Monitoring and Managing Newly Healed Chronic Leg and Foot Ulcer Skin Temperature: A Cooling Intervention (MUSTCOOL) to Prevent Ulcer Recurrence
Phase: PHASE2
Conditions: Venous Hypertension Ulcers, Venous Stasis Ulcer, Venous Ulcer, Venous Insufficiency, Leg Ulcer, Foot Ulcer, Varicose Ulcer, Diabetic Foot
Sponsor: Medical University of South Carolina

 
 
 
 
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Cover letter for Protocol 
 
Official title: Cooling Leg and Foot Ulcer Skin Post Healing to Prevent Ulcer Recurrence (MUSTCOOL) 
 
NCT02626156 
 
Document date: 07/23/2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
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PI Name: 
 
Teresa J. Kelechi, FAAN, RN, PhD. 
 
Study Title: 
 
Monitoring and managing newly healed chronic leg and foot ulcer skin  
 
 
 
temperature: a cooling intervention (MUSTCOOL) to prevent ulcer recurrence 
 
TABLE OF CONTENTS 
PAGE  
 
 
 
A. 
SPECIFIC AIMS 
 
 
 
 
 
 
 
 
2. 
 
 
B. 
BACKGROUND AND SIGNIFICANCE 
 
 
 
 
 
3. 
 
 
C. 
PRELIMINARY STUDIES 
 
 
 
 
 
 
 
3. 
 
 
D. 
RESEARCH AND DESIGN METHODS 
 
 
 
 
 
6. 
 
 
E. 
PROTECTION OF HUMAN SUBJECTS 
 
 
 
 
 
16. 
 
E.1. 
RISKS TO SUBJECTS 
 
 
 
 
 
 
 
16. 
 
E.1.a. Human Subject Involvement and Characteristics 
 
 
 
17. 
 
E.1.b. Source of Materials  
 
 
 
 
 
 
 
18. 
 
E.1.c. Potential Risks 
 
 
 
 
 
 
 
 
18. 
 
 
E.2. 
ADEQUACY OF PROTECTIONS AGAINST RISKS 
 
 
 
19. 
 
E.2.a Recruitment and Informed Consent 
 
 
 
 
 
19. 
 
E.2.b Protection against Risk 
 
 
 
 
 
 
 
20. 
 
 
E.3. 
POTENTIAL BENEFITS OF THE PROPOSED RESEARCH 
 
 
20. 
 
 
E.4. 
IMPORTANCE OF THE KNOWLEDGE TO BE GAINED   
 
 
21. 
 
 
E.5. 
SUBJECT SAFETY AND MINIMIZING RISKS  
 
 
 
 
21. 
 
 
F. 
REFERENCES/LITERATURE CITATIONS  
 
 
 
 
28. 
 
 
G. 
CONSULTANTS 
 
 
 
 
 
 
 
 
33. 
 
 
H. 
FACILITES AVAILABLE 
 
 
 
 
 
 
 
33. 
 
 
I. 
INVESTIGATOR BROCHURE  
 
 
 
 
 
 
36. 
 
 
J. 
APPENDIX 
 
 
 
 
 
 
 
 
 
36. 
Medical University of South Carolina 
Protocol 

 
 
 
 
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A. SPECIFIC AIMS 
Purpose: Elevated skin temperature after closure of a chronic ulcer is predictive of ulcer recurrence due 
to aberrant and persistent inflammation resulting in tissue destruction 1-3. The proposed randomized 
controlled 
trial 
(RCT) 
will 
test 
a 
patient-directed 
self-monitoring/self-management 
intervention 
(MUSTCOOL) with respect to its ability to prevent recurrence of chronic venous leg ulcers (VLUs) and 
diabetic foot ulcers (DFUs) while improving symptoms, physical activity, and quality of life. This will be 
achieved by: 1) monitoring newly healed ulcer skin temperature with a non-invasive hand-held dermal 
thermometer; and, 2) modifying the local skin environment (i.e., elevated temperature) by cooling the 
focal area with a cooling “pack” noted for its anti- inflammatory properties 4-6. 
Negative impact of chronic ulcers: Chronic ulcers affect 6.5 million individuals, 5 million of whom have 
ulcers of the legs and feet related to diabetes, vascular and/or neuropathic disorders. These ulcers 
represent a substantial portion of the health and cost burden of those chronic illnesses 7-9. For example, 
in 2008, the National Institute of General Medicine Sciences reported ~$20 - 25 billion was spent for 
ulcer care, and this does not account for the costs of human suffering and the negative impact on 
physical activity and quality of  life 10,11. Dollar and human suffering costs are increased when ulcers 
become chronic and recalcitrant to treatment. Unfortunately, incidence and prevalence of leg and foot 
ulcers are expected to increase as a result of the growing aging population suffering with diabetes and 
obesity 12. 
High recurrence rates: VLUs and DLUs show extremely high recurrence rates: 70 – 96% of VLUs recur 
within 2 to 3 months of healing 13,14 while the five-year cumulative DFU recurrence rate is 66% 15,16. If 
even half of these recurrent ulcers could be prevented, $10 billion in savings on expenditures for hospital 
and outpatient ulcer care would be saved and associated suffering eliminated. 
Our prevention intervention: Our prior research supported and refined MUSTCOOL, a self-
management prevention model for VLUs (Drs. Kelechi & King) and DFUs (Drs. Bharara & Shibuya)2,3,17-19.  
This collaborative 
team will extend MUSTCOOL’s ulcer prediction (monitor for elevated skin 
temperature) and prevention (cooling pack therapy) intervention by determining if prophylactically cooling 
previously ulcerated skin due to a chronic VLU or DFU three times weekly during the immediate and 
intermediate post healing remodeling phase (closure to 6 months) will prevent ulcer recurrence, reduce 
pain, enhance physical activity, and improve    quality of life. Specifically, for a skin temperature increase 
2°F above baseline for two days in a row, a bolus dose of cooling for 5 consecutive days will be 
implemented. 
Enhancements to intervention: For this RCT, we have made several technical and methodological 
refinements to MUSTCOOL. First, we will use an extremely low cost infrared camera to map temperature 
gradients of the healed leg and foot skin to identify any “hot spot(s)” which will visualize overall tissue 
health and will be monitored by participants using the thermometer.  Second, a user-friendly cooling pack 
(local cooling) will be used instead of the cuff (regional cooling) based on acceptability data from our 
ongoing RO1 study participants. Third, we will quantitatively measure physical activity using state of the 
art accelerometry. Finally, we will test a new data-driven temperature-monitoring schedule, targeting the 
skin of newly healed chronic ulcers that took longer than 12 weeks to heal. In 180 patients with a newly 
healed chronic ulcer, 90 patients will be randomized to receive the experimental cooling pack + standard 
of care (compression, elevation or footwear) or control placebo pack + standard of care to apply to the 
affected “hot spot” in the presence of elevated skin temperature.  Randomization will be stratified by ulcer 
type, VLU versus DFU (n=90 in each group).  During the 6-month study period, this trial aims to: 
1. Test the MUSTCOOL intervention (cooling pack) compared to control group (placebo pack) on: 
outcome of incidence of ulcer recurrence; and, impact on pain, physical activity and quality of 
life. 
 

 
 
 
 
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2. Assess the implementation self-management process measures including: a) appropriate use of 
thermometer, b) application of pack to the “hot spot” for 5 consecutive days for 30 minutes 
(fidelity to self-management), c) utilization of supportive reinforcement, d) reactions/satisfaction 
of participants, and e) staff ratings and perceptions for replicability. 
 
Impact: Our preliminary data suggest significant improvements in health outcomes: a reduction in leg 
ulcer development, improved pain, and higher quality of life. However, analysis of monthly data from our 
ongoing RO1 has found a non-sustained reduction in skin temperature during 30 days of a 30-minute 
daily initial cooling dose. Thus we have modified MUSTCOOL’s cooling delivery to be based on skin 
temperature elevation above an individual’s baseline and have participants prophylactically cool the 
affected skin at home under real-life conditions. 
 
B. BACKGROUND AND SIGNIFICANCE 
This study addresses morbidity and quality of life issues with a very challenging population with chronic 
ulcers. It addresses an RFA priority, the purpose of which is to test a self-monitoring/management 
strategy that can be implemented in community settings, chiefly the home.  Chronic ulcers cause pain 
and suffering, negatively affecting physical activity and quality of life. Populations with chronic 
ulcers, such as individuals with chronic venous disease, and/or diabetes and/or neuropathy have major 
life-style issues.  They are often obese and plagued with multiple co-morbid conditions such as 
hypertension and arthritis.  Many have experienced multiple ulcers in their lifetimes that take months, 
even years to heal. Additionally they are physically inactive leading to significant mobility problems 11. 
Chronic ulcer patients who are physically inactive suffer disproportionately; many experience prolonged 
ulcer healing and other complications such as amputations 16. They are physically de-conditioned, some 
able to take only a few steps at a time, are much less active, have poor balance, slower walkers, and 
experience pain 20,21. Our MUSTCOOL leg and foot ulcer prevention intervention, while a self-care 
approach, may be viewed by these patients as a means by which their physical activity and quality of life 
could be improved. Unfortunately they are poor candidates for surgical or pharmacologic intervention due 
the severity of the disease process or co- morbidities, or they have failed these therapies in the past. 
 
C. PRELIMINARY STUDIES 
We have conducted and published preliminary work in the area of pain and physical activity. First, we 
developed a conditioning activities for lower leg function (CALF) intervention combined   with a 
behavioral component, motivational enhancement communication (MECALF), delivered by wound care 
clinic providers to leg ulcer patients. It was found to be feasible and acceptable by both patients and 
providers 22. Signals of significance were found in leg function, in particular in pain reduction (p = 0.04) in 
the lower legs of leg and foot ulcer patients over the course of the six-week study compared to patients 
who received an exercise handout only. Secondly, in another study, the CALF intervention was delivered 
by a exercise sciences 
coach through online face-to-face Internet sessions via Skype® and 
demonstrated statistically significant improvements in ankle dorsiflexion and leg strength (both p = 0.03) 
23. Patients had a history of leg ulcers and participated in three daily doses of CALF. The face-to-face 
Internet interactions were feasible, even for patients who lived in subsidized housing. While the goal of 
this study was to test the feasibility of the physical activity program, we observed a very high level of 
patient satisfaction with being able to initiate contact with the coach via Skype® and signals of efficacy in 
improvement in function even with small daily doses. Finally, in a recent randomized study evaluating the 
effectiveness of two offloading modalities for diabetic foot ulcer healing we demonstrated the need for 
objective physical activity assessment (Dr. Bharara, manuscript in progress). Our data suggest while 
walking may delay healing, unprotected standing may be an even more unrealized and sinister culprit for 

 
 
 
 
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chronic non-healing ulcers and recurring ulcers in individuals with diabetes. 
 
The remodeling phase of healing (final repair process) of chronic ulcers is prolonged, has 
inflammatory components, and elevated skin temperature. Healing normally proceeds through four 
programmed stages: hemostasis, inflammation, proliferation, and remodeling. The remodeling phase 
overlaps with other phases of wound healing and is highly regulated by growth factors and cytokines 
secreted by inflammatory cells 24. In acute wounds, wound healing progress requires precise integration 
of multiple physiology events including cell migration, cell infiltration, cell proliferation, and extracellular 
matrix (ECM) deposition 
25. In chronic non-healing ulcers, however, defective remodeling of the 
extracellular matrix due to prolonged inflammation is observed 
25. Factors intrinsic to underlying 
metabolic disease, such as diabetic hyperglycemia, or increased hydrostatic pressure associated with 
venous disease, can enhance and perpetuate the inflammatory response 26. Studies have shown 
differences in cellular infiltration and extracellular matrix composition of chronic diabetic and venous 
ulcers versus acute wounds 27. These non-healing wounds fail to progress through the normal phases of 
wound repair, instead, they remain in a chronic inflammatory state characterized by abundant neutrophil 
infiltration and elevated pro-inflammatory cytokines such as TGF-b, IL-  1, IL-6, and TNF-α 26,27. 
Furthermore, studies in diabetic transgenic mice also indicate that prolonged persistence of neutrophils 
and macrophages during the late phase of repair impairs wound healing 28. The persistence of 
inflammatory cells promotes an inflammatory environment and stimulates the production of tissue-
degrading proteinases 29. It has been hypothesized in many studies that such an excessive or prolonged 
inflammatory response results in increased tissue injury and that an unbalanced inflammatory response 
may continue after the tissue has closed 30-33.  This is particularly notable in chronic ulcers after closure 
34-36 as evidenced by persistently elevated skin temperature 37.  Drs. Bharara’s and Kelechi’s science 
underpins this proposed study by suggesting that detecting inflammation in the foot 2,17  and leg 38  in 
“remission” could provide insights into the remodeling phase of ulcer healing. Preliminary work: Our 
science has advanced the field by providing a mechanism by which persistently elevated skin 
temperature is measureable and predictive of ulceration. This proposed study builds on the landmark 
research of skin temperature elevation’s measurement suitability in predicting diabetic/neuropathic foot 
ulcers after healing in high-risk patients 1,39-41.  Dr. Kelechi has demonstrated temperature elevation in  
lower leg skin inflamed by venous disease is as equally predictive 3,42. Drs. Bharara and Shibuya continue 
to advance the field in diabetic foot ulcer populations by exploring new infrared and physical activity 
monitoring technology and cryotherapeutic modalities.  Taken together, our work in the field over the past 
10 years has evolved a model of ulcer prediction based on self monitoring of skin temperature using 
infrared thermometers 2,43  as ulcers progress through the remodeling phase. Our team and others have 
demonstrated that infrared and thermal technologies are well established as validated and reliable 
instruments to measure skin temperature of chronically inflamed skin 44-50  and skin affected by other 
conditions, such as neuropathy 51,52. 
 
1.1. 
Cooling (cryotherapy) reduces tissue metabolism and prevents tissue destruction, thus 
has the potential to prevent leg and foot ulcer recurrence. While the specific physiological 
mechanisms associated with cooling chronically inflamed skin are poorly understood, cooling causes an 
initial vasoconstriction in skin blood vessels, which results in decreased local blood flow to the area. 
Cooling also prevents localized fluid leakage from the microcirculation and thus reduces inflammation 
(i.e., edema, redness, eczema). Used for centuries as a treatment modality for musculoskeletal injuries 
and acute inflammatory conditions 53  cryotherapy reduces the metabolic rate of tissue, and impedes the 
destruction of otherwise uninjured adjacent tissue by limiting injury 54. It has been shown to prevent 
diabetic foot ulcers from becoming inflamed 55. Skin heats up before it breaks down (skin temperature is 
increased by approximately 1.8C in venous-affected skin and spikes prior to ulceration) 38, and 

 
 
 
 
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prophylactically cooling a focal or localized area of affected skin reduces the risk of skin changes and 
ulceration by reducing microcirculatory blood flow, vessel permeability and tissue metabolism 
55. 
Preliminary work. The preliminary findings from our cryotherapy R21 suggested a signal of efficacy in 
reducing tissue metabolism (blood flow), pain reduction and ulcer prevention 19. Cooling the skin 
significantly reduced blood flow on average by 6 perfusion units (PU), from 15 to 9 PU (normal is 3 – 5 
PU) after four weeks of cooling 18. We also found that vasoconstriction and reduced blood flow can 
persist for greater than one hour after removal of cryotherapy, even in the presence of skin rewarming at 
room air 56.  We developed this proposed study’s protocol based on principles of heat transfer, 
microcirculatory thermoregulation, studies of cryotherapy and healthy skin, and pathophysiologic 
mechanisms of venous disorders, supplemented with consultation with Dr. Shibuya, and additional 
preliminary work conducted post R21.In regards to pain, cryotherapy offers an analgesic effect that can 
be realized within 3 minutes by locally destimulating pain receptors, which are located in the 
subcutaneous tissue 57,58. These findings led to the currently funded R01 to test the efficacy of a 
sequenced cooling regimen over a 9-month period for patients with venous disease, damaged skin and/or 
a history of healed venous ulcers. The ongoing study is evaluating efficacy on pain, ulcer occurrence and 
quality of life (in year 4).  While we are in the last year of the study and will analyze data to determine  
outcomes on ulcer prevention, first month data (§Figure 1) suggest that an initial acute daily cooling 
regimen, compared to a placebo, demonstrated a clinically, but no statistically significant difference in 
skin temperatures measured daily (cyrotherapy cuff treatment + leg elevation versus  placebo cuff + leg 
elevation.)  There was a non-significant trend towards lower skin temperatures in both groups.  These  
findings suggest that an acute cooling  period is  unnecessary and that a reduced frequency (three times 
weekly for 30 minutes based on our preliminary data) could be adequate as a maintenance dose to keep 
the skin temperature “in check”.  These findings are further supported by Dr. Bharara’s inflammation 
proof of concept work in diabetes 59  and Dr. Shibuya’s post-operative cryotherapy research 60. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 1. 
 
Summary: This trial is significant due to the burden of chronic ulcers, the complex physical 
 

 
 
 
 
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characteristics of the population, and need to reach them with a supportive strategy. We hypothesize that 
this novel model will significantly improve the health and quality of life of these patients, and that the 
intervention will become a feasible standard of care, activating patients to be better self-care managers. 
We want to develop this self- management cooling approach as an evidence-based practice guideline 
and as such, this 
 
D. RESEARCH DESIGN AND METHODS (including data analysis)  
D.1. 
Study overview 
This six-month randomized controlled trial will use a two-group longitudinal design to test MUSTCOOL 
home- based self-monitoring and self-management ulcer prevention intervention for patients at high risk 
of leg and foot ulcer recurrence. The study targets individuals with newly healed chronic VLUs and DFUs 
that took longer than 12 weeks to heal. For aim 1, real time physical activity monitoring using an 
accelerometer, self-monitoring of skin temperature using infrared thermometry, and self-management of 
newly healed skin using a small cooling pack or placebo pack to maintain the skin environment will be 
studied for reduced ulcer recurrence rates, pain, physical activity and quality of life. We will test the 
intervention on 180 patients with newly healed leg and foot ulcers randomized to receive the experimental 
cooling pack or control placebo pack.  The design incorporates methods that maximize reproducibility, 
control bias and transparency of reporting, as noted in Aim 2. Table 1 summarizes the changes in 
protocol from our preliminary work to the current study. 
 
D.2 
Interdisciplinary  team   
Our interdisciplinary team includes Dr. Kelechi, PhD, RN a nurse scientist and practicing certified wound 
care nurse. She will lead the team as principal investigator. She has extensive expertise in managing 
clinical trials for populations with chronic venous disease, using infrared technology, and cryotherapy and 
physical activity interventions. Her clinic population includes patients with chronic venous and diabetic 
foot ulcers. Dr. Bharara, PhD, is a bioengineer with expertise in infrared and cooling technologies and 
their application to patients with diabetic foot ulcers.  He also has expertise in using objective 
biomechanical assessment instruments that will be used in the study to assess physical activity.  Dr. 
Shibuya, DPM, is a podiatric surgeon with expertise in cryotherapy and its application to patients with 
diabetic foot ulcers. He is presently serving as the cryotherapy consultant on Dr. Kelechi’s ongoing R01.  
Drs. Bharara and Shibuya bring extensive expertise in diabetic foot ulcers and will guide the study 
procedures related to this population.  Dr. King, MD has provided medical oversight on all of Dr. Kelechi’s 
previous studies, has extensive experience with chronic populations, and expertise in clinical trials and 
risk/safety monitoring.  Dr. King is currently serving as the chair of our R01 and R21 (palliative wound 
care intervention study) DSMB. We will develop our DSMP under Dr. King’s watchful guidance. Dr. 
Mueller, PhD, who has expertise with managing R01 level NIH RCTs, and who has provided biostatistical 
support for Dr. Kelechi for the past 8 years, will provide statistical expertise and coordinate data 
analyses. 
 
D.3  
Setting, eligibility, recruitment and enrollment 
TABLE 1: REFINEMENTS THAT INFORMED NEW MUSTCOOL INTERVENTION 
 
Old 
New 
Rationale 
Cooling device 
Regional cooling: Cuff 
encircled lower leg or foot 
Local cooling: Pack that 
comes in three sizes, 3X3, 
5X5, 10X10 with net tubing 
to anchor to foot or leg 
User complaints: cuff too heavy, made pt. 
feel cold all over: will cool affected area 
“hot spot” only (unpublished R01 exit 
data)19 

 
 
 
 
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Thermometer 
Contact thermometer without 
memory 
Non-contact thermometer 
with laser pointer and 100 
reading memory 
Reduced burden on patient to record 
temperatures (60% of patients make 
errors in recording) 
Skin site (affected 
area “hot spot”) 
VLU: 5 cm above medial 
malleolus; DFU, site of 
previous ulcer 
VLU: Infrared image of 
ant./lat./med/ gaitor area: 
DFU: plantar surface of foot 
Identify the “hot spot” with thermography 
that will be targeted for home monitoring 
2 
Baseline 
temperature 
No baselines were 
established for VLU or DFU 
“hot spots” 
Baseline will be established 
by averaging the first 30 
daily morning temperatures 
Our R01 data of morning leg temperatures 
showed no statistically                  
significant variation among temperatures 
taken 12 hours after treatment for 30 days 
19 
Frequency of 
temperature 
monitoring 
VLU: Before and after cooling 
and 12 hours later (morning); 
DFU, daily (no specific time 
recommended) 
Morning only 
Standardized for this study; reduced 
effects of footwear and ambulation that 
could potential increase surface 
temperature on plantar region of foot 61 
Skin temperature 
target 
Cool if 4°F (2.2°C) above 
baseline 
Cool if 2°F above baseline 
By the time the tissue reaches 4°F, there 
is significant inflammation and tissue 
destruction 41 
Population 
Any VLU or DFU patient 
regardless of length of time to 
healing 
Only those with previously 
healed chronic ulcers (≥ 12 
weeks to heal) 
Focus of RFA is on chronic ulcers; the 
emphasis for this study is prevention 
 
D.4 
Setting:  The study will recruit participants from 5 major wound care centers and specialty 
practices (§ letters of support) within a 75-mile radius of Charleston, SC, as well as from one located in 
Greenville, NC.  These centers and practices serve a large proportion of urban and rural residing, racially 
and ethnically diverse patients with leg and foot ulcers. The study will be conducted at the Research 
Nexus (CTSA) on the campus of the Medical University of South Carolina, at the Spartanburg Regional 
Healthcare System’s Wound Healing Center, and at East Carolina University, NC.  
 
D.5 
Sample eligibility criteria: English speaking adults age 18 years-of-age or older with a healed 
VLU or DFU will be invited to participate (§Table 2). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
D.6 
Recruitment  and retention plan: 
TABLE 2: INCLUSION & EXCLUSION CRITERIA 
Inclusion for enrollment 
Exclusion 
Newly healed leg or diabetic foot ulcer within 
past six weeks 
Open leg or foot ulcers 
Ankle brachial index 0.8- 1.3mmHg (rule out 
absence of arterial disease) 
Cognitive impairment: unable to recall 2 or 
more words or draw clock Mini-Cog™ (0.84) 
for cognitive impairment 62 
Willing to wear compression stockings and 
appropriate footwear 
Chronic inflammatory or vascular conditions 
where blood flow of skin may be impaired such 
as Lupus erythematosus, Raynaud’s, 
scleroderma, chronic regional pain syndrome, 
multiple sclerosis, hypersensitivity to cold, on 
chemotherapy 
Working freezer 
Unable to preform required protocol activities 
without assistance (return demonstration to 
study staff) 
Willing to travel for study visits 

 
 
 
 
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We have developed an extensive recruitment plan for our previous studies and have refined several 
strategies to ensure enrollment targets are met for this study.  Based on our recruitment metrics from our 
ongoing R01 and Dr. Kelechi’s experience as the director of recruitment of MUSCs CTSA, we expect to 
enroll 1 subject for every 5 approached and screened (#1 reason for not enrolling is an abnormal ankle 
brachial index). The goal is to enroll ~6 subjects per month for 3 1/2 years, accounting for an expected 
attrition rate of ~25% (nature of the chronically-ill population with frequent hospital admissions).  Our 
recruitment plan includes referrals from centers and practices (25% of subjects will be referred). However 
we anticipate using other recruitment methods that we have found particularly successful including 
television, radio and billboard advertisements, use of our CTSA’s SCResearch.org website, and our 
community based participatory research advisory groups. At MUSC, a chart review will be 
conducted 
for 
the 
identification 
of 
potentially 
eligible 
patients 
per 
the 
study 
inclusion/exclusion criteria and recruitment purposes. Potentially eligible patients, that 
have agreed to be contacted for future research by logging their MUSC Research 
Permissoins preference in MyChart will be contacted by phone and invited to participate 
in the study. All other identified patients will be initially approached and contacted 
through their provider about the study, if the provider feels the study is appropriate.  
Additionally, we will create an online REDCap survey that will be accessible through a 
PI 
designated 
research 
web-page 
(https://www.musc.edu/nursing/initiatives/researchoffice/currently_active_studies.htm) 
on MUSC secure servers that will allow potentially eligible individuals to self-prescreen 
through yes/no questioning and have the researchers contact them should they elect to 
do so. We have budgeted for these strategies accordingly, based on our current experience with our 
ongoing R01. There is a need to incentivize center and practice referrals and to that end, we will provide 
$20 for every enrolled participant in the form of a “credit” gift card that can be used for whatever purposes 
deemed appropriate by the practice. We also have implemented a very successful contingency 
management approach for retention at one of   our study sites (a drawing from a fish bowl at each visit 
with the opportunity to win from $1 to $100). The attrition rate for this site is ~17% compared to 30% 
(average of other sites’ attrition rates).  We will include this same strategy in the proposal study. 
 
D.7 
Randomization, masking and allocation concealment: A permuted block randomization  
strategy developed by Dr. Mueller will be used to assign newly healed VLU and DFU patients to 
treatment or placebo. Randomization will be stratified by type of ulcer, VLU or DFU. The research 
assistants, PI and consultants will be blinded (masked) to treatment assignment. To minimize the 
likelihood that the mask will be broken, e.g., the next treatment assignment can be guessed, the block 
size will be varied. At baseline, a research assistant will consent, determine eligibility, enroll, collect 
baseline data, (i.e., demographics, physical activity, pain and quality of life), instruct participants on 
treatment procedures and provide all study supplies, except for the pack. Both groups will receive 
identical instructions via a 3-minute videotape shown during the baseline visit. They will complete a 5-
item verbal test to demonstrate understanding of procedures. To ensure allocation concealment, after the 
participant has been successfully instructed on the protocol (100% passing on test), another 
researcher will randomize participants within the study REDCap database to receive the cooling pack 
treatment or placebo, and will give the appropriate pack to the participants. Researchers conducting study 
visits, collecting measures and performing data entry will remain blinded to treatment during return 
visits 1 – 4. 
 
D.8 
Sample size determination including clear justification and power analysis. 
The primary efficacy outcome for sample size calculation for this study is recurrence of at least one 
venous or diabetic ulcer over the study period. Based on a two group continuity corrected Chi-square test 

 
 
 
 
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of equal proportions, with 90 subjects per group we will have >90% power to detect a difference in 
proportions with an odds ratio for recurrence of VLU/DFU of 3.0, assuming 25% of subjects experiencing 
a recurrent ulcer in the cooling group compared to 25% in the placebo group, = 0.05 (Type I error 
rate), two-sided test. To account for drop-out immediately after randomization, and the dilution effect of 
intent-to-treat (ITT) analysis, we inflate the sample size by 25% to obtain a final sample size of 120 
subjects randomized to each group (N=240) for ITT analysis. For the analysis of continuous efficacy 
outcome measures (change from baseline in quality of life and pain) we will have 85% power to detect a 
difference of 0.45 s between the groups assuming = 0.05 (Type I error rate), two sided; independent 
sample t-test comparison of means; equality of variance between groups. Based on our previous pilot 
study comparing gel-cooling to leg elevation short term this effect size is equivalent of a raw effect size of 
1.3 units on the VEINES Quality of Life scale (assuming s=2.8) and a raw effect size of 1.1 units on the 
visual analog pain scale (assuming s=2.5). 
D.9 
Protocol 
Aim 1: Test the MUSTCOOL intervention (cooling pack) compared to control group (placebo pack) 
on: outcome of incidence of ulcer recurrence; and, impact on pain, physical activity and quality of 
life. 
Intervention components – The self-monitoring and self-management strategies in the MUSTCOOL 
intervention are identical for both groups. The only difference is the material composition used in the placebo 
is developed from cotton. Participants will agree to standard of care: VLU will wear compression stockings 
and DFU will wear diabetic footwear. 
Pre-intervention temperature mapping of lower leg and foot “hot spots”.  After participants are 
enrolled, the skin site of the recently healed VLU or DLU will be imaged (photographed) with an infrared 
camera (Scout® by WoundVision LLC, Indianapolis, IN) by study personnel. These thermal images and 
participant data (including: subject ID#, skin thermal characteristics, and study visit date) will be 
instantaneously uploaded via the internet and stored on WoundVision’s HIPAA compliant secure servers. 
Images will be taken at baseline, months 1, 3 and 6.  The “hot spot” or area that has the highest temperature 
reading will be marked with a dermal ink pen, the site where participants will take daily skin temperatures at 
home. They will be instructed to remark the same spot each day or after bathing/showering. We will track 
whether the marked “hot spots” have changed in size or location. Camera software analyzes % change in 
Benchmarks for success: surface area that will be compared at each study visit. The affected skin of the 
cooling patch group, compared to the placebo, will have smaller and fewer “hot spots” at each visit and at the 
end of the study.  
In accordance with HHS OHRP Guidance on Engagement of Institutions in Human Subject Research B(7) 
(http://www.hhs.gov/ohrp/policy/engage08.html) WoundVision will not be considered engaged in human 
subject research as they will be unable to readily ascertain the identity of participants from the data they will 
be hosting (subject ID#, skin thermal characteristics, and study visit date) from each of the participating sites. 
WoundVision will not have access to any keys that link subject names and/or address, telephone numbers 
etc. to their study ID#. MUSC and WoundVision LLC will enter in a service agreement for the provision of 
data hosting services and protection of data confidentiality. At the end of the study WoundVision will provide 
the MUSC researchers with a copy of all study data, and delete all hosted study data from their HIPAA 
compliant secure servers. 
Self-monitoring with infrared thermometer. Participants in both groups will be instructed to self-monitor 
the marked “hot spot” daily prior to getting out of bed in the morning with a non-contact infrared thermometer 
(IRT730K, General Tools & Instruments, NY, NY ) (§Table 2). The thermometer has a laser pointer that 
targets the marked area and automatically stores the last 100 readings for recall.  The handle of the 
thermometer has a “trigger” that when pulled, emits a laser beam at the marked spot and when released, 
records the temperature. The thermometer will be programmed at the second visit to automatically sound an 

 
 
 
 
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alarm when the temperature rises 2°F above the mean temperature. The mean will be calculated by the 
research assistant at visit 1 by averaging the first 30 daily readings.  While the thermometer date and time 
stamps each reading, we will ask participants to record the daily readings on a paper log given to them on a 
clipboard with an attached pen at the start of the study. This “back up” log will be available in the event of a 
mechanical error with the thermometer. It is also a reliability/validity measure of participant self-report which 
may be important to future dissemination studies. 
 
 Self-management with cooling pack – Participants in both groups will apply the pack (cooling or 
placebo) at a consistent time each day (e.g. 7 PM) to the affected leg or foot skin “hot spot”, both 
prophylactically (maintenance) and preventatively (bolus dosing) (§Table 2). The rationale for using 
cooling packs compared to cuffs or wraps is based on exit interview comments from participant 
experiences in our ongoing cyrotherapy R01 in which a lower leg cooling cuff (regional cooling of the 
lower leg) was used. Some of the user comments include: “I felt cold all over when using the cuff”, “why 
do we need to cool so much skin when it’s just that one area that has the problem?”, “that cuff was too 
heavy and weighed down my leg”, and “the nurse worked so hard to make it fit but it didn’t feel right on 
my leg”. In response, the proposed study will use readily available small packs, applied only locally 
(versus regionally) to the “hot spot” on the leg or foot (§Table 3 for refinements to study protocol). The 
topical cooling pack (Therapy Pack, Elastogel, Southwest Technologies, Kansas City, MO) to be used in 
the cooling treatment group is a flexible glycerin-based sheet hydrogel that does not freeze to a solid 
state and is available in various sizes.  We have conducted extensive safety testing of the material prior 
to our previously conducted R21 and have had no adverse events (e.g., skin injury) reported during the 
R21 and the ongoing cryotherapy R01. The placebo pack has a cotton filing (manufactured by same 
company and used in our ongoing R01). Both packs have the same feel and look and are covered with a 
protective polyethylene covering that can be laundered. Both packs will be stored in the      freezer (will 
give subjects freezer thermometers to make sure freezer temperature is maintained at 0°F) and  will be 
applied to the affected site only.  Once removed from the freezer, the placebo pack warms to room 
temperature within 2 minutes. The packs will be anchored with a tubular retainer that is an expandable 
elastic latex-free net. Participants will record the date and times they apply the packs to the skin (three 
times each week for maintenance and 5 consecutive days for bolus dosing) on the “back up” log. 
 
 
 
 
 
 
 
There are two approaches to the self-management strategy (§Table 3): 
Maintenance prophylactic dosing: Participants in both groups will be instructed to apply the pack to 
the affected skin site of the previously healed ulcer three times each week for 30 minutes with both legs 
elevated on pillows (we will show the proper height during participant instruction). In preliminary data 
analysis from our ongoing R01, this dosing regimen has been found to be safe and acceptable.  We 
cannot fully analyze our R01 data to determine outcomes on ulcer prevention until the study is completed. 
TABLE 3: SELF MONITORING & MANAGING SIX- MONTH DOSING 
REGIMEN FOR BOTH GROUPS 
Monitoring 
Measure skin temperature of “hot 
spot” with infrared thermometer 
Daily each 
morning 
Temperature date 
and time stamped 
in thermometer 
Management dosing 
Maintenance 
Bolus 
Apply experimental cooling or control 
placebo pack to “hot spot” on lower 
leg or plantar surface of foot; anchor 
with retention net 
3 X/ week for 30 
minutes at a 
consistent time 
of day 
Daily for 5 
consecutive days 
at a consistent 
time of day 

 
 
 
 
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Bolus preventative dosing: If the temperature is 2°F above the mean temperature, calculated as the 
average of the first 30 days of cooling, for 2 consecutive days, an alarm will sound from the thermometer, 
and participants in both groups will be instructed to initiate the bolus cooling dose for 30 minutes over 5 
consecutive days. They will resume the maintenance cooling 3 days later. 
Benchmarks for success: The cooling pack group compared to the placebo will required fewer 
preventative bolus dosages over the course of the 6-month study. 
 
Participant instructions: We will develop a 3-minute YouTube video and DVD of study procedures (self 
monitoring, self management) that will be shown to participants during the baseline visit in order to 
standardize the instruction.  This technique was rated as highly useful by participants in our ongoing 
cryotherapy R01. An example of instructions includes showing how the pack should be applied directly to 
the leg or foot affected skin, anchored with retention net, while reclining in a recumbent position with both 
legs elevated. The flow of information for both groups is as follows: 
• 
Wear the compression stockings and/or diabetic footwear during the day. 
• 
Measure skin temperature of marked “hot spot” with the infrared thermometer each morning before 
getting out of bed to control for the effects of diurnal patterns, eating, drinking caffeinated or alcohol- 
containing beverages, and exercise, which influence skin temperature during the day. Thermometer, 
“back up” log sheet and clipboard with pen will be provided. 
• 
Apply the pack (cooling or placebo) to the lower leg or foot skin and anchor with stretchy net at a 
consistent time each day (e.g., 7 PM). Participants in the control group will be instructed to remove the 
pack from the freezer and use after it has been exposed to room air for 2 minutes. The pack material 
(cotton) is unable to retain the cold. 
• 
Lie supine in the bed or couch with legs elevated 10 inches on pillows during the 30-minute treatment, 
three times each week. Timer will be provided. Participants who have difficulty with the supine position 
may use the reclining position and if possible, use pillows to raise the feet. 
• 
After the treatment, participants will place packs in accompanying plastic storage bag and return to the 
freezer. Freezer temperature should be set at 0°C, the industry standard. All participants will receive a 
freezer thermometer to make sure temperatures are kept at 0°C. If returning the pack to the freezer 
immediately after cooling the leg or foot is difficult for participants who prefer to do the procedure in the 
bed, they can replace the pack the next morning without affecting its temperature, which requires 4 hours 
in the freezer to achieve maximum coldness. Freezer thermometer will be provided. 
• 
If bolus preventative cooling dose is required, participants will do the treatment (cooling and placebo) for 
5 consecutive days, and record dates on “back up” log. 
• 
Re-mark the skin site with the dermal pen (provided) after bathing or showering. 
• 
Wear wrist accelerometer each day during waking hours to monitor physical activity. 
Benchmarks for success: Both groups will score 100% correct on the 5-item post-test administered after 
the instruction. 
 
Outcome measures for Aim 1: 
Incidence of leg ulcers - we will track any ulcers that develop during the course of the study using 
supportive phone calls, logs and participant reports during return visits at months 1, 3 and 6.  These data 
will be entered into REDCap. During month 1, supportive phone calls will be made weekly and then 
monthly by research assistants, who will inquire about new ulcer development. Leg and foot skin will be 
assessed during each visit.  Participants will be instructed to call the research assistant in the event an 

 
 
 
 
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ulcer develops, at which time the participant will be withdrawn from the study.  The effect of cooling on 
ulcers is unknown and could pose a safety risk. 
Benchmarks for success: Although it is difficult to precisely predict the effect of cooling on ulcer incidence 
during the study in these two groups, we view a 50% reduction in the incidence of a leg ulcer in the 
cooling pack group compared to placebo 7,9. 
 
Impact on pain, physical activity and quality of life – pain will be assessed using a visual  analog 
scale (0.99 interrater reliability) 63  and the Brief Pain Inventory (Cronbach’s 0.88) 64, physical activity 
with an accelerometer (Basis Smart Watch, Basis Science, Inc., San Francisco), a user-friendly activity 
monitor  http://www.mybasis.com/and International Physical Activity Questionnaire (IPAQ) (pooled 
Spearman R 0.81) 65, and quality of life with the VEINES QOL/sym Questionnaire (internal consistency 
0.87; test-retest reliability 0.86) 66, the Neuropathic Pain Questionnaire (NPQ) (internal 
consistency 0.82), the Geriatric Depression Scale, and the SF-12 Health Survey. The 
VEINES will be administered to the VLU participant population and the NPQ to the DFU 
participant population. While we recognize that wrist monitors may not be the most accurate in terms 
of energy expenditure, we are working with an atypical population where hip or bicep-type accelerometer 
sensors found  in (i.e.,Bodymedia Fit, and Fitbit Zip), may not be feasible. Thus, we have selected a wrist 
accelerometer based on data that suggest this design may be better suited for chronic populations; 
results revealed acceptable agreement between the Basis watch and indirect calorimetry found in hip 
sensors 67. Basis captures resting movements, is less easy to misplace/lose than hip accelerometers, 
has multiple-sized wrist bands, and numerous programmability options. These three outcomes will be 
assessed at baseline, and months 1, 3 and 6. Benchmarks for success: Compared to the placebo group, 
the cooling pack group will have lower pain scores (lower VAS and IPAQ scores), increased physical 
activity (e.g., more steps taken and participates more frequently in activities,  and higher ratings on the 
SF-12), and improved quality of life (higher ratings on VEINES or NPQ, and GDS). 
 
Analysis plan for Aim 1 
The primary efficacy outcomes are recurrence of ulcers, both venous leg ulcers and diabetic foot ulcers, 
since enrollment into the study (categorical), and changes in pain, quality of life and physical activity from 
baseline to the three subsequent visits at 1, 3, and 6 months post-baseline (continuous). In primary 
analysis we will compare differences in proportions of participants developing a VLU/DFU over the entire 
study period between the cooling pack and placebo groups using chi-square analysis. We will obtain 
odds ratios for the categorical outcome measure recurrence of VLU/DFU adjusted for putative 
covariables such as demographic (age, gender, race/ethnicity, marital status, job category and area of 
residence) and clinical (time since last ulcer, and wearing compression stockings or footwear [yes/no]) 
characteristics using logistic regression modeling (LRM). Modeling will be carried out in a sequential 
fashion. For example a first model will contain recurrence of VLU/DFU (yes/no) as response variable, 
treatment (cooling vs, placebo) as primary variable of interest and time since last ulcer as adjustment 
variable. The model will be further adjusted using sets of putative predictive covariables such as 
demographic and clinical characteristics as well as secondary outcomes pain, quality of life and physical 
activity (step counts). We will examine effect modifications of covariables through inclusion of a 
covariable-by-treatment interaction term in the multivariable models. Analyses will be repeated within the 
ulcer subgroups (VLU and DFU) as appropriate. 
 
Survival distributions for recurrence of VLU/DFU will be obtained for each group using the Kaplan-Meier 

 
 
 
 
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product limit method, and will be compared using the logrank test 63, 64, 65. Cox proportional hazards 
regression modeling (PHM) will be used with time since last ulcer to recurrence of new ulcer as the 
dependent variable and treatment (cooling vs. placebo) as the primary independent variable. Additional 
covariables and interaction terms will be added as described above for LRM analyses. 
 
In analysis of the continuous efficacy outcome measures, we will compare unadjusted mean differences 
in pain and quality of life total scores from baseline to 1, 3 and 6 months via paired t-tests (or 
equivalently non- parametric Wilcoxon Signed-rank test) between the (cooling vs. placebo) groups. We 
will use a general linear models (GLM) approach to compare mean differences for the change from 
baseline outcome measures adjusted for putative predictive covariables. Modeling will be carried out in a 
sequential fashion for each outcome variable individually analogous to the modeling described above. 
Using quality of life as example, the first model will contain change in quality of life from baseline to 6 
months as response variable, treatment (cooling vs. placebo) as primary variable of interest and baseline 
quality of life as adjustment variable. This procedure will be repeated for pain measures as well as the 
accelerometer step counts/physical activities. For the accelerometer, baseline will be established by 
averaging the first 30 daily step counts/activities; change from baseline will be assessed at 6 months as 
described above. 
 
In additional analyses, to examine pain (or analogous quality of life and step counts) change over time, 
the longitudinal profile of pain (quality of life, step counts) will be compared over the active treatment 
period using mixed effects models (MEM) analyses. These analyses will estimate the average change in 
pain (quality of life, step counts) within each group (cooling vs. placebo) and individual change in pain 
(quality of life, step counts) for each participant. MEM analyses allow for missing data, measurement of 
study subjects at different time points during the study, and time varying covariates. MEM can also take 
into account the effect of clustering, i.e. correlation of repeated pain (quality of life, step counts) 
measurements within one subject. The efficacy variable pain (quality of life, step counts) will be used as 
the dependent variable with treatment status (cooling vs. placebo), time (visit) and time-by-treatment 
interaction as primary independent variables. In a second step, additional covariables will be included in 
the models to adjust for putative predictive variables such as demographic and clinical characteristics as 
well as secondary outcomes as appropriate. Effect modifications of covariables will be examined through 
inclusion of a covariable-by-treatment interaction term in the multivariable models. MEM methods (e.g., 
generalized linear mixed models, GLMM) for binary, count, or ordinal outcomes will be applied where 
appropriate. Further, we will determine frequency distributions of adverse events (AEs) and serious 
adverse events (SAEs for the two groups and compare proportions within categories of AEs for cooling 
vs. placebo via chi-square analyses. 
 
Methods for handling missing data: 
The research staff will make every attempt to keep participants in the study and to obtain required 
measurements in order to ensure the completeness of the study data. If study visits are missed to 
minimize potential bias due to missing observations, participants will be contacted by phone and reasons 
for missing   data will be carefully documented. Participation will only be terminated due to developing of 
an ulcer (we will continue to monitor via phone calls), safety reasons, withdrawal of consent, or loss to 
follow-up. Several approaches to handle missing data in the ITT analysis set will be employed. For the 
primary categorical outcome recurrence of venous leg or diabetic foot ulcer every attempt will be made to 
obtain information from participants who dropped from the study. If a participant’s status for recurrence of 
VLU/DFU’s cannot be established we will carry out sensitivity analysis, i.e. assign “developed a 
VLU/DFU” to all participants with missing information (worst case) and compare the results of this 

 
 
 
 
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analysis to the complete analysis (including only participants with complete information for the primary 
outcome variable). For continuous variables using a single end-of-study value (e.g. change from 
baseline), multiple imputation methods will be used. For analyses of longitudinal outcome data, we will 
use longitudinal methods (e.g. mixed models) that are capable to deal with missing data. 
 
Aim 2: Assess the implementation self-management process measures including: a) appropriate 
use of thermometer, b) application of pack to the “hot spot” for 5 consecutive days for 30 
minutes (fidelity to self-management), c) utilization of supportive reinforcement, 
d) reactions/satisfaction of participants, and e) staff ratings and perceptions for replicability. 
Process and fidelity model: Our energetic interdisciplinary team has significant experience with 
rigorous process standards that will be enacted to educate participants in the protocol, provide 
reinforcement, and monitor fidelity, adherence and satisfaction with the treatment protocol in our highly 
supportive CTSA environment. We have created a feasibility/fidelity model 68,69  for our previous studies 
that also includes: recruitment, reach, retention, adherence, documentation, satisfaction, drop-out 
proportions, safety, and side effects. These will be collected by study personnel on the following logs: 
a) Use of thermometer and b.) pack application: Participant treatment forms/checklist. These 
forms have been designed to assist participants to implement the intervention according to directions.  
The forms will undergo cognitive pre-testing and revision early in the award period prior to their use. 
These forms will help investigators answer the following questions: What was adherence to the protocol 
by the participants? What were the challenges and problems to adherence? The design includes check-
boxes for missed applications and reasons to discourage lack of disclosure for lapses. We are cognizant 
of potential bias due to social desirability. During the instructional session research assistants will stress 
the need for participants to be honest, rather then feel they cannot report lapses in adherence.  
 
c.) Reinforcement and d.) participant reactions: Retention telephone, email, and in-person 
reinforcement logs. Contact with participants is part of the monitoring protocol and critical to assuring 
adherence. Contact via supportive phone calls (§C.6.) or emails will also be used to determine whether 
there  are difficulties with adherence, the presence of any side effects, safety, tolerability, comfort, 
concerns about the study, or problems with the disease process. Data pertinent to the operations of the 
trial, participant follow up, and the selection of the efficacy outcomes and measures will be evaluated 
during the treatment phases and at the conclusion of this study. Retention strategies include phone 
contact and contingency rewards. After completion of the intervention and control protocols, participants 
will be asked to complete a brief report form as part of the exit interviews by project director or research 
assistants. This survey will assess their views of the ease or difficulty with the treatment, as well as their 
satisfaction. Participants will be asked what did or did not meet their expectations and asked for 
suggestions on what could be done better if the study were redone. 
Participants will be asked about visits to physicians or other providers during the study and asked to 
report if the study was discussed with them. 
 
e.) Staff observation:  Rating logs and scale. Dr. Kelechi and the project director will observe 10% of 
the participant education sessions on the treatment protocol to monitor fidelity to the participant visit 
protocols (screening, enrollment protocol, and DVD instruction conducted by research assistants). 
 
Other: Participant identification, recruitment, reach and attrition logs. These logs will be kept   
using standardized forms completed by research assistants. These logs will be used to track the 

 
 
 
 
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proportion of persons enrolled in the study each week. To assure sufficient participants are recruited 
each month, Dr. Kelechi and the study coordinator will routinely check logs for completeness and follow-
up, with additional orientation as needed if issues with participant identification and recruitment arise.  We 
will also assess reach (e.g., how far away does participant live from study site, how did he/she learn 
about the study). 
 
Data management logs. These logs will assess feasibility problems and document reasons for 
incomplete instrumentation and missing data. 
 
Aim 2 analysis:  To assess feasibility/fidelity study outcomes we will report the number of contacts with 
participants through telephone and email, the proportion who terminate the study early (drop-outs), 
proportion who are adherent to the study protocol, and proportion who report issues with tolerability and 
are satisfied with the treatment. Participants will complete a researcher developed exit end-
of-study satisfaction survey at the final visit. Differences of fidelity outcomes will be compared 
between the two groups using chi-square tests or t-tests as appropriate (or equivalent non-parametric 
methods). 
 
Data collection time points:  There will be four study visits at which time study personnel will collect 
data on both participant groups. The PI and project manager will also collect data on research staff. 
 
Baseline visit  - demographic information (i.e., age, race, gender, co-morbid conditions, body mass 
index, number of previous ulcers, length of healing time, location, medications taken) and questionnaires 
on pain, physical activity and quality of life will be collected, affected leg or foot skin at the site of the 
newly healed ulcer to identify the “hot spot” will be imaged, procedural instructions for using the 
accelerometer given, protocol for self monitoring of temperature and self management of temperature 
elevation will be shown via DVD and written instructions given, and a test will be administered to assess 
understanding.  Similar to our other studies, we will produce a YouTube video and take-home DVD of 
these instructions for standardization. Supplies include: thermometer, pack and freezer bag (given by 
Research Nexus staff after the research assistant has completed all study procedures) to be kept in 
freezer at all times except during treatment, a freezer thermometer to ensure temperatures are kept at 
O°F, 
skin 
marker, 
study 
logs 
and 
clipboard 
with 
attached 
pen 
for 
recording 
daily 
temperatures/maintenance and bolus cooling (times, dates)/freezer temperature, and timer (for 30 
minutes of cooling). Baseline questionnaires to be administered include: VAS, BPI, IPAQ, SF-12, GDS, and 
the VEINES Qol or NPQ (as applicable). 
 
Visit 1 – (month 1) - the daily month 1 temperature readings taken over 28 – 31 days (depending on the 
month) with the thermometer will be downloaded using a software program and averaged to establish the 
mean skin temperature.  These data will be recorded in REDCap. The infrared thermometer will be 
programmed to sound an alarm when the readings are 2°F above the mean. Also at this visit the skin 
site will be imaged with the infrared camera and uploaded for comparison against the baseline reading. 
Data will also be uploaded from the accelerometer to assess physical activity. Any changes in 
demographics such as taking new medications will be evaluated, and the pain scales will be 
administered. Process measures will be collected including ease of use of thermometer, problems with 
study procedures, and fidelity to self-monitoring assessed (e.g., through downloaded temperature 
readings). Visit 1 questionnaires to be administered include: VAS, BPI, IPAQ, and the VEINES Qol or NPQ 
(as applicable). 
 
Visit 2 – (month 3) – the daily months 2 and 3 temperature measurements and accelerometer 

 
 
 
 
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information will be downloaded, the skin site imaged, and demographic (i.e., changes in co-morbid 
conditions, new medications taken) and pain questionnaires administered. Process measures will be 
collected. Visit 2 questionnaires to be administered include: VAS, BPI, IPAQ, and the VEINES Qol or NPQ 
(as applicable). 
 
Visit 3 – (month 6 final visit) – the daily months 4 – 6 temperature measurements and accelerometer 
information will be downloaded, the skin site imaged, demographic, pain and quality of life questionnaires 
administered. Process measures will be collected. Visit 3 questionnaires to be administered include: VAS, 
BPI, IPAQ, SF-12, GDS, and the VEINES Qol or NPQ (as applicable). During this final visit, an exit 
satisfaction survey interview will be conducted to ascertain information about overall feasibility, problems 
encountered, 
satisfaction, 
recommendations 
for 
changes 
to 
procedures, 
likelihood 
of 
maintaining/sustaining. 
 
Ongoing supportive phone calls: Calls will be made to both groups 24 hours after the start of the 
study, weekly during weeks 1 – 4, and then monthly by research assistants. We will provide 
reinforcement of study procedures, solicit information about problems encountered, adherence, side 
effects, and leg temperatures and answer any questions (§Table 4). 
 
Study staff:  We will elicit feedback using a rating scale we have developed for our ongoing R01 that 
assesses the perceptions of staff, their beliefs regarding the sustainability of the intervention, likelihood of 
implementation into practice, and dissemination potential. 
 
Relevant literature in support of or in disagreement with the potential results on pain: 
We have elucidated the literature in support of monitoring and managing skin temperature, and our 
preliminary work with physical activity suggests a possible benefit (§Significance). The literature is replete 
with the beneficial effects of cooling injured tissue after acute trauma, orthopedic procedures, and 
dermatological therapies, however, less is known about the analgesic effects of cooling the skin on 
chronic ulcer pain 58,70-72,  and in particular, about pain reduction of newly healed skin after prolonged 
healing. We are collecting data in our ongoing R01 to determine if cooling reduces pain, but are unable to 
analyze the data until the study is completed.  If cooling provides pain relief, it may also positively 
influence physical activity and quality of life.  Unfortunately, there is limited research to suggest reduced 
pain/discomfort from cooling previously ulcerated skin positively influences physical activity and quality of 
life in chronic populations. This study seeks to establish this role. 
 
Timeline: Table 4 illustrated the time line for study activities. 
 
TABLE 4: TIMELINE FOR PROPOSED RESEARCH PLAN 
Activities 
YEAR 
1 
2 
3 
4 
Training and hiring of staff, enrollment preparation, DVD design, SOP finalization, 
orientation of staff at Research Nexus, recruitment and marketing plans and 
implementation, participant enrollment, fidelity monitoring 
 
 
 
 
 
 
 
Rolling recruitment and enrollment, ongoing marketing, fidelity monitoring, reports 
 
 
 
 
 
 
 
Data collection including follow-up, reports 
 
 
 
Manuscript preparation/submission, reports 
 
 
 
 
 
 
 

 
 
 
 
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Impact and overall potential problems: In response to RFA-NR-15-001 Chronic Wounds:   Advancing 
the Science from Prevention to Healing (R01), this study will elucidate the impact of cooling newly healed 
chronic venous leg and diabetic foot ulcers. Results of several studies, published in a meta-analysis 73, 
provide evidence that increased skin temperature predicts foot ulcers in patients with diabetes. Our 
research findings suggest increases in lower leg skin predicts VLUs 3.  We have studied self-monitoring 
skin temperature using hand-held infrared thermometers. These patient-centered approaches have 
received considerable attention over the past 20 years for the prevention of diabetic foot ulcers 2,61 and 
for the monitoring of venous leg ulcer-affected skin 3,42,43,50.  This study will further progress skin 
temperature’s role in the self-management to prevent ulcer recurrence. We recognize that there are 
unmodifiable risk factors for ulcer recurrence such as diabetes, cardiac disease and older age 74, 
however, we emphasize that this study addresses a modifiable risk factor, persistent inflammation in the 
remodeling phase of healing. An efficacious cooling intervention that could reduce ulcer recurrence by 
50% will reduce unnecessary health care utilization by thousands of afflicted individuals at potential cost 
savings of $10 billion.  Safety: There have been no reported adverse events associated with our cooling 
treatment. We do recognize that some patients experience neuropathic-type pain (i.e., burning, tingling) 
and will be cognizant of the potential for the cooling therapy to exacerbate these symptoms. Usability: 
The thermometer selected for this study has a memory and thus, we predict that   keeping track of skin 
temperature will be less cumbersome for participants.  We will also assess acceptability of the 
accelerometer for physical activity monitoring. We will ask participants to record temperatures on logs in 
the event of a malfunction. Our experience with clinical trials, and in particular, being able to refine our 
study procedures for this trial, has allowed us to scrutinize our protocols to reduce the potential for 
unanticipated problems. Retention: We will compensate participants $250, will offer a successful 
contingency management plan that includes drawings for additional compensation, and will conduct 
frequent supportive phone calls.   Our long-term goal is to offer an innovative and feasible clinical 
practice approach for the management of   newly healed chronic VLUs and DFUs that are at high risk of 
ulcer recurrence.  Prevention of these complications in a highly challenged population could result in less 
recurrence, fewer days lost from work, less use of pain medications, and improvements in physical 
activity and quality of life. 
 
E. PROTECTION OF HUMAN SUBJECTS 
Participants, 18 years-of-age and older, will be included in the study. The participants must be   able to 
communicate in English. The study will include both genders and to ensure diversity, participants from 
various racial backgrounds representative of the area (~30% black/African-American, ~70% white, ~1% 
Hispanic/ /other) will be invited to participate. There are minimal risks for injury related to MUSTCOOL. 
There have been no reports of skin injury associated with the cryotherapy (cooling) intervention used in 
our ongoing R01, which is the same intervention that will be used in this proposed study to reduce 
inflammation (skin temperature). We have taken more precautions regarding avoidance of frostbite or 
other cooling related injuries (e.g. skin irritation) by reducing the area of the skin to be cooled, from 
regional (cuff applied to entire lower leg) to only a small, localized area of the foot or lower leg. 
Participants will be instructed to report symptoms such as tingling, prickling, and other sensations if noted 
during cooling. The informed consent and Health Insurance Portability and Accountability forms assure 
confidentiality of all information obtained during the study. Participants have the right to withdraw from the 
study at any time without any effect on the care they will receive in the future. Informed consent, 
approved by the Institutional Review Committee, will be obtained by study personnel and signed by the 
participant indicating willingness to participate in the study. 
 
E.1. RISKS TO THE SUBJECTS 

 
 
 
 
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Human participants will be invited to participate in this study to test the preventive cooling intervention 
applied to newly healed skin of healed venous leg and diabetic foot ulcers. The goal is to prevent leg or 
foot ulcer recurrence. We will invite potentially eligible individuals to participate after screening them for 
adequate blood flow using an ankle brachial index (ABI). The healed area will be imaged with an infrared 
camera to capture a skin temperature “map” of the affected skin. Participants will then self-monitor the 
skin temperature of the highest area or “hot spot” with an infrared thermometer daily at home and apply 
a cooling or placebo pack (self-management) to the affected area for 30 minutes, three times each week. 
If an elevation is noted above baseline, they will apply the pack using a bolus-dosing regimen for 5 
consecutive days. The study will be conducted over 6 months and require 4 visits including baseline, then 
months 1, 3 and 6. At each study visit, participants will complete the Geriatric Depression 
Scale (GDS) instrument. Participants with Total GDS scores greater than “5” (suggestive 
of depression) will be provided with 3 referrals to local area mental health care providers 
by study staff. Study staff will document the referral process in the participant’s REDCap 
study eCRF. Process and safety monitoring data will be ascertained during weekly phone calls during 
the first month, then monthly. We will also inquire about safety and tolerability during phone calls and 
during study visits to include adherence (fidelity), side effects, comfort, and any other problems noted 
during the study. Both groups (cooling pack and placebo), during the baseline visit after eligibility is 
determined, will watch a DVD for the sole purpose of standardizing the instructions they receive. 
Participants will then be quizzed on their knowledge of the study procedures, and will demonstrate self-
monitoring with the thermometer, self-managing skin temperature elevation with the pack, when to report 
problems, and the frequency of return visits. 
Targeted/Planned Enrollment Table 
 
Total Planned Enrollment: 180 
 
TARGETED/PLANNED ENROLLMENT: Number of Subjects 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
1 
1 
2 
Not Hispanic or Latino 
107 
71 
178 
Ethnic Category: Total of All Subjects* 
180 
Racial Categories 
 
American Indian/Alaska Native 
0 
0 
0 
Asian 
0 
0 
0 
Native Hawaiian or Other Pacific Islander 
0 
0 
0 
Black or African American 
31 
21 
52 
White 
77 
51 
23 
Racial Categories: Total of All Subjects* 
108 
72 
180 
 
 E.1.a. Human Subject Characteristics. Eligible men and women, 18 years of age and above will be 
approached, invited to participate, and screened to recruit a sample size of 180; 90 participants with 
venous leg ulcers will be randomized to receive the cooling pack or placebo and 90 participants with 
diabetic foot ulcers will be randomized to receive the cooling pack or placebo. The health status 
description of the population is based on the PIs previous experience with study participants from 

 
 
 
 
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previous studies and the demographics of South Carolina. It is anticipated that 95% will have at least one 
co-morbid chronic condition such as hypertension, diabetes, hypercholesterolemia, or arthritis, and 
approximately 60% will be obese. It is anticipated that the average age of the population will be 68 years 
old, 60% female, 40% male. We anticipate< 1% of the population will be Hispanic, 30% black/African 
American, ~70% white, which reflects the ethnic make-up of the recruitment area. We will include English 
speaking individuals only due to limited resources and the special needs of bilingual and culturally relevant 
protocol/materials. We will include individuals with co-morbid conditions such as diabetes, hypertension, and 
high cholesterol. Those with vascular conditions such as peripheral arterial disease will be excluded. 
 
INCLUSION OF WOMEN AND MINORITIES 
Women and underrepresented minorities will be included in the study within the available population.  Although 
in this study race/ethnicity is not believed to have a direct impact on any of the research aims, special efforts 
will be made to recruit eligible underrepresented minority participants. The sites from which we will recruit 
participants have been selected because the underrepresented minority patient populations are 50% or higher. 
In the investigator’s preliminary studies, minority participation ranged from 30–80%, and equal numbers of men 
and women, both black and white were easily recruited for inclusion. Due to the seasonal work issues related 
to the Hispanic population, it is anticipated that ~1% of the patient pool will be recruited for this study. The 
latest U.S. Census Bureau figures show that 15.1% of rural Americans are living in poverty. The national 
average is 13.2%.  The poverty rate in South Carolina is 17.0%. 
INCLUSION OF CHILDREN 
Although vascular disorders appear as early as the first decade of life, venous leg and diabetic ulcers rarely 
occur in children, and therefore, children under 18 will not be recruited. 
 
E.1.b. Sources of Materials. Materials obtained from the human participants include demographic data, 
circulation status (ABI), skin temperature mapping, physical activity with an accelerometer, and   
questionnaires that will be recorded in an electronic documentation web-based data management system 
(REDCap), from laptop/tablet computers. In the event of a failure to access REDCap, paper source 
documents have been created. All paper data will then be entered into the system as soon as possible. 
These documents will then be stored in the PIs office in a locked file. Demographic data about gender, 
age, ethnicity and pertinent medical history will be collected from the participants by self-report in order 
to describe the sample. These data will be used for research purposes only. REDCap is password 
protected and will only be accessible to select members of the research team, including the PI, project 
director and biostatistician. 
 
E.1c. Potential Risks. After informed consent is obtained, screening data collected, and eligibility 
established, 180 individuals will be enrolled. Collecting data poses a minimal risk to confidentiality. All 
enrolled participants w i l l  be given instructions about the study procedures both verbally and in writing. 
The PI, project director, and biostatistician will have access to the data for analysis. If paper documents 
are necessary in the event of REDCap network failure, documents such as source documents, consent 
and HIPAA forms, questionnaires, and interview data will be stored in a locked file in the PIs office. The 
PI and project director will be the only study personnel with access to the paper files. There is minimal 
risk to the participants, as the cooling intervention has had no side effects noted in our ongoing study. All 
procedures are non-invasive and non- pharmacological. There may be some minor inconveniences to 
participants as the tests will take about 1 hour and they will have to remain in the supine position for 
approximately 20 minutes during the study to ascertain the ABI. Every effort will be made to make the 

 
 
 
 
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participants comfortable and provide privacy. 
There are no known alternative treatments for this proposed intervention. 
 
E.2.  ADEQUACY OF PROTECTION AGAINST RISKS  
E.2.a. Recruitment and Informed Consent The recruitment plan includes referrals from our well-
established clinical sites that have been actively involved in our previous research studies. We have 
access to a diverse participant pool from rural settings from which to recruit. We will recruit underserved 
and underrepresented minorities. We have developed an extensive recruitment plan for our previous 
studies and have refined several strategies to ensure our enrollment targets are met for this study.  
Based on our recruitment metrics from our ongoing R01 and Dr. Kelechi’s experience as the director of 
recruitment of MUSCs CTSA, we expect to enroll 1 subject for every 5 approached and screened (#1 
reason for not enrolling is an abnormal ankle brachial index). The goal is to enroll ~6 subjects per month 
for 3 1/2 years, accounting for an expected attrition rate of ~25% (nature of the chronically-ill population 
with frequent hospital admissions).  Our recruitment plan includes referrals from centers and practices 
(50% of participant will be referred), however we anticipate using other recruitment methods that we 
have found particularly successful including television, radio and billboard advertisements, use of our 
CTSA’s SCResearch.org website, and our community based participatory research advisory groups. We 
have budgeted for these strategies accordingly. There is a need to incentivize center and practice 
referrals and to that end, we will provide $20 for every enrolled participant in the form of a “credit” gift 
card that can be used for whatever purposes deemed appropriate by the practice. Retention: We also 
have implemented a very successful contingency management approach for retention at one of our study 
sites (a drawing from a bowl at each visit with the opportunity to win from $1 to $100). The attrition rate 
for this site is ~17% compared to 30% (average of other sites’ attrition rates). 
 
We will provide packets of information about the study to referral sources that will provide information 
about calling a designated number to learn more about the study. Our study team will contact potentially 
eligible participants, discuss study details, and if interest is expressed in participating in the study, and 
the baseline study visit appointment will be arranged. The study will be conducted at the Research Nexus 
(CTSA) at MUSC, the Spartanburg Wound and Healing Center, and at East Carolina University. We will 
visit the referral sites on a regular basis to evaluate participant identification strategies and to assess the 
potential for selection bias. IRB approved flyers and marketing materials will be available at these sites, 
and disseminated through a network of local area provider clinics, and at the Charleston Veteran’s Affairs 
Medical Center (VAMC-534). Participants will receive $250 compensation for participation: $25 first visit 
screening; $50 baseline visit; $50 for visits 2 and 3, $75 for visit 4. 
 
The informed consent and Health Insurance Portability and Accountability Act (HIPAA) forms assure 
confidentiality of all information obtained during the study. Participants have the right to withdraw from the 
study at any time without any effect on the care they will receive in the future. Informed consent, 
approved by the Institutional Review Committee (IRB), will be obtained by the research nurses and 
signed by the patient indicating willingness to participate in the study. All study personnel have 
successfully completed the CITI Course in The Protection of Human Research Participants and Clinical 
Research Training through the National Institutes of Health. Certificates are on file at the IRB. A 
document, required by the IRB, will have recorded information regarding the time and date of consent, 
participant screening time and date, participant   enrollment time and date, and study completion time 
and date. The research assistant obtaining this information will sign after each entry. To determine 
participant understanding of the nature of the study, the research assistant will assess understanding by 
asking the following questions (participants must be able to answer “yes” to all): 

 
 
 
 
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• 
briefly describe the purpose of the study. 
• 
report the purpose of taking skin temperature and using the pack. 
• 
describe the expectations for the study. 
• 
demonstrate how to operate the thermometer and accelerometer. 
• 
demonstrate how to apply pack. 
• 
state that the study lasts for six months. 
• 
report that they will attend a three additional study visits during the six-month intervention trial. 
• 
state that they agree to wear compression stockings and/or diabetic footwear 
 
 
E.2.b. Protection Against Risk 
In the event of an unexpected medical or other event, the patient will be instructed to contact the 
research assistant. Based on the experience of the PI, it is anticipated that the risk of adverse events 
(AEs) will be acceptably very low. In the event of an AE, it will be recorded, the PI notified, and submitted 
to the IRB according to institutional procedures. All AEs will be reviewed by the PI and project director. 
Maximum efforts will be undertaken to ensure the safety of all participants. Study personnel will receive 
extensive training and orientation on procedures and protocols. Participants will be instructed on how to 
access the PI or research assistants in the event of a study-related question. In the event of study-
related illness or injury, participants will be instructed on how to access health care. Although we do not 
anticipate any problems, we will address any that might arise such as reports of uncomfortable sensations 
in the leg or foot during or after pack application or the development of new leg or foot ulcers. This 
information will be recorded and if deemed as an AE by the research team, institutional procedures will 
be followed for reporting them. An order from the primary health provider is not required for participation 
in this study as there is oversight by the study MD, Dr. King and Dr. Flume at the Research Nexus. The 
accelerometer used to measure activity is small and does not pose any problems with being anchored to 
clothing. 
 
Safety and side effects. There has been considerable attention given to the selection the cooling pack 
used   in this study. We have refined the protocol, as noted in the overview to cool less surface area, 
targeting the “hot spot” only. We have taken precautions to use a cooling approach that does not 
aggressively or quickly reduce skin temperature, rather, the material used in the gel wrap does not freeze 
into a solid state, thus does not rapidly pull heat from the tissue. It is also enclosed in two polyethylene 
covers to prevent sticking to the skin. The pack will be anchored with a stretchy net “tubing” that can be 
pulled onto the foot or lower leg. In the event that the participant falls asleep or forgets to remove the 
pack during the procedure, the pack does not continue to transfer heat from the skin after approximately 
15 minutes. There are minimal risks for injury to the skin using the methods of measuring skin 
temperature with the thermometer. 
 
E.3.  POTENTIAL BENEFITS OF THE PROPOSED RESEARCH TO THE SUBJECTS AND OTHERS  
Conditioning the lower legs may improve some of the symptoms associated with leg ulcers such as pain 
and discomfort. The use of the accelerometer and Smartphone for providing patient feedback and giving 
reminders, involves patients in their own care and may help them feel empowered to reduce the negative 
effects of having a chronic disease. The long-term effects of having better conditioned lower legs may 
provide protection for ulcer relapse in high risk groups of patients, and could lead to greater health 
improvements if the potential to engage in more aerobic forms of physical activity is reached. This study 
involves minimal risk as a non- invasive study. The benefits outweigh the slight inconvenience to the 
patient in terms of anticipated new knowledge gained from the study. 

 
 
 
 
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E.4.  IMPORTANCE OF THE KNOWLEDGE TO BE GAINED 
This study will provide valuable information to test an intervention that could potentially improve outcomes 
in participants vulnerable to lower leg and foot ulcer recurrence. The science of using infrared technology 
has led to advancements in ulcer prevention measures for both venous and foot ulcer participants.  Non-
pharmacotherapeutics (i.e., sequential compression devices, temperature mapping) have contributed to 
significant improvements in self-management of venous disease and diabetic foot complications. 
However, there has been little attention directed toward ulcer prevention strategies for chronic ulcer 
recurrence that incorporate an intervention that includes patient self-managing of signals of tissue 
damage such as inflammation. We propose to “re-invent” an old, yet effective cooling method that has 
negated the effects of inflammation associated with acute tissue injuries. This simple, inexpensive 
method, using a small pack, could improve current guideline-guided usual care by focusing on skin 
temperature, using maintenance cooling, and then bolus doses for elevations noted outside of the 
baseline “normal” temperature. This approach is novel in that it targets newly healed chronic ulcers. 
Finally, if the intervention is valid and reliable in this high-risk ulcer population, we envision our strategy 
will become a mainstream practice standard for the prevention of ulcer recurrence in the future. 
 
 

 
 
 
 
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E.5.  SUBJECT SAFETY AND MINIMIZING RISKS (Data and Safety Monitoring Plan) 
The study has a well-developed DSMP that has undergone NIH/NINR SRG review and approval. This plan is 
contained below: 
 
 
Application number: 1 R01 NR015647-01  
Project title: Monitoring and managing newly healed chronic leg and foot ulcer skin temperature: a cooling 
intervention (MUSTCOOL) to prevent ulcer recurrence 
Principal investigator: Teresa J. Kelechi, PhD, RN 
 
DATA SAFETY AND MONITORING PLAN (DSMP) 
 
SECTION A. Monitoring Entity 
Considering the study rationale, population, procedures, and the risk:benefit profile, the overall risk level for 
participation in this study is classified as: Minimum Risk. The study will employ the use of a Data Safety 
Monitoring Committee (DSMC) that will meet semi-annually across all years of the study. The DSMC members 
are charged with reviewing safety and trial progress and providing recommendations to the PI and MUSC IRB 
with respect to study continuation modification, and termination.  
 
 
1) Data Safety Monitoring Committee (DSMC) 
The study’s DSMC is comprised of the following individual members: 
• 
Dana King, MD, Study Physician (SP) and Chair - primary responsibility 
• 
Naohiro Shibuya, DPM, Wound Expert (WE) 
• 
Martina Mueller, PhD, Biostatistician (BS) 
• 
Mohan Madisetti, MS, Project Manager (PM)   
 
2) Individual Roles and Responsibilities 
Principal Investigator, (PI). As PI, Dr. Kelechi will overall be responsible for the immediate protection of all 
human participant study participants.  
Study Physician, Dr. King who is Chair of the Division of Family Medicine, Robert C. Byrd Health Science 
Center, Morgantown WV, has a master’s degree in clinical research, and will serve as the Study Physician 
(SP) and Chair of the DSMC. Dr. King will correspond semi-annually with the DSMC to review de-identified 
cumulative AE study data to assess any impact on the safety of participants or on the ethics of the study. As 
the Chair and SP, Dr. King will be primarily responsible for the reviewing of all cumulative reported SAE that 
are related to study treatment, the provision of DSMC recommendations from data safety monitoring reports to 
the PI, MUSC’s IRB and the NIH/NINR. Dr. King will be immediately notified of the occurrence of any 

 
 
 
 
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reportable SAE by the PM and will be provided with the necessary information to provide an informed 
recommendation in real-time regarding the protocol and human subject safety. Dr. King has no real or 
apparent conflict of interest that would affect his performance in this role on the study. 
Wound Expert, Dr. Shibuya who is an Associate Professor of Surgery in the Division of Podiatry at Texas 
A&M Health Science Center, and specializes in wound management will serve as a member of the DSMC. As 
a member, Dr. Shibuya will also correspond semi-annually with the other members of the DSMC to review de-
identified cumulative AE study data to assess any impact on the safety of participants or on the ethics of the 
study and provide expert safety recommendations. Dr. Shibuya has no real or apparent conflict of interest that 
would affect his performance in this role on the study. 
Biostatistician, (BS). Dr. Mueller will be responsible for conducting semi-annual interim data analyses, 
generating semi-annual AE safety reports from the electronic study research database and disseminating de-
identified information to all members of the DSMC. The interim data analyses will only include safety related 
results; analyses in regards to study outcome will not be performed. The interim AE safety reports will provide 
typology, frequency data and outcomes of all reported and documented AEs in the electronic study database. 
As a member of the DSMC, Dr. Mueller will also participate in semi-annual DSMC meetings. 
Project Manager, (PM). Mr. Madisetti will be responsible for the classification of all reported adverse events 
(AE) and ensuring that all serious adverse events (SAE) are forwarded to the PI and SP in real time and in 
compliance with MUSC IRB and NINR’s reporting requirements. In addition, and in conjunction with the PI, 
the Mr. Madisetti will be responsible for amending the protocol in accordance with the DSMC 
recommendations, submitting reportable SAEs to the IRB, and submitting annual Progress Reports to the 
NIH/NINR through MUSC’s OSRP. As part of the DSMC, he will be responsible for: conducting monthly 
internal quality control audits on all participant records and notifying the PI of any deficiencies; assisting in the 
generation of ad hoc participant data safety reports as requested; and, the forwarding of reportable SAE to the 
NIH/NINR Program Official through MUSC’s OSRP within 72hrs of IRB review and acknowledgement. Mr. 
Madisetti will also be responsible for following up on reported AEs to monitor outcomes and provide for the 
continuity of care for study participants. 
 
 
SECTION B. Procedures for Safety, Risk and Confidentiality 
1) Monitoring Study Safety 
From the initial screening of participant by inclusion and exclusion criteria to the informed consent process to 
the provision of participant study instruction to staff training in Good Clinical Practices (GCP) and regulations 
pertaining to the Conduct of Human Participant Research to weekly contact with participants to internal quality 
control audits and protocol fidelity monitoring to the real-time review of AE by the SP and DSMC to the 
oversight of MUSC’s IRB, procedures for monitoring study safety are consistently afforded throughout study. 
Specific procedures include: 
• 
All participants will be screened for inclusion and exclusion per the protocol 
• 
All participants will be fully informed as to all known risks and the possibility of risk from study 
participation in the informed consent process. These risks are minimal. 
• 
AEs and changes in medical status will be elicited at every participant visit and contact. 
• 
All participants will be given a 24 hrs. AE reporting phone number to the study nurse and instructed to 
notify the researchers of any/all suspected or experienced adverse events whether they believe them 
to be related to the intervention or not. 

 
 
 
 
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• 
The SP will have access to real-time AE study data and will be able to provide immediate 
recommendations to the PI and PM. 
• 
The PM will track all reported participant AEs through to resolution. Please see Section C. 1 – 4. 
• 
The BS shall generate semi-annual AE reports for the PI and DSMC to review. 
• 
The PM will conduct a quarterly internal quality control audit of the study and all participant records to 
ensure compliance with MUSC IRB regulations and notify the PI of any deficiencies; the PM will work 
with the PM to correct any errors. 
• 
The PI and/or designee will observe and evaluate ten (10%) percent of eligibility screening visits, 
informed consents and study instructions performed by IRB approved study personnel and provide 
feedback and/or retraining of study personnel if fidelity to both applicable federal regulations and the 
protocol is not observed. 
• 
All investigators and researchers will maintain active CITI training. 
• 
Investigator performance and compliance will be provided for through MUSC IRB and ORI study 
oversight. 
• 
All reportable events, including protocol deviations will be forwarded to the NIH/NINR Program Official 
through MUSC’s OSRP within 72hrs of IRB review and acknowledgement. 
 
2) Minimizing Research-Associated Risk 
Diligent study safety monitoring will be conducted by the PI and all members of the DSMC throughout the 
conduct of this study in compliance with the following required elements of MUSC IRB’s continuing review 
process: 
1. Tracking and follow-up of participant accrual including  withdrawn consents will minimize risk by 
identifying, disclosing, and mitigating any potentially unknown risk(s) of harm to study participants. 
These risks are minimal. 
2. Timely and appropriate reporting of informed consent process deficiencies, protocol deviations, 
privacy breaches, conflicts of interest, and/or changes in personnel. 
3. Ongoing soliciting, monitoring and appropriate reporting of adverse event activities. 
4. Timely and appropriate IRB submission of safety-related documents such as audit reports, sponsor 
progress reports, ISM reports, and other materials or communications that might impact the safe 
conduct of this study. 
5. Active cooperation with the IRB, ACO, sponsor, and other applicable entities in the event of a random 
or for-cause internal or external audit. 
Institution-Wide Assurances 
This protocol will be conducted fully in keeping with the signed MUSC IRB Principal Investigator Statement of 
Assurance and Department Chair’s Statement of Assurance, when submitted to the IRB as a required 
component of the MUSC IRB Human Research Review Application. An application will be submitted to the 
MUSC IRB if/when this project is approved and funded by NIH/NINR. Assurances include the following safety-
related agreements, signed and dated by the PI. 
3) Protecting Confidentiality of Participant Data 
Participant Screening and Enrollment. All data from participants screened for the study will be entered into 
electronic study database. Designated research staff will collect, gather, and enter required data (written 
informed consent, HIPAA Authorization, medical history and demographics) onto study data forms. Screened 
patients who do not meet study eligibility will have specific screening data entered into the study database. 
The collected data will be helpful in examining the patient population and feasibility of enrollment criteria and 
will include gender, age, race and reason for exclusion. All dates will be shifted and other Personal Health 
Information (PHI) will be removed from the study database upon study completion. All data obtained from this 

 
 
 
 
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study will be used for research purposes only and will comply with Federal HIPAA regulations.  Master 
Screening and Enrollment Logs will be maintained by the PM and will be used to prepare reports on accrual 
and attrition for the PI and DSMC. 
Case Report Forms. All proposed study specific case report forms (source documents) for data collection will 
be designed by the PM in concert with the PI and BS, and transferred by the PM into electronic Case Report 
Forms (eCRFs) for use in the study’s REDCap database. These study specific eCRFs source documents 
(study logs for correspondence, contact with provider, compensation and other forms such as pre-eligibility 
screens) will be coded by the participant’s unique study ID# for all data collected including study instruments 
will be maintained in the participant research record and/or their electronic medical record that will be made 
accessible to study monitors. Completed instruments that require signature on a paper CRF will be scanned 
and uploaded into the study database to all for remote electronic safety monitoring as well as maintained on 
file in accordance with MUSC policies and applicable Federal Regulations for the Conduct of Human 
Participant Research.  
Binders. The PM will prepare and maintain a participant-specific binder for each participant containing all non-
eCRFs records. A regulatory file will also be maintained to include the IRB-approved Protocol, original 
Informed Consent documents, HIPAA forms and other study-related regulatory documents. All paper research 
records and CRFs will be maintained in a locked file cabinet, stored in a room for research files that is 
accessible only via a password protected entry system that features security cameras, within the College of 
Nursing. Access to the research records, study database and PHI’s will be restricted to study personnel as 
approved by the PI and MUSC IRB. As with all studies conducted at MUSC, this study is also eligible for a 
random audit by MUSC Office of Compliance. 
Data Processing. This study will use Research Electronic Data Capture (REDCap) for data capture and 
management. REDCap is a software toolset and workflow methodology for the electronic collection and 
management of research and clinical trials data. REDCap provides secure, web-based, flexible 
applications, including real-time validation rules with automated data type and range checks at the time of 
data entry. Exports are made available for several statistical packages including SPSS, SAS, SATA, R and 
Microsoft Excel. The study-specific REDCap electronic database will be designed and developed by the PM in 
concert with the BS.  The provision of REDCap is made available through the South Carolina Clinical & 
Translational Research (SCTR) Institute at MUSC with NIH Grant awards UL1RR029882 and UL1TR000062.  
Data Security. Ensuring data security, compliance with 45 CFR 46 and maintaining the integrity of PHI is a top 
priority. MUSC has Standard Operating Procedures (SOP) to ensure a high level of data security while 
coordinating electronic and paper data management activities for clinical research trials. The REDCap study 
database will be hosted in the Biomedical Informatics secure data center at MUSC, a secure environment for 
data systems and servers on campus, and includes firewall, redundancy, failover capability, backups and 
extensive security checks. The secure data center has strict access control; only authorized core personnel 
may access the facility un-escorted. Only authorized users are allowed to connect to the network, and the 
security of the network is actively monitored.  Power and environmental controls have several layers of 
backups, from interruptible power supplies to alternate and redundant feeds to the local utility company. The 
REDCap system administrator contributes to the maintenance of institutional disaster recovery and business 
continuity plans.  Load balancers and a highly fault tolerant SAN infrastructure contribute to high availability.  
The REDCap system itself has several additional layers of protection including password protection. Access to 
the data and its security is managed institutionally by sponsored login IDs through a Shibboleth login with an 
MUSC issued NetID and features a user account management filter that controls who can access the data and 
to what degree. All personnel must pass an employment background check before being issued an ID. 
Password complexity, history and expiration standards are implemented at the institutional level. Access to 
individual REDCap projects and their data is managed by the owner of the project. All transactions are 
securely delivered to the application using Secure Sockets Layer (SSL – SHA-1 with RSA Encryption; 2048-

 
 
 
 
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bits). It is then transmitted internally (behind the firewall) to the database server. All transactions are logged at 
the server layer (httpd logging), application layers (REDCap logs activity to a database table), and the 
database layer, using both query and binary logging. This feature provides audit trails for all changes, queries, 
data exports and reports. MUSC Information security policies are available at: https://mainweb-
v.musc.edu/security/policy/  
Data Entry. Only MUSC IRB approved study personnel that are authorized to have access to the REDCap 
study database will be granted password access. Study personnel using computers that are connected to the 
Internet will directly enter data into the remotely housed database. As such, no electronic study data will be 
stored on hardrives and/or any portable electronic devices. Additionally, all personnel with access to the 
database will have current University of Miami CITI training in the Conduct of Human Subject Protections, and 
their respective institution’s HIPAA and Information Security trainings that are completed annually. Each 
participant will be assigned a unique study identifier, all PHIs will be masked, and data exports will be limited to 
the PI, the PM and the BS for generating reports and the conduct of statistical data analysis. 
Data Monitoring. Ongoing quality control procedures will be implemented for data collection, storage and 
processing. The PM will conduct monthly monitoring of the study database and generate a report for the PI to 
review at team meetings. Standing agenda items for these meetings will include participant recruitment and 
retention, AE’s, protocol deviations, data integrity and overall study conduct. The PM will work to resolve and 
validate discrepant data. Discrepancies that warrant clarification will be sent to appropriate parties for review 
and resolution. All data entry and changes made in the study database by authorized study personnel will be 
automatically logged by REDCap, and provide a transparent visible audit trail for reviewers. 
 
SECTION C.  
Procedures for Identifying, Reviewing and Reporting Adverse Events 
1) Identifying. Potential minimum risks identified for participants are outlined in the Protection of Human 
Participants and will also be outlined in the IRB-approved informed consent document. Additional unknown 
risks may occur and, if so, will be identified through diligent monitoring by the PM and the frontline research 
team throughout the conduct of this study. During the informed consent process, participants will be advised 
of the potential minimum risks of participation as identified in the IRB-approved informed consent document 
and reminded throughout the study that the researchers should be promptly informed about any concerns 
regarding potential side effects, adverse events, or clinical deterioration. Participants will also be instructed to 
notify the PI and/or designee of any suspected adverse events immediately if possible. Throughout the course 
of study enrollment, at each study visit, the researchers will elicit information about experienced AEs and 
monitor participant progress. The PM will maintain an electronic record of all reported adverse events and 
notify the PM and SP of all reportable events as they occur. The SP will have real-time access to the study 
database to review and monitor all SAEs that were reported as related to the intervention. The PM will 
generate and provide de-identified semi-annual administrative human participant safety reports for the DSMC 
to review participant progress, accrual and attrition rates. Additionally, the BS will generate semi-annual 
safety reports for the DSMC to provide for the monitoring of the frequency of all reported side effects and 
AEs. 
2) Reviewing. Adverse events will be assessed and evaluated by the members of the DSMC according to the 
following MUSC’s IRB Adverse Event Reporting Policy 
http://academicdepartments.musc.edu/research/ori/irb/HRPP/HRPP%20Guide%20Section%204.7: 
• 
Expected/Anticipated—Identified in nature, severity, or frequency in the current protocol, informed 
consent, investigator brochure, or with other current risk information. 

 
 
 
 
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• 
Unexpected/Unanticipated—Not identified in nature, severity, or frequency in the current protocol, 
informed consent, investigator brochure, or with other current risk information. 
• 
More Prevalent—Occurs more frequently than anticipated or at a higher prevalence than expected. 
• 
Serious—Results in death, is life threatening, requires inpatient hospitalization or  prolongs existing 
hospitalization, results in persistent or significant disability/incapacity, cancer, overdose, or causes a 
congenital anomaly/birth defect. 
The relationship of adverse events to study participation will be determined by the DSMC according to the 
MUSC IRB Adverse Event Reporting Policy: 
• 
Unrelated—There is not a reasonable possibility that the adverse event may have been  caused by the 
drug, device or intervention. 
• 
Possibly Related—The adverse event may have been caused by the drug, device, or  
intervention, 
however there is insufficient information to determine the likelihood of this possibility. 
• 
Related—There is a reasonable possibility that the adverse event may have been caused by the drug, 
device or intervention. 
3) Reporting. All reportable AE, SAE and unanticipated problems experienced by participants will be reported 
to the NIH/NINR and MUSC IRB in compliance with their Adverse Event Reporting Policy requirements, using 
the IRB's password protected on-line secure server adverse event reporting system. Within 24 hours after a 
reportable AE, SAE or unanticipated problem has been reported by the participant, it will be initially graded by 
the PM, forwarded to the study’s SP for review and approval, and then will be submitted by the PI to MUSC 
IRB. The Institutional Official(s) will review the event and discuss the report with the IRB Chair and the Director 
of the Office of Research Integrity. After IRB review and acknowledgement, the PI will further review, and the 
PM will forward a copy of the reportable AE, SAE or unanticipated problem and IRB acknowledgement letter to 
the NIH/NINR Program Officer through MUSC’s OSRP. The activities will be reported to the NIH/NINR within 
72hrs. In addition, all cumulative reportable AE, SAE and unanticipated problems included in the ISM reports 
will be submitted to the NIH/NINR in the PI’s Annual Progress Reports. 
4) Examples of Potential Reportable Adverse Events: In accordance with MUSC IRB Adverse Event 
Reporting Policy, an AE is reportable is it meets all of the following criteria: 1) is unexpected 2) is related 
and/or possibly related, and 3) is serious and/or suggests that the research places participants or others at a 
greater risk of physical or psychological harm than was previously known or recognized. Additionally, per 
MUSC’s policy all participant deaths, protocol deviations, complaints about the research, and breaches of 
confidentiality are reportable events. From our previous work among this comorbid population, an example of 
an AE would be the appearance of edema of the lower extremities that is related to the participant’s underlying 
chronic venous insufficiency. Depending on the severity, the possible steps to be taken include referral to a 
medical provider, and/or withdrawing the participant from the study and inviting him or her to restart after acute 
symptoms subside. An example of an SAE would be the death of a participant from acute renal failure, which 
although would be viewed as unexpected and unrelated to the intervention is nonetheless a reportable serious 
event. No further steps would be taken except to review, grade and report the event to all applicable agencies. 
An example of an unanticipated problem would be the participant strains his or her back while taking their 
temperature of the ulcer “hot spot”. The steps in this case would be to withdraw the participant from the study 
and invite him or her to restart the study after the strain has resolved. These events and problems will be 
reported in accordance with the IRB and NIH/NINR policy as noted in Section C.3. 
 

 
 
 
 
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SECTION D. Multi-site Monitoring and Compliance 
This is not a multi-site study. 
 
SECTION E. Assessment of External Factors 
The PI will conduct a semi annual assessment of external factors through a review of literature related to new 
developments in the areas of diabetic foot ulcer and venous leg ulcer prevention, and other approaches that 
may have an impact on the safety of participants or on the ethics of the study. To determine whether any 
changes are necessitated to the study protocol, the DSMC will review any identified literature or product safety 
data that may pose as a potential impact to the risk benefit ratio study and/or safety of study participants. 
 
SECTION F. Interim Analysis 
Based upon our prior extensive research in this field among this same population and the minimal risk 
associated with the intervention, there is no stopping rule for this study. Accordingly, interim futility analysis will 
not be performed. However, the BS and PM will generate semi-annual qualitative interim analysis reports on a) 
adverse events; and b) data obtained during phone call and returned end-of-study surveys to understand 
issues related to the uptake, usability, and adoption of the cooling protocol among this population. We will 
evaluate the screening and enrollment procedures, barriers to participation and retention, including, safety, 
adherence, acceptability, technology problems (thermometer malfunction) encountered if any, and user 
feedback from the participants. The information gained from this structured process will inform the design for an 
implementation/dissemination study aimed to facilitate the use a leg and foot ulcer prediction/prevention standard 
of care. 
 
 
 

 
 
 
 
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F. REFERENCES/LITERATURE CITATIONS 
1. 
Lavery LA, Higgins KR, Lanctot DR, Constantinides GP, Zamorano RG, Armstrong DG, Athanasiou 
KA, Agrawal CM. Home monitoring of foot skin temperatures to prevent ulceration. Diabetes care. 
2004;27(11):2642---2647. 
2. 
Bharara M, Schoess J, Armstrong DG. Coming events cast their shadows before: Detecting 
inflammation in the acute diabetic foot and the foot in remission. Diabetes/metabolism research and 
reviews. 2012;28 Suppl 1:15---20. doi: 10.1002/dmrr.2231. 
3. 
Sayre EK, Kelechi TJ, Neal D. Sudden increase in skin temperature predicts venous ulcers: A case 
study. Journal of vascular nursing : official publication of the Society for Peripheral Vascular 
Nursing. 2007;25(3):46---50. doi: 10.1016/j.jvn.2007.06.002. 
4. 
Enwemeka CS, Allen C, Avila P, Bina J, Konrade J, Munns S. Soft tissue thermodynamics before, 
during, and after cold pack therapy. Medicine and science in sports and exercise. 2002;34(1):45--- 50. 
5. 
Nemet D, Meckel Y, Bar---Sela S, Zaldivar F, Cooper DM, Eliakim A. Effect of local cold---pack application 
on systemic anabolic and inflammatory response to sprint---interval training: A prospective comparative 
trial. European journal of applied physiology. 2009;107(4):411---417. doi: 10.1007/s00421---009---1138---y.    
PubMed  Central PMCID:  PMC2762537. 
6. 
Castellani JW, IK MB, Rhind SG. Cold exposure: Human immune responses and intracellular 
cytokine expression. Medicine and science in sports and exercise. 2002;34(12):2013---2020. doi: 
10.1249/01.MSS.0000041400.21166.79. 
7. 
Margolis DJ, Malay DS, Hoffstad OJ, Leonard CE, MaCurdy T, Lopez de Nava K, Tan Y, Molina T, 
Siegel KL. Prevalence of diabetes, diabetic foot ulcer, and lower extremity amputation among 
medicare beneficiaries, 2006 to 2008: Data points #1. Data points publication series. Rockville 
(MD)2011. 
8. 
DeCotiis M, Konz EC. Minimizing complications of pain and dressing adherence in the treatment of 
venous leg ulcers. Ostomy/wound management. 2008;54(11):12---16. 
9. 
Margolis DJ, Bilker W, Santanna J, Baumgarten M. Venous leg ulcer: Incidence and prevalence in 
the elderly. Journal of the American Academy of Dermatology. 2002;46(3):381---386. 
10. 
Gonzalez---Consuegra RV, Verdu J. Quality of life in people with venous leg ulcers: An integrative 
review. Journal of advanced nursing. 2011;67(5):926---944. doi: 10.1111/j.1365--- 2648.2010.05568.x. 
11. 
Heinen MM, Evers AW, Van Uden CJ, Van der Vleuten CJ, van de Kerkhof PC, Van Achterberg T. 
Sedentary patients with venous or mixed leg ulcers: Determinants of physical activity. Journal of 
advanced nursing. 2007;60(1):50---57. doi: 10.1111/j.1365---2648.2007.04376.x. 
12. 
Sen CK, Gordillo GM, Roy S, Kirsner R, Lambert L, Hunt TK, Gottrup F, Gurtner GC, Longaker MT. 
Human skin wounds: A major and snowballing threat to public health and the economy. Wound 
repair and regeneration : official publication of the Wound Healing Society [and] the European 
Tissue Repair Society. 2009;17(6):763---771. doi: 10.1111/j.1524---475X.2009.00543.x. PubMed Central 
PMCID: PMC2810192. 
13. 
Reeder S, de Roos KP, de Maeseneer M, Sommer A, Neumann HA. Ulcer recurrence after in--- 
hospital treatment for recalcitrant venous leg ulceration. The British journal of dermatology. 
2013;168(5):999---1002.  doi:  10.1111/bjd.12164. 
14. 
Nelson EA, Bell---Syer SE. Compression for preventing recurrence of venous ulcers. The Cochrane 
database of systematic reviews. 2012;8:CD002303. doi: 10.1002/14651858.CD002303.pub2. 
15. 
Lavery LA, Lavery DC, Hunt NA, La Fontaine J, Ndip A, Boulton AJ. Amputations and foot---related 

 
 
 
 
Version 10.0 
 
        
07/23/18  
 Page 32 of 39 
 
hospitalisations disproportionately affect dialysis patients. International wound journal. 2013. doi: 
10.1111/iwj.12146. 
16. 
Hunt D. Diabetes: Foot ulcers and amputations. American family physician. 2009;80(8):789. 
17. 
Bharara M, Schoess J, Nouvong A, Armstrong DG. Wound inflammatory index: A "proof of concept" 
study to assess wound healing trajectory. Journal of diabetes science and technology. 2010;4(4):773-
--779. PubMed Central PMCID: PMC2909505. 
18. 
TJ, Mueller M, Zapka JG, King DE. The effect of a cryotherapy gel wrap on the microcirculation 
of skin affected by chronic venous disorders. Journal of advanced nursing. 2011;67(11):2337-
--2349.  doi:  10.1111/j.1365---2648.2011.05680.x.    PubMed  Central  PMCID: PMC3158956. 
19. 
Kelechi TJ, King, D.E., Mueller, M., Pieper, B. A., Naohiro, S. Preventing venous leg ulcer with 
cryotherapy: A randomized clinical trial. Funded 2011 --- 2015 through National Institute of 
Nursing Research. Study ongoing. 2014. 
20. 
Roaldsen KS, Biguet G, Elfving B. Physical activity in patients with venous leg ulcer------between 
engagement and avoidance. A patient perspective. Clin Rehabil. 2011;25(3):275---286. Epub 
2010/12/15. doi: 0269215510371424 [pii] 
10.1177/0269215510371424. PubMed Central PMCID: PMC3122380. 
21. 
Roaldsen KS, Elfving B, Stanghelle JK, Talme T, Mattsson E. Fear---avoidance beliefs and pain as 
predictors for low physical activity in patients with leg ulcer. Physiotherapy research international 
: the journal for researchers and clinicians in physical therapy. 2009;14(3):167---180. doi: 
10.1002/pri.433. 
22. 
Kelechi TJ, Mueller M, Spencer C, Rinard B, Loftis G. The effect of a nurse---directed intervention to 
reduce pain and improve behavioral and physical outcomes in patients with critically 
colonized/infected chronic leg ulcers. Journal of wound, ostomy, and continence nursing : official 
publication of The Wound, Ostomy and Continence Nurses Society / WOCN. 2014;41(2):111---121. doi:    
10.1097/WON.0000000000000009. 
23. 
Kelechi TJ, Green A, Dumas B, Brotherton SS. Online coaching for a lower limb physical activity 
program for individuals at home with a history of venous ulcers. Home Healthc Nurse. 
2010;28(10):596---605. Epub 2010/11/09. doi: 10.1097/NHH.0b013e3181f7e99d 00004045---201011000-
--00004     [pii]. 
24. 
Bennett NT, Schultz GS. Growth factors and wound healing: Part ii. Role in normal and chronic 
wound healing. The American Journal of Surgery. 1993;166(1):74---81. 
25. 
Demidova---Rice TN, Hamblin MR, Herman IM. Acute and impaired wound healing: Pathophysiology and 
current methods for drug delivery, part 1: Normal and chronic wounds: Biology, causes, and 
approaches to care. Advances in skin & wound care. 2012;25(7):304. 
26. 
Eming SA, Krieg T, Davidson JM. Inflammation in wound repair: Molecular and cellular 
mechanisms. Journal of Investigative Dermatology. 2007;127(3):514---525. 
27. 
Loots MA, Lamme EN, Zeegelaar J, Mekkes JR, Bos JD, Middelkoop E. Differences in cellular 
infiltrate and extracellular matrix of chronic diabetic and venous ulcers versus acute wounds. 
Journal of Investigative Dermatology. 1998;111(5):850---857. 
28. 
Wetzler C, Kämpfer H, Stallmeyer B, Pfeilschifter J, Frank S. Large and sustained induction of 
chemokines during impaired wound healing in the genetically diabetic mouse: Prolonged 
persistence of neutrophils and macrophages during the late phase of repair. Journal of 
Investigative  Dermatology.  2000;115(2):245---253. 

 
 
 
 
Version 10.0 
 
        
07/23/18  
 Page 33 of 39 
 
29. 
McCarty SM, Percival SL. Proteases and delayed wound healing. Advances in wound care. 
2013;2(8):438---447. 
30. 
McKelvey K, Xue M, Whitmont K, Shen K, Cooper A, Jackson C. Potential anti---inflammatory 
treatments for chronic wounds. Wound Practice & Research: Journal of the Australian Wound 
Management Association. 2012;20(2):86. 
31. 
Menke NB, Ward KR, Witten TM, Bonchev DG, Diegelmann RF. Impaired wound healing. Clinics in 
dermatology. 2007;25(1):19---25. 
32. 
Mi Q, Rivière B, Clermont G, Steed DL, Vodovotz Y. Agent-based model of inflammation and 
wound healing: Insights into diabetic foot ulcer pathology and the role of transforming growth factor-β1. 
Wound Repair and Regeneration. 2007;15(5):671---682. 
33. 
Wang X---J, Han G, Owens P, Siddiqui Y, Li AG. Role of tgfβ---mediated inflammation in cutaneous 
wound healing. Paper presented at: Journal of Investigative Dermatology Symposium 
Proceedings2006. 
34. 
Raffetto JD. Dermal pathology, cellular biology, and inflammation in chronic venous disease. 
Thrombosis research. 2009;123 Suppl 4:S66---71. doi: 10.1016/S0049---3848(09)70147---1. 
35. 
Raffetto JD. Inflammation in chronic venous ulcers. Phlebology / Venous Forum of the Royal 
Society of Medicine. 2013;28 Suppl 1:61---67. doi: 10.1177/0268355513476844. 
36. 
Raffetto JD, Mannello F. Pathophysiology of chronic venous disease. International angiology : a 
journal of the International Union of Angiology. 2014;33(3):212---221. 
37. 
Demidova---Rice TN, Hamblin MR, Herman IM. Acute and impaired wound healing: Pathophysiology and 
current methods for drug delivery, part 1: Normal and chronic wounds: Biology, causes, and approaches 
to 
care. 
Advances 
in 
skin 
& 
wound 
care. 
2012;25(7):304---314. 
doi: 
10.1097/01.ASW.0000416006.55218.d0. PubMed Central PMCID: PMC3428147. 
38. 
Kelechi TJ, Haight BK, Herman J, Michel Y, Brothers T, Edlund B. Skin temperature and chronic 
venous insufficiency. Journal of wound, ostomy, and continence nursing : official publication of 
The Wound, Ostomy and Continence Nurses Society / WOCN. 2003;30(1):17---24. doi: 
10.1067/mjw.2003.10. 
39. 
Lavery LA, Armstrong DG. Temperature monitoring to assess, predict, and prevent diabetic foot 
complications. Current diabetes reports. 2007;7(6):416---419. 
40. 
Lavery LA, Higgins KR, Lanctot DR, Constantinides GP, Zamorano RG, Athanasiou KA, Armstrong 
DG, Agrawal CM. Preventing diabetic foot ulcer recurrence in high---risk patients: Use of temperature 
monitoring as a self---assessment tool. Diabetes care. 2007;30(1):14---20. doi: 10.2337/dc06---1600. 
41. 
Armstrong DG, Holtz---Neiderer K, Wendel C, Mohler MJ, Kimbriel HR, Lavery LA. Skin temperature 
monitoring reduces the risk for diabetic foot ulceration in high---risk patients. The American journal of 
medicine. 2007;120(12):1042---1046. doi: 10.1016/j.amjmed.2007.06.028. 
42. 
Kelechi TJ, McNeil RB. A prospective, descriptive study of hour---to---hour and day---to---day 
temperature variability of skin affected by chronic venous disorders. Ostomy/wound 
management. 2008;54(4):18---34. 
43. 
Kelechi TJ, Michel Y. A descriptive study of skin temperature, tissue perfusion, and tissue oxygen in 
patients with chronic venous disease. Biological research for nursing. 2007;9(1):70---80. doi: 
10.1177/1099800407299424. 
44. 
Barone S, Paoli A, Razionale AV. Assessment of chronic wounds by three---dimensional optical imaging 

 
 
 
 
Version 10.0 
 
        
07/23/18  
 Page 34 of 39 
 
based on integrating geometrical, chromatic, and thermal data. Proceedings of the Institution of 
Mechanical Engineers. Part H, Journal of engineering in medicine. 2011;225(2):181--- 193.  
45. 
Bagavathiappan S, Saravanan T, Philip J, Jayakumar T, Raj B, Karunanithi R, Panicker TM, Korath 
MP, Jagadeesan K. Infrared thermal imaging for detection of peripheral vascular disorders. Journal of 
medical physics / Association of Medical Physicists of India. 2009;34(1):43---47. doi: 10.4103/0971-
--6203.48720. PubMed Central PMCID: PMC2804148. 
46. 
Lahiri BBB, S.; Jayakumar, T.; Philip, J. Medical applications of infrared thermography: A review. 
Infrared Physics & Technology. 2012;55(4):221---235. 
47. 
Dargaville TR, Farrugia BL, Broadbent JA, Pace S, Upton Z, Voelcker NH. Sensors and imaging for 
wound 
healing: 
A 
review. 
Biosensors 
& 
bioelectronics. 
2013;41:30---42. 
doi: 
10.1016/j.bios.2012.09.029. 
48. 
Mehmood N, Hariz A, Fitridge R, Voelcker NH. Applications of modern sensors and wireless 
technology in effective wound management. Journal of biomedical materials research. Part B, 
Applied biomaterials. 2014;102(4):885---895. doi: 10.1002/jbm.b.33063. 
49. 
Mirabella C, Ballandi, S., Granziani, G., Tolomei, L., Manetti, L., Fortuna, D. Hemodynamic 3d 
infrared thermal stereoscopic imaging (tsi) investigation in chronic vascular leg ulcers: A feasibilty 
study. Wounds. 2011;23(9):276---284. 
50. 
Kelechi TJ, Good A, Mueller M. Agreement and repeatability of an infrared thermometer. Journal of 
nursing  measurement.  2011;19(1):55---64. 
51. 
Bagavathiappan S, Philip J, Jayakumar T, Raj B, Rao PN, Varalakshmi M, Mohan V. Correlation 
between plantar foot temperature and diabetic neuropathy: A case study by using an infrared 
thermal imaging technique. Journal of diabetes science and technology. 2010;4(6):1386---1392. 
PubMed Central PMCID: PMC3005049. 
52. 
Cunningham JE, Kelechi T, Sterba K, Barthelemy N, Falkowski P, Chin SH. Case report of a patient 
with chemotherapy---induced peripheral neuropathy treated with manual therapy (massage). 
Supportive care in cancer : official journal of the Multinational Association of Supportive Care in 
Cancer.   2011;19(9):1473---1476.   doi:   10.1007/s00520---011---1231---8. 
53. 
Freiman A, Bouganim N. History of cryotherapy. Dermatology online journal. 2005;11(2):9. 
54. 
Bodendorf MO, Grunewald S, Simon JC, Paasch U. Efficacy and cosmetic results of contact gel 
cooling of the skin during non---ablative laser procedures. Journal der Deutschen Dermatologischen 
Gesellschaft = Journal of the German Society of Dermatology : JDDG. 2008;6(8):647---652. doi: 
10.1111/j.1610---0387.2008.06610.x. 
55. 
Armstrong DG, Sangalang MB, Jolley D, Maben F, Kimbriel HR, Nixon BP, Cohen IK. Cooling the foot 
to prevent diabetic foot wounds: A proof---of---concept trial. Journal of the American Podiatric  Medical  
Association.  2005;95(2):103---107. 
56. 
Khoshnevis S, Craik NK, Diller KR. Cold---induced vasoconstriction may persist long after cooling ends: 
An evaluation of multiple cryotherapy units. Knee surgery, sports traumatology, arthroscopy 
: official journal of the ESSKA. 2014. doi: 10.1007/s00167---014---2911---y. 
57. 
Nicolaides AN, Allegra C, Bergan J, Bradbury A, Cairols M, Carpentier P, Comerota A, Delis C, Eklof 
B, Fassiadis N, Georgiou N, Geroulakos G, Hoffmann U, Jantet G, Jawien A, Kakkos S, Kalodiki E, 
Labropoulos N, Neglen P, Pappas P, Partsch H, Perrin M, Rabe E, Ramelet AA, Vayssaira M, 
Ioannidou E, Taft A. Management of chronic venous disorders of the lower limbs: Guidelines 
according to scientific evidence. International angiology : a journal of the International Union of 

 
 
 
 
Version 10.0 
 
        
07/23/18  
 Page 35 of 39 
 
Angiology. 2008;27(1):1---59. 
58. 
Muldoon J. Skin cooling, pain and chronic wound healing progression. British journal of 
community nursing. 2006;11(3):S21, S24---25. 
59. 
Bharara M, Viswanathan V, Cobb JE. Cold immersion recovery responses in the diabetic foot with 
neuropathy. International wound journal. 2008;5(4):562---569. doi: 10.1111/j.1742--- 481X.2008.00454.x. 
60. 
Shibuya N, Schinke TL, Canales MB, Yu GV. Effect of cryotherapy devices in the postoperative 
setting. Journal of the American Podiatric Medical Association. 2007;97(6):439---446. 
61. 
Roback K. An overview of temperature monitoring devices for early detection of diabetic foot 
disorders. Expert review of medical devices. 2010;7(5):711---718. doi: 10.1586/erd.10.35. 
62. 
Borson S, Scanlan J, Brush M, Vitaliano P, Dokmak A. The mini---cog: A cognitive 'vital signs' 
measure for dementia screening in multi---lingual elderly. International journal of geriatric 
psychiatry.  2000;15(11):1021---1027. 
63. 
Averbuch M, Katzper M. Assessment of visual analog versus categorical scale for measurement of 
osteoarthritis 
pain. 
Journal 
of 
clinical 
pharmacology. 
2004;44(4):368---372. 
doi: 
10.1177/0091270004263995. 
64. 
Tan G, Jensen MP, Thornby JI, Shanti BF. Validation of the brief pain inventory for chronic 
nonmalignant pain. The journal of pain : official journal of the American Pain Society. 
2004;5(2):133---137.   doi:   10.1016/j.jpain.2003.12.005. 
65. 
Craig CL, Marshall AL, Sjostrom M, Bauman AE, Booth ML, Ainsworth BE, Pratt M, Ekelund U, 
Yngve A, Sallis JF, Oja P. International physical activity questionnaire: 12---country reliability and 
validity. 
Medicine 
and 
science 
in 
sports 
and 
exercise. 
2003;35(8):1381---1395. 
doi: 
10.1249/01.MSS.0000078924.61453.FB. 
66. 
Lamping DL, Schroter S, Kurz X, Kahn SR, Abenhaim L. Evaluation of outcomes in chronic venous 
disorders of the leg: Development of a scientifically rigorous, patient---reported measure of 
symptoms and quality of life. Journal of vascular surgery. 2003;37(2):410---419. doi: 
10.1067/mva.2003.152.  
67. 
Lee JM, Kim Y, Welk GJ. Validity of consumer---based physical activity monitors. Medicine and 
science in sports and exercise. 2014. doi: 10.1249/MSS.0000000000000287. 
68. 
Robbins LB, Pfeiffer KA, Wesolek SM, Lo YJ. Process evaluation for a school---based physical activity 
intervention for 6th--- and 7th---grade boys: Reach, dose, and fidelity. Evaluation and program planning. 
2014;42:21---31. doi: 10.1016/j.evalprogplan.2013.09.002. 
69. 
Spillane V, Byrne MC, Byrne M, Leathem CS, O'Malley M, Cupples ME. Monitoring treatment fidelity in 
a randomized controlled trial of a complex intervention. Journal of advanced nursing. 2007;60(3):343-
--352. doi: 10.1111/j.1365---2648.2007.04386.x. 
70. 
Hampton S. A small study in healing rates and symptom control using a new sheet hydrogel 
dressing. Journal of wound care. 2004;13(7):297---300. 
71. 
Hampton S. A focus on actiformcool in the reduction of pain in wounds. British journal of 
community nursing. 2007;12(9):S37---42. 
72. 
Zoellner P, Kapp H, Smola H. Clinical performance of a hydrogel dressing in chronic wounds: A 
prospective observational study. Journal of wound care. 2007;16(3):133---136. 
73. 
Houghton VJ, Bower VM, Chant DC. Is an increase in skin temperature predictive of neuropathic foot 

 
 
 
 
Version 10.0 
 
        
07/23/18  
 Page 36 of 39 
 
ulceration in people with diabetes? A systematic review and meta---analysis. Journal of foot and ankle 
research. 2013;6(1):31. doi: 10.1186/1757---1146---6---31. PubMed Central PMCID: PMC3750703. 
74. 
Finlayson K, Edwards H, Courtney M. Factors associated with recurrence of venous leg ulcers: A 
survey and retrospective chart review. International journal of nursing studies. 2009;46(8):1071--- 1078. 
doi: 10.1016/j.ijnurstu.2008.12.012. 

 
 
 
 
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G. CONSULTANTS  
Letters of Support have been uploaded. 
 
H. FACILITES AVAILABLE 
The proposed clinical trial will be conducted at MUSC at the Research Nexus and builds on a referral network 
of existing professional collaborations both within and outside of the University.  
 
MEDICAL UNIVERSITY OF SOUTH CAROLINA 
College of Nursing. Office areas at MUSC are well lighted, well ventilated, and appropriately appointed 
for scholarly activities, paperwork, and modes of communication (voice, data, analog, digital, etc.) that 
are common and appropriate at a contemporary health professional university and academic medical 
center. Competent support staff and standard office services are readily available to facilitate the 
academic and scientific activities of faculty, trainees, and technical staff. Dr. Kelechi and her research 
team have adequate office space in the College of Nursing to implement this research study. 
 
CON Office of Research. The College of Nursing has made a commitment to develop an intensive 
research environment and has a dedicated Office of Research (OR). The OR advances the research and 
scholarship mission of the CON and university with a focus on facilitating the efforts of faculty and 
graduate students to obtain external funding to support research. The OR coordinates faculty and 
graduate student access to a wide range of support services available within the CON and university. 
The OR is staffed with the Associate Dean   of Research, grants specialist, program manager, scientific 
editor, pre-and post-award manager, methodologist, statisticians, and a data manager. The OR provides 
extensive pre- and post-award support for all funded projects, including assistance with biostatistics, 
grant and manuscript development, technical editing and manuscript assistance, grants management, 
and reporting and regulatory issues.  
 
Office of the Chief Information Officer, Information Services (OCIO-IS). The FOOTFIT project will 
include data transferred from accelerometers and Smartphones, and some hard copy questionnaire data 
related to feasibility, as well as results of physical functioning tests (walking, range of motion, strength) 
performed at the study site in Spartanburg, SC. The computer and network infrastructure to gather, store 
and analyze these data securely is managed by the Office of the Chief Information Officer, Information 
Services (OCIO-IS). Information Services, a division of the Office of the Chief Information Officer (OCIO), 
manages MUSC’s campus-wide data and voice communication network as well as other core 
infrastructure systems and applications.  
 
South Carolina Clinical Translational Research Institute (SCTR). We have utilized the SCTR clinical 
and laboratory services for our other studies and for early phases of our iterative design based SMASH 
project. SCTR serves as the catalyst for changing the culture of biomedical research, facilitating sharing 
of resources and expertise, and streamlining research-related processes to bring about large-scale 
changes in the clinical and translational research efforts in South Carolina. SCTR facilitates the kind of 
cross-disciplinary research that can provide answers to complex problems by coordinating expertise and 
resources throughout the state. SCTR also catalyzes the development of teams of researchers with 
unique and complimentary perspectives who will create and implement effective, culturally sensitive 
primary and secondary prevention and treatment interventions based on fundamental discoveries. SCTR 
has robust collaborations with affiliate members including the University of South Carolina, Health 

 
 
 
 
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Sciences South Carolina, Clemson University, South Carolina State University, Claflin University, 
Greenwood Genetics Center, South Carolina Research Authority, and VA Medical Centers to expand 
innovative research and training activities across the SCTR region. Health Sciences South Carolina is a 
public/private partnership of the state's largest healthcare systems and three SC research universities 
(MUSC, USC and Clemson University). 
 
The SUCCESS Center, one of the initiatives of the SCTR provides links across the campus and across 
the state for the researchers seeking expertise or services in a variety of research areas. The 
Recruitment Core, head by PI, Dr. Teresa Kelechi, provides investigators with strategic strategies to 
recruit and retains subjects for their particular study designs. REDCap Database and Survey Service is 
run by the SUCCESS Center. REDCap is being used on the proposed project. It was initiated at 
Vanderbilt University and includes more than 70 active institutional partners from CTSA, GCRC, RCMI 
funded institutions, including MUSC, and others. REDCap (Research Electronic Data Capture) is a 
secure, web-based application designed exclusively to support data capture for research studies. 
REDCap provides: 1) an intuitive interface for data entry (with data validation); 2) audit trails for tracking 
data manipulation and export procedures; 3) automated export procedures for seamless data downloads 
to common statistical packages (SPSS, SAS, Stata, R); 4) procedures for importing data from external 
sources; and 5) advanced features, such as branching logic and calculated fields. REDCap Survey is a 
powerful tool for building and managing online surveys. Surveys can be created and designed in a web 
browser, collect responses from survey participants on line or from printed PDF of the survey.  
 
The Biomedical Informatics Program is another important resource for our MUSTCOOL project. The 
program’s goal is to integrate the informatics programs of SCTR and HSSC institutions, their medical 
centers, physician networks, major healthcare systems and populations across South Carolina while also 
providing robust tools for researchers. The MUSTCOOL project will utilize the data base storage and 
analysis available through this program. 
 
The Department of Public Health Sciences (formerly Division of Biostatistics and Epidemiology/DBE), 
has more than 30 faculty members with expertise in biostatistics and epidemiology, many with joint 
appointments in other areas of MUSC. As an example, Co-I, Dr. Martina Mueller, is a faculty member in 
the Department and has an appointment in the College of Nursing as well. This enables frequent 
impromptu meetings among the group in addition to regular research meetings. DBE houses and 
supports two institutional research resource units: the Collaborative Unit and the Data Coordination Unit. 
The Department has two units and extensive computing resources. Faculty members in the Biostatistics 
Unit have expertise in such areas as categorical, longitudinal, multivariate, survival, recurrent events, 
multiple outcomes, and Bayesian biostatistical methods. They coordinate various clinical trials and health 
related studies on national and local level and in single and multisite programs, and they develop 
innovative models and methods for efficient and informative data analysis by incorporating scientific 
knowledge from the pertinent biological and clinical areas. 
 
The South Carolina Research Nexus, available through SCTR is another valuable resource to the 
FOOTFIT project. Our team has utilized the Research Nexus as an evaluation site for several studies         
including our cryotherapy study and physical activity development pilot work. The Research Nexus is a 
specialized, JCAHO-accredited, patient care unit whose goal is to both facilitate patient-oriented research 
in a cost-effective manner and help strengthen the discipline of clinical and translational science. The 
Research Nexus supports clinical and translational research projects within the institution and SCTR 
affiliate members as well as pilot studies that may lead to future NIH or other sources of peer-reviewed 

 
 
 
 
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clinical/translational   research grant support. Two other important functions of the Research Nexus 
include furnishing a clinical research training environment and assurance of research subject safety 
through the Research Nexus’s Research Subject Advocate, whose role is to oversee the safe 
implementation of research studies within the unit. The specialized staff of the Research Nexus consist 
of research nurses, laboratory personnel, nutritionists, IT specialists, and professional/administrative 
personnel. A core laboratory, fully-equipped outpatient clinic, dental suite, and imaging suite comprise 
the highly-technical physical facilities that are on  hand to support research. Research Nexus laboratory 
staff are qualified and trained in processing a myriad of sample types, including serum, plasma, urine, 
stool and breast milk.  In addition, the staff is proficient in the latest DNA/RNA isolation techniques and 
offer a wide variety of specialized assays. We have utilized the Research Nexus core clinical services to 
perform physical and functional measurements in our other studies and for some of our physical activity 
development and pilot work. 
 
RESEARCH RESOURCES 
Research Development and Administration 
The MUSC research infrastructure includes pre- and post-award functions reporting to the Vice President 
for Academic Affairs & Provost through the Associate Provost for Research. The Office of Research 
Development focuses on program and proposal development, identifies funding opportunities, develops 
proposal concepts, networks faculty members with complementary interests, provides grant-writing 
consultation and workshops, offers pre-submission critiques, compiles institutional data, and prepares 
competitive proposals for research resources and research training. The Office of Research and 
Sponsored Programs (ORSP) handles 
certifications and assurances, ensures that policies and 
procedures are followed, helps prepare budgets, negotiates terms and conditions, maintains proposal 
and awards data, administers the program of intramural research grants, and oversees re-budgeting and 
close-out activities. ORSP is the institutional interface with Grants.gov and coordinates all aspects of 
electronic research administration. The Office of Research Integrity provides oversight and staffing for 
activities focused on compliance with regulations for research involving humans, vertebrate animals, and 
biohazard agents. It also coordinates management of conflict of interest, financial disclosure, and 
scientific integrity issues. 
 
Protection of Human Subjects 
The participation of human subjects in research falls under the jurisdiction of federal regulations (45 CFR 
46 and 21 CFR 50 and 56). MUSC investigators are granted the privilege of working with human subjects 
under normal assurance to the government that such research complies with regulations protecting 
human subjects. The university has a federal-wide assurance for research with human subjects (FWA 
00001888, Feb. 2002), and is in compliance with federal policy governing use of human subjects. 
Individuals involved in human subject research at MUSC are required to complete the Collaborative IRB 
Training Initiative (CITI) offered on line by the University of Miami. Registration and course work can be 
found at http://www.miami.edu/citireg. All human subject protocols are reviewed through an academic 
Institutional Review Board (IRB) process. The Office of Research Integrity coordinates the activities of 
three IRB committees. 
 
Compliance 
The MUSC University Compliance Program is a proactive program to ensure full compliance with all 
applicable policies, procedures, laws, and regulations. This involves a confidential Compliance Helpline 
to encourage all members of the MUSC community to ask questions or voice concerns about laws and 
regulations on such topics as coding and billing, research integrity, professional ethics, human subjects, 

 
 
 
 
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animal research, biological safety, conflict of interests, and patient confidentiality. The program office 
proactively trains employees and facilitates discovery of concerns, followed by appropriate investigation 
into problem areas and timely resolution of issues. This program directly assists MUSC’s management at 
all levels in maintaining and enhancing an environment where ethics are paramount considerations in 
strategic and operational decisions throughout the organization. 
 
I. INVESTIGATOR BROCHURE  
Not Applicable 
 
 
J. APPENDIX