mb] will be measured continuously during the 6-
min walking test (7). 
 
Quality of life assessment: The 36-item Short-Form Health Survey domain scores for 
physical functioning, physical role function (i.e., limitations due to physical problems), 
bodily pain, and general health perceptions on a scale from 0 (severe limitation) to 100 
(no limitation). In addition, self-reported ambulatory ability will be obtained with a 
validated questionnaire for PAD patients that assesses ability to walk at various speeds 
and distances and to climb stairs. 
 
Potential risks to subjects: 
 
6-minute walking test: Exercise-induced pain is a hallmark feature of intermittent 
claudication and therefore exercise tests are used as a diagnostic tool as well as well for 
the assessment of claudication severity and functional status of the patient (4). Typically 
patients experience ischemic pain in the foot, calf, thigh or buttocks during the test. The 

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pain is temporary and subsides within a couple of minutes after the test is terminated (4). 
The 6-minute walk test has been validated as an outcome measure and is increasingly 
recognized as a meaningful outcome measure in patients with PAD (4). The tests will be 
performed according to available guidelines from the American Thoracic Society (3). 
When performed following these guidelines, the 6-minute walking test is reported to be 
very safe and reflect walking in the daily life of the patients (4). However, there is a 
chance that patients may experience: 1) chest pain, 2) intolerable dyspnea, 3) leg cramps, 
4) staggering, 5) diaphoresis, and 6) dizziness. The investigators will monitor the patients 
closely to test. Patients will be asked to stop walking and sit on a chair if any of these 
symptoms occur.  
 
Leg heating: Hot water (47-50ºC) will be perfused through the water-circulating garment 
with goal to increase skin temperature in the calf to 40ºC. It is possible that the tubes in 
contact with the skin could cause discomfort due to a sensation of warmth/heat. Should 
the tubing that is in contact with the skin cause discomfort we will readjust the suit or 
turn down the temperature of the water. Ninety minutes of heating will likely lead to skin 
redness and flushing, which are typical responses to local heating. These effects are 
temporary and will fade once the heating stimulus is terminated.  Once instance of skin 
being burned to the point of blistering has occurred.  The research coordinator will 
examine the patient’s skin during each treatment session for potential signs of injury or 
adverse reactions to the treatment. 
 
A sophisticated, research-grade heated bath circulator will be used to circulate water 
through the garment. The actual device we use (SC100) and its technical specifications 
are displayed in the document entitled “SAHARA S21 Stainless-Steel Heated Bath 
Circulators.” The temperature stability of this heated bath circulator is 0.02ºC. This is a 
remarkably small variation, which supports the notion that there are no risks of sudden 
oscillations water temperature.  
 
The actual temporal behavior of skin temperature during 90-minutes of thermotherapy 
application is shown on the figure on page 4 of the protocol. There are no abrupt changes 
in temperature. The response follows an exponential rise to a peak of around 39.5ºC at 90 
minutes. This temperature is safe and far below the temperature required to burn the skin, 
which is typically above 43ºC. 
 
Our initial study revealed that the proposed protocol leads to a progressive increase in leg 
skin temperature from a baseline of 33ºC to ~39.5ºC.  A research coordinator will 
supervise each treatment session. If the patient experiences any discomfort or burning 
sensations, the coordinator will readjust the suit or turn down the temperature of the 
water.  Subjects will be reminded to remain in a semi-recumbent position during 
treatment and will also be asked to rate heat sensation every 15 minutes using a thermal 
sensation scale to monitor for excessive heat levels on the skin.  If subject reports a grade 
of 3 ("Hot") or above, or any discomfort, the coordinator will readjust the suit and turn 
down the temperature of the water. If, after reducing the temperature and readjusting the 
suit the patient again reports a grade of 3, we will keep repeating the aforementioned 
steps until the score drops down and the patient feels comfortable.  Water temperature 

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will be assessed and recorded every 15 minutes using the temperature display on the 
pump. 
 
In preliminary experiments we observed that thermotherapy application induces a minor 
reduction in blood pressure in some patients. The research coordinator will measure 
blood pressure prior to and every 15 minutes throughout the application. If the patients 
experience dizziness, lightheadedness or any other symptom of hypotension, the therapy 
will be terminated and the participant will be placed supine with the legs elevated. Blood 
pressure will be checked every 5 minutes until the symptoms disappear and blood 
pressure returns to baseline levels. 
 
Venous blood sampling: During catheter insertion there is a risk of pain from the needle. 
Bleeding, local swelling, bruising and formation of a hematoma might also occur around 
puncture site. By using appropriate phlebotomy techniques, the risks associated with 
catheter placement and repeated sampling are minimized.  
 
Blood pressure measurements: There are no risks associated with the blood pressure 
measurements. 
 
Measurement of calf muscle oxygenation: There are no risks associated with blood 
pressure measurements. 
 
MRI scan: Potential risks associated with MR imaging include: 
- 
Claustrophobia: the confining conditions of the MR scanner can cause 
claustrophobia. If the patient experiences claustrophobia the scan will be stopped. 
- 
Nerve stimulation: Some subjects undergoing the rapid scanning procedures 
which will be used in this scan have experienced minor nerve stimulation effects, 
such as muscle twitches and tingling sensations.  
- 
Hearing: The MR scanner produces tapping sounds during operation, which may 
reach objectionable levels. To minimize any discomfort, subjects will be provided 
with disposable earplugs or headphones 
- 
Collision hazard: The magnetic field near the MR Scanner is strong enough to 
attract objects containing iron with great force. Near the magnet this force can be 
strong enough to pull objects in and cause them to fly down into the magnet. Such 
objects can become projectiles that can cause injury or death. We have established 
a security zone to prevent objects containing iron from coming into proximity of 
the magnet. 
- 
Radio-wave effects: If metal wires or electrodes, such as electrocardiograph 
(ECG) leads are attached to a person being imaged, the radio-wave energy 
radiated by the imaging coils of the MR scanner may induce sufficient electrical 
currents in the wires to cause burns where the electrodes or wires contact the skin. 
The scanner operator is well aware of this risk and knows the proper methods to 
use to avoid this problem. 
 
Reactive hyperemia: Inflation of a cuff around the thigh to supra-systolic pressures (75 
mmHg above brachial systolic blood pressure or 250 mmHg) for 5 min to provoke 

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ischemia might cause discomfort in some subjects, including pain, numbness and tingling 
in the tissue located downstream from the occlusion site. These sensations are temporary 
and disappear immediately after cuff deflation. 
 
 
6.0 
Reporting of Adverse Events or Unanticipated Problems involving Risk 
to Participants or Others 
 
If the patient is injured due to participation in this study, he/she will be instructed to 
contact the study investigators. Patients will also be advised to contact the Human 
Subject Office at Indiana University if they have questions about their rights while taking 
part in the study. 
 
7.0 
Study Withdrawal/Discontinuation 
 
Participation in this study is voluntary. Participants may choose not to participate or, if they 
agree to participate, they can withdraw their participation at any time without penalty or 
loss of benefits to which they are otherwise entitled.      
 
 

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8.0 
Statistical Considerations 
 
Sample size was estimated based on the ability to detect a significant change in 6-min 
walk distance from baseline to 6 weeks in the TT-treated group as compared to the 
control group. The studies of McDermott and co-workers (5) and Gardner and co-
workers (2), which investigated the impact of home-based exercise training on walking 
tolerance in patients with IC, were used as a reference for the sample size calculations. 
We estimated the variance of improved walk distance by the MSE of Table 3 in the study 
of Gardner et al (2), which is 48.69 meters. Since both studies reported a non-significant 
change in 6-min walk in the attention-control group (95% confidence interval for 
McDermott's study is (-25.4 to 3.2) and for Gardner's study is (-6.33 to 14.33)), we 
predict that the change in 6-min walk in the control group, in our study, will be negligible 
(0). As pointed out by Perera et al (6), a change of 50 meters in the 6-min walk test is 
considered substantial and clinically meaningful in elderly subjects. Using this effect size 
(50-0)/48.69, we determined that 16 subjects per group are needed to detect a 
substantial improvement by TT therapy with a power of 0.802.  
 
9.0 
Privacy/Confidentiality Issues 
 
Information produced by this study will be stored in the investigator’s file and identified 
by a code number only. The code key connecting the patient’s name to specific 
information about the patient will be kept in a separate, secure location. Information 
contained in the patient’s records may not be given to anyone unaffiliated with the study 
in a form that could identify the patient without their written consent, except as required 
by law.   
The results of this study may be published in a medical book or journal or used for 
teaching purposes. However, the patients’ name or other identifying information will not 
be used in any publication or teaching materials without their specific permission.   
 
The patient’s name and social security number will be given to the business office for 
facilitating payment, but will not be used for any other purposes.  
 
10.0 Follow-up and Record Retention 
 
Records relating to this study will be retained for at least 7 years after completion of the 
research. Paper records will be shredded and recycled.  Records stored on a computer 
hard drive will be erased using commercial software applications designed to remove all 
data from the storage device.  
 
 
References: 
 
1. 
Broatch JR, Petersen A, and Bishop DJ. Postexercise cold water immersion 
benefits are not greater than the placebo effect. Med Sci Sports Exerc 46: 2139-2147, 
2014. 
2. 
Gardner AW, Parker DE, Montgomery PS, and Blevins SM. Step-monitored 
home exercise improves ambulation, vascular function, and inflammation in symptomatic 

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patients with peripheral artery disease: a randomized controlled trial. Journal of the 
American Heart Association 3: e001107, 2014. 
3. 
Laboratories ATSCoPSfCPF. ATS statement: guidelines for the six-minute 
walk test. American journal of respiratory and critical care medicine 166: 111-117, 
2002. 
4. 
McDermott MM, Guralnik JM, Criqui MH, Liu K, Kibbe MR, and Ferrucci 
L. Six-minute walk is a better outcome measure than treadmill walking tests in 
therapeutic trials of patients with peripheral artery disease. Circulation 130: 61-68, 2014. 
5. 
McDermott MM, Liu K, Guralnik JM, Criqui MH, Spring B, Tian L, 
Domanchuk K, Ferrucci L, Lloyd-Jones D, Kibbe M, Tao H, Zhao L, Liao Y, and 
Rejeski WJ. Home-based walking exercise intervention in peripheral artery disease: a 
randomized clinical trial. JAMA 310: 57-65, 2013. 
6. 
Perera S, Mody SH, Woodman RC, and Studenski SA. Meaningful change and 
responsiveness in common physical performance measures in older adults. J Am Geriatr 
Soc 54: 743-749, 2006. 
7. 
Roseguini BT, Hirai DM, Alencar MC, Ramos RP, Silva BM, Wolosker N, 
Neder JA, and Nery LE. Sildenafil improves skeletal muscle oxygenation during 
exercise in men with intermittent claudication. Am J Physiol Regul Integr Comp Physiol 
307: R396-404, 2014. 
8. 
Versluis B, Backes WH, van Eupen MG, Jaspers K, Nelemans PJ, Rouwet 
EV, Teijink JA, Mali WP, Schurink GW, Wildberger JE, and Leiner T. Magnetic 
resonance imaging in peripheral arterial disease: reproducibility of the assessment of 
morphological and functional vascular status. Investigative radiology 46: 11-24, 2011. 
9. 
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