Home-based Leg Heat Therapy for Patients With Symptomatic Peripheral Arterial Disease
Phase: NA
Conditions: Peripheral Arterial Disease
Sponsor: Indiana University

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Bruno Roseguini, Ph.D. 
 
 
 
 
 
 
Heat therapy for Intermittent Claudication 
NCT03763331 
Document Date: April 10, 2017 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Bruno Roseguini, Ph.D. 
 
 
 
Study protocol: We will conduct a randomized, controlled trial to evaluate the benefits of participating for 8 
weeks in a home-based daily treatment with HT or a thermoneutral control intervention, as assessed by vascular 
function, walking tolerance and quality of life. The treatment duration (8 weeks) was chosen based on the recent 
report of Brunt and co-workers that the improvement in endothelium function promoted by repeated HT in 
sedentary individuals peaks at 8 weeks following the onset of treatment (Brunt et al., 2016b). Men and women 
with a history of stable IC and resting ankle-brachial index (ABI) of <0.9 but >0.4 in at least one leg, will be 
recruited to participate in this study. The exclusion criteria are: (1) uncontrolled diabetes (HbA1C > 8.5 measured 
within 3 months prior to date of consent), (2) heart failure, (3) chronic obstructive pulmonary disease (COPD), 
(4) critical limb ischemia (ischemic rest pain or ischemia-related, non-healing wounds or tissue loss, (5) prior 
amputation, (6) exercise-limiting comorbidity (i.e., angina, dyspnea or arthritis), (7) recent (<3 months) 
infrainguinal revascularization (surgery or endovascular revascularization), (8) plans to change medical therapy 
during the duration of the study, (9) active cancer, (10) chronic kidney disease (eGFR <30 by MDRD or Mayo or 
Cockcroft-Gault formula), (11) HIV positive, active HBV or HCV disease, (12) presence of any clinical condition 
that in the opinion of the principal investigator makes the patient not suitable to participate in the trial, (13) 
peripheral neuropathy, numbness, or paresthesia in the legs, (14) class 2 or 3 obesity (BMI ≥ 35 kg/m2) or unable 
to fit into water-circulating pants, and (15) contraindications to MRI (Levine et al., 2007). Participants will be 
asked to report to the laboratory for a total of 9 experimental visits throughout the study as, detailed below in 
Table 1. After providing written informed consent, patients will be familiarized with the treadmill cardiopulmonary 
exercise test and the 6-min walk test. At least 72 hrs after the familiarization visit, subjects will be asked to return 
for the first experimental session, during which they will undergo: (1) a resting blood draw, (2) ABI measurement, 
and (3) a symptom-limited, treadmill exercise test. The second experimental session will be conducted at least 
48 hrs after the first session, and will encompass the following measurements: (1) calf reactive hyperemia using 
arterial spin labeling MRI, (2) cutaneous microvascular reactivity of the leg using a local heat challenge, (3) 
maximal walking distance on a 6-min walk test, and (4) QOL testing using the VascuQol and SF36 
questionnaires. After baseline characteristics are established, patients will be randomized into one of two groups 
as detailed below. Outcomes will be reassessed at the halfway point (end of week 4), at the completion of the 
intervention (end of week 8) and at a follow-up visit, 4 weeks after the end of the intervention (week 12). To 
ensure that the chronic rather than the acute effects of HT are investigated, participants will be asked to interrupt 
the treatment 48 hrs prior to the outcome sessions. The primary outcome will be the change in 6-min walk 
distance at 4 and 8 weeks relative to baseline. 
 
Visit # Time point 
Procedures 
1 
Baseline 
Consenting and familiarization with treadmill test and 6-min walk test 
2 
Baseline 
Blood draw, ABI measurement, treadmill test 
3 
Baseline 
Calf MRI, cutaneous microvascular reactivity, QOL, 6-min walk test 
4 
Mid-treatment (week 4) 
Blood draw, ABI measurement, treadmill test 
5 
Mid-treatment (week 4) 
Calf MRI, cutaneous microvascular reactivity, QOL, 6-min walk test 
6 
End of treatment (week 8) 
Blood draw, ABI measurement, treadmill test 
7 
End of treatment (week 8) 
Calf MRI, cutaneous microvascular reactivity, QOL, 6-min walk test 
8 
Follow-up (week 12) 
Blood draw, ABI measurement, treadmill test 
9 
Follow-up (week 12) 
Calf MRI, cutaneous microvascular reactivity, QOL, 6-min walk test 
 
Table 1: Study timeline and experimental procedures that will be performed on each session 
 
Study Groups and Randomization: A total of 32 patients will be recruited by Dr. Raghu Motaganahalli from the 
stable vascular disease clinic at the Richard L. Roudebush VA Medical Center and at the Indiana University 
Methodist Hospital, as well as by the staff from the Indiana CTSI Research Networks office. After the initial 
outcome measurements are collected, patients will be randomized (blocked and stratified by sex), using SAS 
Version 9.4, into one of two groups: those receiving HT (n=16) or those receiving thermoneutral control (n=16). 
Patients in both groups will be provided with identical water-circulating trousers and a portable heating pump 
(HTP-1500, Adroit Medical Systems), and will be instructed on how to operate the equipment. The pump given 
to participants in the HT group will be adjusted to circulate water at 48ºC through the trousers, while the pump 
given to patients in the thermoneutral control group will circulate water at 33ºC to maintain skin temperature at 
baseline levels (Neff et al., 2016). We will ask subjects to apply the therapy daily for 90 min while seated or in 

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Bruno Roseguini, Ph.D. 
 
 
the supine position. This treatment duration was chosen based on our recent findings that leg blood flow 
increases progressively during exposure to HT, attaining peak levels at 80 min (Neff et al., 2016). A built-in timer 
inside the pumps and inaccessible to patients, will provide an estimate of patient compliance with the therapy. 
Patients in both groups will also receive weekly telephone calls from the study coordinator to verify compliance 
and will receive a logbook to record their sessions. Throughout the course of the study, daily walking will be 
monitored using a step activity monitor attached to the ankle of the most symptomatic leg (StepWatch3, Ortho 
Innovations). Participants will be asked to wear the monitor during waking hours and to remove it before sleeping 
and while showering. The step activity monitor continuously records the number of steps per minute and the 
number of minutes spent walking each day, for up to 50 days. Data will be downloaded from the monitor on week 
4, on week 8 and at the follow-up visit at week 12. 
 
Outcome Measures: 
6-min Walking Test (Primary outcome): 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. We recently 
reported that the distance covered in 2 tests conducted 10 min apart in patients with symptomatic PAD is 
remarkably similar (Neff et al., 2016). This observation lends support to the concept that test-retest reliability of 
the 6-min walk test is excellent in this patient population (McDermott et al., 2014). 
Treadmill Exercise Test: Participants will perform a graded, symptom-limited exercise test on a treadmill following 
the Gardner protocol (treadmill speed of 2 mph, 0% grade with increments of 2% every 2 min), as described 
previously by our group (Roseguini et al., 2014). During the test, the microvascular oxygenation status of the 
gastrocnemius muscle of the most symptomatic leg will be continuously monitored using a near-infrared 
spectrometer (NIRS) (Roseguini et al., 2014). 
Calf Reactive Hyperemia: Peak hyperemic perfusion of the calf muscles will be assessed using pulsed arterial 
spin labeling (PASL) MRI (Lopez et al., 2015). MRI scans will be performed on a Siemens 3 Tesla (T) Magnetom 
Prisma scanner (Siemens AG Healthcare Sector, Erlangen, Germany). Subjects will have a transmit/receive 
knee coil placed around the most symptomatic leg. Initially, baseline perfusion images will be acquired after 30 
min of rest. Next, a blood pressure cuff firmly wrapped around the lower thigh will be inflated to suprasystolic 
values (>75 mmHg above systolic blood pressure) for 5 min. Hyperemic flow will be measured for 5 min after 
cuff deflation. Regions of interest (ROIs) for each muscle group in the calf will be drawn to obtain perfusion 
measurements in ml/min-100 g (Lopez et al., 2015). 
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 for 40 min. Next, to induce maximal vasodilation, the local skin temperature will be 
elevated to 43°C. 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) (Wong and Fieger, 2010, Wong and Minson, 2011). 
Quality of Life: QOL will be assessed by responses to VascuQol (Regensteiner et al., 1996) and SF36 (Ware et 
al., 1996) questionnaires. 
 
Statistical Analysis and Sample Size: Baseline differences in demographics and clinical characteristics 
between groups will be determined using independent two-sample t-tests. Linear mixed effects models will be 
used to model all outcomes with baseline outcome treated as a covariate. Sex will also be included as a covariate 
since several outcomes are known to differ by sex (Gardner et al., 2010, Gardner et al., 2014b); however, 
treatment effects are not expected to differ by sex (McDermott et al., 2014) so we have not powered the study 
to test for sex interactions. The sample size (n=32; 16 per group) is based on the ability to detect a clinically 
significant change in 6-min walk distance (from baseline) over 8 weeks (primary outcome) in the HT-treated 
group as compared to the control group. The studies of McDermott and co-workers (McDermott et al., 2013) and 
Gardner and co-workers (Gardner et al., 2014a), in which the benefits of home-based exercise training on 
walking tolerance in patients with IC were investigated, were used as a reference for the sample size calculations. 
We estimated the standard deviation of change in 6-min walk distance to be 48.69 meters, based on the standard 
deviation of the change scores observed in Table 3 of Gardner et al (Gardner et al., 2014a). Since investigators 
in both studies reported a non-significant change in 6-min walk in the attention-control group [95% confidence 
interval for McDermott's study (health education control group, 6 month follow-up) is (-25.4 to 3.2) and for 
Gardner's study (light resistance training control group, 12 week follow-up) is (-6.33 to 14.33)], we hypothesize 
that the change in 6-min walk in the control group in our study will be non-significant (0 on average). As pointed 

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Bruno Roseguini, Ph.D. 
 
 
out by Perera et al (Perera et al., 2006), 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)/48.42=1.03), we determined that 16 
subjects per group will be needed to detect a clinically meaningful improvement by HT therapy, with a power of 
80% and based on a two-sided, two-sample t-test with significance level 0.05. Power will be improved through 
our linear mixed models approach. Based on our expected enrollment rate of 2 patients/month, we will be able 
to complete accrual in 16 months. 
 
REFERENCES 
 
Gardner, A. W., Parker, D. E., Montgomery, P. S. & Blevins, S. M. 2014a. Step-monitored home exercise 
improves ambulation, vascular function, and inflammation in symptomatic patients with peripheral artery 
disease: a randomized controlled trial. J Am Heart Assoc, 3, e001107. 
Gardner, A. W., Parker, D. E., Montgomery, P. S., Khurana, A., Ritti-Dias, R. M. & Blevins, S. M. 2010. 
Gender differences in daily ambulatory activity patterns in patients with intermittent claudication. J Vasc 
Surg, 52, 1204-10. 
McDermott, M. M., Guralnik, J. M., Criqui, M. H., Liu, K., Kibbe, M. R. & Ferrucci, L. 2014. Six-minute walk 
is a better outcome measure than treadmill walking tests in therapeutic trials of patients with peripheral 
artery disease. Circulation, 130, 61-8. 
Perera, S., Mody, S. H., Woodman, R. C. & Studenski, S. A. 2006. Meaningful change and responsive- 
ness in common physical performance measures in older adults. J Am Geriatr Soc, 54, 743-9.