Spinal Cord Injury Exercise and Nutrition Conceptual Engagement (SCIENCE)
Phase: NA
Conditions: Spinal Cord Injuries, Metabolic Syndrome, Dietary Modification, Paraplegia, Tetraplegia
Sponsor: University of Miami

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1. Protocol Title
Spinal Cord Injury Exercise and Nutrition Conceptual Engagement (SCIENCE)
2. Objectives
The specific objectives for the current proposal are to assess the impact of home-based 
functional electrical stimulation leg cycle ergometry plus diet (HBFESLCE + Diet) 
versus Diet Alone on (Primary Variables) body composition (%BF, FM and FFM), 
insulin sensitivity (SI), glucose effectiveness (SG), and BMR, as well as (Secondary 
Variables) lower extremity bone mineral density, lipid profiles, and hsCRP in adults with 
motor complete SCI between C4-T4. Specific objectives to be addressed in the current 
proposal are: 
1. To determine the impact of HBFESLCE + Diet on body composition, insulin 
sensitivity, glucose effectiveness and BMR in adults with motor complete 
tetraplegia or high paraplegia above T4. Additionally, lower extremity bone 
mineral density & content, lipid profiles, and hsCRP will be compared before 
and after intervention. 
2. To determine the impact of HB Diet Alone on body composition, insulin 
sensitivity and glucose effectiveness in adults with motor complete tetraplegia 
or high paraplegia. Additionally, lower extremity bone mineral density, lipid 
profiles, and hsCRP will be compared before and after intervention. 
3. To compare the efficacy of HBFESLCE + Diet with that of HB Diet Alone 
relative to the parameters listed above. 
4. To create a robust dataset of variables that are associated with visceral adipose 
tissue (VAT) to predict determinates of epicardial VAT (EAT) and abdominal 
VAT (AVAT) in subjects with chronic motor complete C4-T4 SCI. 
5. To compare the change in epicardial adipose tissue, abdominal visceral adipose 
tissue, intramuscular fat, and subcutaneous adipose tissue before and after 
home-based FES-LCE plus diet vs. diet alone in adults with chronic motor 
complete C4-T4 SCI.              
6. To compare changes in circulating proinflammatory adipokines before and 
after FES-LCE plus diet vs. diet alone in adults with chronic motor complete  
C4-T4 SCI. 
3. Background
There are an estimated 1.5 million persons in the United States with SCI, Men 3x > 
Women, with ~50% having tetraplegia and recent literature would imply that more than 
60% are overweight or obese by BMI standards, more than 50% are glucose intolerant, 
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while one out of five is frankly diabetic.1 This special population already has significant 
functional deficits including reduced mobility, myocardial atrophy, restrictive lung 
dysfunction, bowel and bladder dysfunction, and a high risk for skin breakdown. The 
additional deficits of visual impairment, gastroparesis, renal disease, peripheral 
polyneuropathy, and impaired wound healing associated with obesity and diabetes 
impacts independence to a much greater extent in SCI than in the able-bodied population. 
The potential to reverse and prevent obesity, diabetes and heart disease in this population 
has tremendous implications on quality of life and reduced health care costs. Further, the 
“side-effects” associated with exercise and diet intervention, including improved 
cardiovascular fitness, improved cholesterol profiles, improved functional mobility, 
reduced body fat, improved gastric mobility, and reduced spasticity will also positively 
impact the SCI person’s ability to maintain a greater degree of independence and 
contribute to the work force and society. Exercise and diet to reduce obesity has 
tremendous potential, therefore, to improve health and quality of life for persons with 
high paraplegia and tetraplegia. Additionally, translation of these findings to other 
persons with disabilities and aging populations with issues of sarcopenia, obesity and 
glucose intolerance is highly probable. 
Energy expenditure is 25-50% lower for persons with spinal cord injury, particularly at 
levels above T4 due to reduced muscle mass, sympathetic blunting and neuroendocrine 
dysfunction. Energy intake must match or be lower than energy expenditure in order for 
an individual to lose weight. However, rapid diet alone without significant muscle 
overload almost always results in additional muscle atrophy due to selective protein 
“cannibalism” as the body attempts to meet its “set-point” energy needs. Subsequent 
weight loss will include not just fat mass, but also significant lean body mass – further 
compromising metabolic expenditure. In brief, diet alone typically re-sets basal 
metabolism to a lower level than it had been prior to diet initiation, increasing the 
likelihood of future fat gain even at similar levels of energy intake. As an example, a man 
with C5 AIS A tetraplegia will continue to gain fat on a 1200 kcal/day diet if his daily 
energy expenditure is only 1000 kcal/day. Further dietary restriction to below 1200 kcal/d 
severely limits palatable food choices of appropriate nutrient density; such that dietary 
adherence becomes highly unlikely. For those few who have such discipline, “set-point” 
reduction will ultimately sabotage their attempts at weight loss as they further reduce 
metabolically active tissue. To preserve or increase basal energy expenditure, exercise 
most likely must be employed. 
1. SCI Limits Exercise: Injury to the spinal cord obstructs the transmission of neural 
messages through the cord and results in the loss of somatic and autonomic control over 
trunk, limbs and viscera distal to the site of the lesion. Systemic responses to exercise 
seen in able-bodied individuals are blunted in persons with spinal cord injury and vary to 
a greater degree as the level of injury is higher. This causes a diminished ability to 
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perform physical activity and exercise, at a conscious (somatic) and subconscious 
(autonomic) level. Problems peculiar to SCI include blunted cardiovascular, ventilatory, 
thermoregulatory, & hormonal exercise responses, while associated SCI features of 
autonomic dysreflexia, osteopenia, upper extremity overuse syndromes, spasticity, & 
pressure injuries make the exercise prescription for this population especially difficult.2 
2. Energy Balance and Obesity: ‘‘Obesity is a chronic, relapsing, neurochemical disease 
produced by the interaction of environment and host.”3 In the late 1970s and 1980s, 
health researchers began to report an association between body fat and cardiovascular 
disease comorbidities, including hypertension, hyperlipidemia, and diabetes. Obesity was 
defined as an accumulation of excess body fat, with thresholds associated with 
cardiovascular disease > 22% body fat (%BF) for men and > 35% for women.4 Body fat 
accumulates when energy intake exceeds energy expenditure, resulting in a positive 
energy balance. 
The concept of energy balance reflects an ever-dynamic relationship between relative 
rates of change for energy intake and energy expenditure. Energy intake reflects the 
caloric gain through ingestion of foodstuffs, whereas energy expenditure reflects calories 
used to sustain life, perform movement and digest food. Energy intake is provided 
through the ingestion of foodstuffs of varying caloric densities. Fats contain roughly 9 
kcal/g, carbohydrates and proteins contain ~ 4 kcal/g and alcohol contains ~7 kcal/g. The 
perceived need for energy is mediated through the lateral (appetite center) and 
ventromedial (satiety center) nuclei of the hypothalamus, but afferent signals to these 
centers may be impaired or blocked after SCI.5
Energy expenditure is the sum of basal metabolic rate (BMR), the thermic effect of food 
digestion (TEF) and the thermic effect of physical activity (TEA). Of the three, BMR 
contributes the most to total daily energy expenditure (TDEE), representing 
approximately 60-70% of the total. BMR represents the minimal energy expenditure 
required to sustain life, and equations developed around the beginning of the 20th century 
remain in use, although modified in recent decades to reflect a larger anthropometric 
body type.6 Fat-free lean mass (FFM), comprised of muscle, bone and organs contributes 
the greatest energy expenditure of BMR, and of the FFM components, skeletal muscle 
contributes up to 85% of the variance.7,8 Practically speaking, this means that increases or 
decreases in skeletal muscle mass significantly impact not only caloric expenditure 
during activity, but also total energy expenditure at rest. The TEF is the least variable of 
the components of TDEE, since digestion, absorption, and sympathetic nervous system 
activation following consumption of foodstuffs remains relatively constant with normal 
physiology and is not dependent upon body weight or composition. TEF represent ~ 8% 
of TDEE in most individuals.9 Intermediate and most variable among the components of 
TDEE is the thermic effect of activity (TEA). Not only is it dependent upon total body 
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and skeletal muscle mass, it varies significantly with the mode, intensity, duration and 
frequency of activities. 
Regardless of genetic influences, a person’s energy balance is profoundly impacted by 
spinal cord injury. Injury to the somatic nervous system results in immediate and 
sustained loss of neurotrophic influences to skeletal muscles below the level of SCI, 
while sympathetic blunting to injuries above T6 further impair energy metabolism. 
Paralyzed muscle atrophies rapidly (obligatory sarcopenia) following acute SCI, 
drastically reducing BMR and TEA directly with the level of injury such that higher 
levels of SCI result in greater reductions in BMR and TEA. TEA is further reduced in 
traumatic SCI because of activity, range of motion (ROM) and weight-bear restrictions 
associated with surgical repair and bony healing. Subsequently, predicted energy 
expenditure equations used to determine caloric and nitrogen needs overestimate actual 
needs by an average of ~ 25% in persons with new SCI. These reductions are sustained 
following the acute phase of SCI,10–16 due to reduced FFM, sympathetic blunting, 
cardiopulmonary dysfunction, reductions in work capacity, diminished anabolic 
hormones and reduced ability to utilize the relatively large muscle mass of the lower 
extremities. If equivalent reductions in energy intake are not employed, the person with 
SCI will rapidly accumulate adipose tissue beyond that expected of non-SCI individuals 
in similar circumstances.
3. Adipose Pathology & Metabolic Syndrome: Once considered benign, adipose tissue in 
recent years has been demonstrated to mediate severe metabolic consequences when 
accumulated in excess, and has been implicated as the causative agent for cardiovascular 
inflammation, hyperlipidemia, insulin resistance, hypertension, and thromboemboli 
associated with the metabolic syndrome. Adipose tissue, particularly that in visceral 
regions, has been demonstrated to secrete large amounts of proinflammatory proteins 
called cytokines, including interleukin-6 (IL-6) and tumor-necrosis factor- (TNF-).17 
IL-6 is a potent proinflammatory cytokine released from both visceral and subcutaneous 
adipocytes that independently causes low-grade vascular inflammation, stimulates the 
release of cortisol from the adrenal cortex and stimulates hepatic production of C-
Reactive Protein (CRP), an acute phase reactant which is also tied to vascular 
inflammation. 
As adipose tissue accumulates, lipolysis that typically occurs in the fasted state produces 
non-esterified fatty acids (NEFA) at an accelerated rate, even in the face of rising insulin 
levels. Circulating NEFA are deposited in the liver and skeletal muscle at increasing 
rates, contributing to insulin resistance by inhibiting the phosphorylation of insulin 
receptor substrates (IRS-1 and IRS-2) and subsequently the phosphatidylinositol 3-kinase 
(PI-3 kinase) cascade necessary for activation of the GLUT1 and GLUT4 receptors that 
allows them to translocate to the cell membrane and facilitate passage of glucose into the 
cell.18 
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As NEFA and associated triglycerides accumulate within the liver, hepatic production of 
very low density (VLDL-c) and low density (LDL-c) lipoproteins increases, as does that 
of apolipoprotein B, the major protein of LDL-cholesterol.[19, 20] Simultaneously, net 
apolipoprotein A production is slowed, resulting in reductions of high density lipoprotein 
(HDL-c), the primary scavenger of peripheral lipids. Whole body lipid profiles reflect the 
local hepatic changes in lipid metabolism with elevated triglycerides, VLDL-c, LDL-c in 
the face of diminishing HDL-c, creating an atherogenic environment throughout the 
vascular tree.19
Central obesity causes hypertension through a number of mechanisms. Chronic exposure 
to adipose derived proinflammatory cytokines can damage the arterial endothelium, 
resulting in arterial stiffness and dysfunction. Visceral fat also secretes the hormone 
leptin which directly increases sympathetic nervous system activity, increasing 
vasoconstriction and subsequently mean arterial pressure.9,20 Adipocyte secretion of 
TNF- increases hepatic synthesis of angiotensinogen, a potent vasoconstrictive 
agent.[13] Specifically, these agents stimulate aldosterone production from the adrenal 
cortex with subsequent renal sodium reabsorption and volume expansion.21 Visceral 
obesity can also cause direct mechanical compression of the kidneys, which causes 
elevated intrarenal pressures and sodium retention.20
4. Obesity in SCI: Obesity, i.e., body fat relative to body weight of greater than 22% in 
men, or 35% in women, is a significant risk factor for glucose intolerance and heart 
disease in SCI, but is poorly identified in this special population.1 Body Mass Index 
(BMI) is calculated as a person’s weight relative to their squared height (Weight 
(kg)/Height2 (m2 ), and is the most commonly used indicator of obesity in our society. 
For able-bodied individuals, BMI ≥ 25 kg/m2 is considered overweight, while BMI ≥ 30 
kg/m2 is considered obese, and places one at significantly higher risk for coronary artery 
disease, diabetes mellitus, osteoarthritis and certain types of cancer. When the World 
Health Organization (WHO) “redefined” obesity according to BMI in 1998, significant 
sensitivity for the true definition of obesity4  (%BF > 22 in men, %BF > 35 in women) 
was compromised, resulting in gross underestimation of obesity in certain populations, 
including those with SCI.1,22,23 Additionally, standard body composition assessment 
techniques are based on non-SCI cadaveric dissections performed over 50 years ago, and 
have not been validated in SCI. Limitations for each of the current techniques used for 
body composition assessment in SCI have been reported previously.1,22,23 Computed 
tomography (CT) is considered the gold standard for fat assessment, while methods such 
as BMI and waist circumference serve only as a surrogate marker of fat and do not yield 
a precise measure of body composition (e.g., fat-free mass (FFM) and fat mass (FM)). CT 
provides the distribution of fat/adipose tissue (i.e. android vs gynoid or subcutaneous 
[SAT] vs visceral [VAT] adipose tissue) and is a fast, relatively inexpensive (compared 
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to MR imaging), and widely used tool for assessment of body composition in the able-
bodied population.24  
Several studies using variable techniques have suggested reduced fat-free body mass 
(FFB) and increased fat mass in persons with SCI.25–32 Wang et al have further organized 
and described up to 5 compartment models, most of which discriminate additional 
components of the FFB mass.33 For example, FFB can be further discriminated into 
protein/mineral and water compartments in the 3- compartment water molecular model, 
or bone mineral and bone-free lean tissue in the 3-compartment tissue model. The 4-
compartment model, which is currently accepted as the gold-standard for body 
composition assessment in most exercise physiology laboratories, is comprised of fat, 
mineral, water, and protein. This model is especially appropriate for populations such as 
those with SCI because it actually measures the components of FFB mass which are 
otherwise erroneously assumed in the other models.34 
The true prevalence of obesity in SCI remains unclear. In a sample of 7,959 veterans with 
SCI managed in VA hospitals in 2001, we reported 53% to have BMI > 25 kg/m2 , while 
68% had BMI > 23 kg/m2 .21 A smaller sample reported from a single mid-western VA 
hospital similarly demonstrated 255 (65.8%) of 387 veterans with SCI to have BMI > 25 
kg/m2; an additional 27.9% were reported to have BMI in “normal” (20-25 kg/m2) 
range.35 These studies suggest that at least half of these individuals with SCI and 
“normal” BMIs also fall into the obese range if %BF were accurately assessed. 
Nonetheless, the best data available at this time suggests that two of every three persons 
with SCI is likely obese and appears at risk for the metabolic consequences of obesity. 
5. Metabolic Syndrome in SCI: Collectively, the constellation of obesity, vascular 
inflammation, dyslipidemia, insulin resistance and hypertension has been referred to as a 
“metabolic syndrome,” although the relative impact of each of the components on overall 
health has been debated among different groups of physicians and scientists. In 1998, the 
WHO definition of the metabolic syndrome focused on the central role of diabetes 
mellitus, plus at least two of the following: obesity (BMI > 30kg/m2 or Waist-to-hip ratio 
> 1), dyslipidemia (TG  150 mg/dl &/or HDL-c < 35 mg/dl in men or < 40 mg/dl in 
men, < 50 mg/dl in women), hypertension (BP  130/85 mm Hg), and fasting glucose > 
110 mg/dl.[30] Most recently, the International Diabetes Federation (IDF) definition of 
metabolic syndrome has emphasized the role of central obesity (waist circumference  94 
cm in men,  80 cm in women) plus any two of the following: dyslipidemia (TG  150 
mg/dl or on treatment; HDL-c < 40 mg/dl for men, < 50 mg/dl for women or on HDL-c 
treatment), hypertension ( 130 mm Hg systolic or  85 mm Hg diastolic, or on treatment 
for hypertension), fasting glucose  100 mg/dl or previously diagnosed with type 2 
diabetes mellitus.36 Obesity is now recognized as the primary mediator of the metabolic 
consequences of the metabolic syndrome and causative for hypertension, low grade 
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inflammation, cardiovascular disease, glucose intolerance and dyslipidemia. Despite the 
recent report on carbohydrate and lipid disorders in SCI of the AHRQ ERTA (2008) 
which was restricted to large, randomized controlled investigations,11 it remains our 
contention that metabolic dysfunction is, in fact, at epidemic proportions in the SCI 
population, but simply has not received sufficient rigorous attention necessary to identify 
its true prevalence and significance. Since that report, multiple studies have demonstrated 
increased incidence of metabolic syndrome in persons with SCI when compared to able-
bodied individuals.12–15,24,37 Specific components of the metabolic syndrome in SCI are 
addressed below. Interestingly, while SCI neuropathophysiology should lead to 
neurogenic hypotension, we have recently reported hypertension in 22% of a large 
veteran cohort with SCI; 68% of the cohort had BMI>23 kg/m2, supporting a relationship 
between hypertension and obesity in this population.38 The prevalence of hypertension in 
veterans with SCI is not clearly known, but may be as high as 45% as recently reported 
by Lee et al in a smaller veteran cohort.39
6. Insulin Resistance & Dyslipidemia in SCI: Glucose intolerance has been reported in a 
large percentage (50-67%) of SCI patients and is characterized by hyperinsulinemia in 
response to a glucose challenge for this population. Petry et al found that glycosylated 
hemoglobin (HbA1c) levels above 6.0 in SCI patients significantly correlated with 
impaired glucose tolerance or frank diabetes, and recommended routine HbA1c screening 
for patients with SCI.40 Aksnes et al noted an association between whole body insulin-
mediated glucose uptake and skeletal muscle mass in tetraplegics, suggesting loss of 
muscle mass as the primary reason for insulin insensitivity. The hyperinsulinemia in 
these patients may therefore be related to body composition changes as has been reported 
in the general population.41,42 Bauman & Spungen reported that 62% of quadriplegics 
with a mean duration of injury of 17 years had abnormal glucose tolerance tests, as 
compared to only 18% of age-matched controls with similar body mass index (BMI).43 
That same study failed to demonstrate a significant correlation between insulin resistance 
and body composition, although body composition was estimated using DXA, and not 4-
compartment modeling, now considered the gold standard. Finally, Dearwater et al 
(1986) compared SCI sedentary controls with SCI athletes and found no significant 
differences in fasting glucose or insulin concentrations but did not conduct glucose 
tolerance tests.44
Persons with SCI have similar total cholesterol levels, but significantly lower HDL-c 
when compared to able-bodied controls(42±7.9 vs.47±6.7 mg/dl), particularly noticeable 
in the male population (39±8.3 vs. 45±7.0).[47] Bauman and Spungen recently reported 
HDL-c in 224 veterans with SCI; 63% had HDL-c < 40 mg/dl, 44% had HDL-c <35 
mg/dl, and 19% had HDL-c <30 mg/dl.45 Several studies have also demonstrated the 
inverse relationship between elevated C - reactive protein (CRP) and HDL-c in persons 
with SCI.13,15,46 As seen in the able-bodied population, there appears to be a direct 
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relationship between physical activity and HDL-c in persons with SCI.47–49 Maki et al 
noted reduced HDL-c was significantly correlated with abdominal adiposity in 46 men 
with SCI as measured by waist circumference, although correlation with visceral fat 
imaging was not performed.50 Similar findings have recently been reported in additional 
SCI cohorts.13,15 Few training interventions have actually been examined for changes in 
cholesterol profiles in the population with SCI, however. A few studies have 
demonstrated no significant improvement in lipid profiles following 10-16 weeks of 
aerobic upper extremity exercise in persons with SCI. Few training interventions have 
actually been examined for changes in cholesterol profiles in the population with SCI, 
however. A few studies have demonstrated no significant improvement in lipid profiles 
following 10-16 weeks of aerobic upper extremity exercise in persons with SCI.51,52 
However, Hooker & Wells(1989) demonstrated improved cholesterol profiles(TC/HDL-c 
from 5.0 to 4.0, HDL from 39 to 47 mg%) in SCI patients who had completed 8 weeks of 
moderate upper extremity exercise training.53
7. Exercise on Insulin Sensitivity: Aerobic exercise has been shown to improve glucose 
tolerance and reduce insulin resistance in the able-bodied.54–56 Dengel et al examined the 
effects of moderate aerobic exercise three times weekly for 6 months on obese sedentary 
men, and found oral glucose tolerance significantly improved, and glucose disposal rate 
increased by 22% as determined by the hyperinsulinemic euglycemic clamp.54 A previous 
study by Dengel’s group (1996) investigating the combination of aerobic exercise and 
caloric restriction for weight loss found similar improvements in glucose tolerance and 
glucose disposal rates.55 A significant correlation was noted between area under the 
glucose curve and change in percent body fat. A large, multicenter, multicultural 
epidemiological trial examined the relationship between physical activity and insulin as 
determined by the frequently sampled intravenous glucose tolerance test (IVGTT) 
developed by Bergman.57 and found that while higher intensity physical activity 
improved insulin sensitivity to a greater extent, even low levels of activity were related to 
improved insulin sensitivity in this population of normal to mild non-insulin-dependent 
diabetes mellitus.56  Similarly, Smutock et al reported improved glucose tolerance and 
reduced insulin AUC during oral glucose tolerance tests following 20 weeks of moderate 
aerobic exercise consisting of treadmill walking and/or jogging when compared to 
controls.58
8. Functional Electrical Stimulation for SCI: Computerized functional electrical 
stimulation (FES) has been developed as a neuromuscular aid to restore purposeful 
movement of limbs paralyzed by upper motor neuron lesions. In use for over 40 years, it 
has been refined with sophisticated computer technology to be used as an exercise 
enhancement tool for patients with spinal cord injury. Phillips in 1987 proposed medical 
guidelines for patient participation in FES rehabilitation, including medical criteria for 
inclusion and exclusion.59 Briefly, FES of the lower extremities can be used to stimulate 
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strength60–62 and endurance,53,60,61 and has the potential to improve energy expenditure, 
increase stroke volume,63,64 increase total body peak power output (POPeak), VO2Peak and 
ventilatory rate,53,65,66 reverse myocardial disuse atrophy,[70] increase HDL levels and 
improve body composition,67,68 and possibly increase lower extremity bone mineral 
density.68,69 
9. FES on Insulin Sensitivity and Bone Mineral Density: Atrophied lean body mass, 
particularly skeletal muscle, is not as metabolically active in SCI compared to able-
bodied individuals. A few recent studies have evaluated the effect of lower extremity 
functional electrical stimulation (FES) on glucose tolerance and insulin sensitivity in SCI. 
One year of FES performed 3 days per week for 30 minutes sessions resulted in a 25% 
increase in insulin sensitivity, as assessed by a hyperinsulinemic, euglycemic clamp, in 
ten subjects with a SCI in the cervical or thoracic region.70 Similarly, eight weeks of daily 
lower extremity FES resulted in 33% improvement in insulin sensitivity for 5 men with 
cervical spinal cord injury.64 Euglycemic, hyperinsulinemic clamps were performed 48 
hours after a single exercise bout to determine if a single bout of moderate intensity 
exercise would alter tissue sensitivity to insulin in SCI.  With low statistical power, 
results showed no change in insulin sensitivity with the SCI or controls in response to the 
single exercise bout. Both groups were insulin sensitive, however, and the SCI group was 
active at the onset of the study, so it is not surprising that neither group responded to the 
exercise stimulus with augmented capacity for glucose disposal following a single 
exercise bout. Atrophied lean body mass, particularly skeletal muscle, is not as 
metabolically active in SCI compared to able-bodied individuals. 
10. SCI Dietary Guidelines: There is a paucity of information about dietary interventions 
for SCI, particularly motor complete high paraplegia and tetraplegia. The few studies that 
have been performed have demonstrated relatively high caloric consumption (though 
significantly lower than for non-SCI), poor nutrient density and relatively high BMI.[76-
81] BMR or TDEE are rarely reported, and dietary adjustments have previously been 
based on estimates of energy expenditures done more than a decade ago.[82, 83] 
Although the American Dietetic Association (ADA) recently provided dietary guidelines 
for persons with SCI, they are relatively broad and note that best practices would include 
indirect calorimetry to estimate true caloric needs.[84] Lieberman et al (2014) has tried to 
characterize dietary intake for persons with SCI, and his findings indicated mean caloric 
intake of >2600 kcal/d without reference to energy expenditure or body composition.[85] 
A recent 7-month randomized, controlled trial (Online: ahead of print) demonstrated no 
improvement in lipid profiles or weight loss in persons with SCI provided nutritional 
education alone, without regard to true energy expenditure or body composition.[86] Our 
three recent manuscripts have provided more detail for managing diet in SCI, including 
the need for indirect calorimetry and body composition monitoring.[87-89]
3.2 Previous Data
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1. Body Composition & Energy Expenditure: A preliminary investigation in our 
laboratory has demonstrated the accuracy of using DXA as a proxy for 4-compartment 
modeling (Heymsfeld, 1990) to assess body composition in SCI adults.[26] In comparing 
body composition analyses techniques in 72 individuals with SCI, we recently found 
Total Error to be 4.8% with Dual X-ray Absorptiometry, 5.7% with hydrodensitometry, 
16.0% with bioelectrical impedance analysis), and 6.2% with standard skinfold equations 
when compared to 4-compartment modeling, the currently accepted gold standard for 
body composition assessment. We also participated in a multisite trial to develop a 
compendium of physical activity energy expenditures for SCI, and provided significant 
data demonstrating reduced energy expenditure at rest and during activities when 
compared to AB literature.[90] 
2. Prevalence of Metabolic Syndrome in Persons with SCI. We have previously reported 
on the incidence of obesity and hypertension in a large cohort (n=7959) of veterans with 
SCI in which 53% had BMI>25, and a surprising 22% had clinically significant 
hypertension.[27] Additionally, we conducted a nationwide survey that demonstrated 
diabetes prevalence is greater among veterans with an SCI/D compared with the civilian 
population, but similar to that of other veterans, although it may occur at a younger age in 
those with an SCI/D.[40] Our lab previously reported retrospective data on 477 veterans 
with SCI screened for metabolic syndrome using the International Diabetes criteria 
previously reported. Within the sample, 56.5% had BMI > 25 kg/m2 , 63.4% had HDL-c 
< 40 mg/dl, 48.7% had fasting blood glucose > 100 mg/dl, 56.5% had hypertension, and 
44.8% met criteria as having the metabolic syndrome.[91] We have recently reviewed an 
expanded data set of the same variables and have a manuscript in preparation with similar 
results. 
3. Fat Mass & Glucose Tolerance: Previous work in our laboratory demonstrated a strong 
relationship (r=0.67, p<0.001) between body composition and glucose area under the 
curve following OGTT in SCI subjects at all levels of injury. Glucose AUC was more 
strongly correlated (r=0.86, p<0.001) with %BF in those persons with T6-L2 SC. 
Additional work in our laboratory (Figure 1) has demonstrated significant relationships 
between visceral adipose tissue (VAT) and plasma glucose levels.[92, 93] Although 
relationships were also demonstrated for subcutaneous abdominal adipose tissue (SAT) 
and plasma glucose, these were not significant. Plasma insulin was somewhat variable 
presumably due to the nature and longevity of the person’s glucose intolerance; those 
with acute glucose impairments were more likely to have hyperinsulinemia. For 
Individuals with SCI, increases in VAT, SAT, or VAT/SAT ratio are associated with an 
adverse metabolic profile, manifested by impaired glucose tolerance, insulin resistance, 
and dyslipidemia. [92, 93]
4. OGTT & Level of SCI. In 20 non-diabetic SCI subjects tested before exercise 
intervention, mean % Body Fat determined by 4-compartment modeling was 35.9 ± 6.7, 
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whereas %BF for able-bodied (AB) adults generally ranges from 12-25%. Further, 
Glucose AUC during 3-hour OGTT was significantly elevated in C7- T5 (965 ± 102 
mg%•min) and T6-L2 SCI (723 ± 52) compared to non-diabetic AB adults (679 ± 18), 
and significantly different from each other (P<0.05); see figure 2. Of note, the 
glucose:insulin AUC ratio, a gross measure of insulin sensitivity, appeared elevated in 
our SCI subjects compared to AB adults (3.68 ± 3.02 vs1.41 ± 0.89), although not 
significantly so.
5. Intravenous Glucose Tolerance Test (IVGTT). Dr. Gater learned the IVGTT procedure 
during his VHA and NIH Career Development Awards and has been proficient 
performing IVGTTs for over 18 years. Dr. Gater has supervised over 150 IVGTTs in the 
past 4 years, and the U Miami CTSI CRC staff routinely performs IVGTTs for several of 
the metabolic protocols being done there. Based on our recent results from FESLCE on 
glucose kinetics, HBFES LCE + Diet is expected to reduce % Body Fat and improve 
insulin sensitivity and glucose effectiveness during intravenous glucose tolerance tests.
6. Bone Mineral Density (BMD) in SCI. We’ve previously demonstrated a strong 
relationship between time since SCI and lower extremity BMD using DXA.[94] The 
regional bone measurements were determined using specified region of interest (ROI) 
analyses specified by the DXA manufacture (Lunar DPXIQ; Software version 4.3, 
Madison, WI). The resulting precision of the arm, leg, and trunk BMD measurements 
was 0.0202, 0.0128, and 0.0086 g/cm2, respectively, while % coefficient of variation of 
arm, leg and trunk BMD were 1.92 %, 0.86 %, and 0.86 %, respectively. Although we 
did not see a significant increase in BMD with our most recent FES interventional trial, it 
appeared that BMD remained constant or slightly increased over the 4-month 
intervention. We will be monitoring for similar trends in the Home-based interventional 
trial.
7. Novel Home Based FES (HBFES): Dr. Gater was a co-investigator on several FES 
trials while at the U Kentucky, U Michigan, and Virginia Commonwealth University and 
has authored several publications about patient selection criteria, potential complications 
and rate of exercise progression required for functional electrical stimulation.[95-99] He 
was part of a VA multi-site grant on implanted neuroprostheses for standing with the lead 
group at the Cleveland FES Center of Excellence, and a paper summarizing that data was 
recently published.[100] His group utilized FES in several protocols for paraplegia which 
have recently been completed and additional manuscripts are in preparation. In 
comparison with arm crank ergometry, paraplegic subjects assigned to the FES-LCE 
group demonstrated similar improvements in body composition, glucose effectiveness 
and insulin sensitivity. Our lab has continued to demonstrate positive body composition 
changes, as well as response to different FES stimulation patterns. [98, 99, 101-103] 
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Dr. Gater's lab recently piloted a program for VACO Prosthetics and Orthotics of rent-to-
purchase RT300s for veterans in whom 90-day exercise compliance with the equipment 
can be documented. Patients were screened by their physicians and initial exercise trials 
monitored in the SCI Exercise Laboratory before sending the RT300 (Restorative 
Therapeutics, Inc., Baltimore, MD) to the veteran’s home for the 3-month trial. 
Preliminary work with n=17 veterans with paraplegia over 12 months has demonstrated 
ease of use, ability to monitor and adjust settings by internet, and 80% successful 
completion by those participating. The telemedicine program has demonstrated capacity 
to use the VitelCare® T400 (Bosch, Vienna, VA) to monitor HR & BP during home-
based exercise, and we will purchase similar systems and web cams to monitor our 
subjects at home. As preliminary work for the current proposal, we demonstrated 
improvements in several individuals with tetraplegia using HBFES 5 days/week for 1 
year up to 56 months, with increased FFM and RMR, but %BF didn’t decrease as 
expected, likely due to unmonitored dietary intake. [104, 105] Previous studies have not 
used persons with high SCI due to concern of autonomic dysreflexia and inability to 
monitor exercise in the home. 
8. Novel Home Based Dietary Approach for SCI: Early in his career, Dr. Gater conducted 
exercise and dietary interventional studies assessing changes in body composition and 
glucose tolerance in able-bodied populations.[106, 107] He has utilized dietary 
assessments in his most recent studies, and has contributed to the sparse literature on 
dietary interventions for persons with SCI.[1, 5, 87-90] Of note, BMR for high SCI often 
falls below 1,000 Kcal/day. Dr. Gater's group recently published a review article on the 
role of nutrition after SCI further elucidating the need for this research, [88] and another 
demonstrating the relative efficacy of 24-hour dietary recall in persons with SCI. [87]
3.3 Study Rationale 
Spinal cord injuries (SCI) predispose individuals to impaired fitness, obesity, glucose 
intolerance and insulin resistance, placing them at greater risk for diabetes and coronary 
artery disease. These health risks are only moderately reduced with upper extremity 
exercise, due to the relatively small muscle mass utilized, and upper extremity exercise 
has very limited potential for persons with high paraplegia or tetraplegia. Functional 
electrical stimulation leg cycle ergometry is likely to improve whole body composition, 
energy expenditure and glucose metabolism. Closely monitored diet intervention may 
also reduce body weight but is more likely to result in loss of lean tissue, i.e., 
metabolically active muscle tissue, with subsequent reductions in energy metabolism and 
the re-accumulation of adipose tissue. Both types of interventions have been tried in 
institutional settings previously, but compliance has typically been an issue due to 
distance and environmental barriers that prevent easy access. The purpose of this 
proposal is to evaluate and compare the health benefits of home-based functional 
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electrical stimulation leg cycle ergometry plus diet (HBFESLCE + Diet) to home-based 
(HB) Diet alone.
4. Inclusion and Exclusion Criteria
Inclusion criteria: 
•
Adults 18-65 years of age (inclusive) 
•
Sex: male or female
•
Women of child-bearing potential who agree to refrain from getting pregnant 
during the trial
•
C4-T4 motor complete (AIS A, B & C) spinal cord injury for duration greater 
than 12 months
•
<5% change in body weight over the past 12 months
Exclusion criteria: 
•
<22% body fat
•
Unresponsive to neurostimulation
•
Those who have participated in a FES or ACE exercise program (>60 
minutes/week) within the past 3 months
•
Known orthopaedic limitations
•
Coronary artery disease
•
Type 1 diabetes mellitus, insulin-requiring Type 2 or untreated diabetes 
mellitus (fasting glucose>126 or HgbA1c>7.0)
•
Uncompensated Hypothyroidism (Stable on medication >1 year or not on 
medication)
•
Renal disease
•
Uncontrolled autonomic dysreflexia, recent (within 3 months)
•
Deep vein thrombosis (within the past 3 months)
•
Anticoagulation therapy
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•
Pressure ulcers > Grade II
•
Decisional impairment
•
Any potential causes of autonomic dysreflexia at the discretion of the PI
•
Prisoners 
•
Pregnant or nursing women
5. Number of Subjects
Forty (40) subjects will participate in the study; however, it may be necessary to screen 
up to 60 subjects to allow for those who do not meet inclusion/exclusion criteria. 
Study Timelines
It is anticipated that subjects will be enrolled in the study for 21weeks.
It is anticipated that enrollment of subjects will occur between August 15, 2020 and 
December 31, 2024. 
6. Study Endpoints
Primary Study Endpoints: 
1. Body composition (%BF, FM and FFM) 
2. Insulin sensitivity 
3. Glucose effectiveness 
4. BMR 
5. Thickness of epicardial adipose tissue as measured by echocardiography
6.  Volumes of subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), 
intramuscular fat, (IMF) as measured by CT.
 Secondary Study Endpoints 
1. Lipid profiles 
2. Lower extremity bone mineral density 
3. hsCRP in adults 
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4. Proinflammatory adipokines: tumor necrosis factor-, interleukin-6, monocyte
 chemoattractant protein-1, plasminogen-activator inhibitor-1, vascular cell
 adhesion molecule-1 and intercellular adhesion molecule-1
5. Anti-inflammatory adipokines: Adiponectin and Interleukin-10
7. Procedures Involved
Overview: 
Primary outcome measures will include body composition by iDXA, CT, 
Echocardiography, insulin sensitivity, glucose effectiveness and BMR, while 
secondary outcomes will include lower extremity BMC and density, lipid profiles, 
hsCRP, fasting insulin, TNF, IL-6, PAI-1, ICAM-1, VCAM-1 MCP-
1,adiponectin and IL-10, Non-esterified free fatty acids determined before and 
after the 16-week interventions. Subjects will be randomly assigned (50% chance) 
to either HBFES LCE + Diet on an RT300 ergometer or Home-based (HB) Diet 
Alone intervention as determined by a random number generator.
Study Procedures include: 
•
History and Physical Examination: Each subject will undergo a complete 
history and physical examination by a physiatrist board certified in SCI medicine. 
This will include general demographics, past medical history, medications, family 
and social history, race and ethnicity. Subjects will undergo  an AIS exam which 
is a system of tests used to define and describe the extent and severity of a 
patient’s spinal cord injury. 28 key sensory points will be tested on each side of 
the body for light touch and pinprick sensations. There will also be a strength 
assessment of ten muscles on each side of the body. The subject will be graded 
based on their sensations and strength assessment. Subjects who have had a 
neurological physical exam with ASIA completed in the last year by a licensed 
physiatrist board certified, will not need a repeat exam. Women of childbearing 
potential will have a pregnancy test obtained. 
•
ECG: A resting 12-lead ECG will be performed on each subject to rule out any 
coronary artery disease.
•
Surface Neurostimulation: The physical exam will conclude with a surface 
neurostimulator trial to determine muscle response to electrical stimulation at 
bilateral gluteus maximus, hamstrings, vastus lateralis, and vastus medialis. If 
there is no muscle response, the patient may not be included in the study.
•
Dobutamine Echocardiogram/Epicardial Adipose Tissue
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•
Screening Labs: A full electrolyte panel (fasting sodium, potassium, chloride, 
bicarate), BUN, creatine, glucose and HgbA1c will be drawn at the Clinical 
Translational Research Site, 7th floor during the IVGTT.
•
Blood labs
o
Blood Lipids, hsCRP and inflammatory panels: Each subject will have 
lipid profiles (HDL-c, LDL-c, total cholesterol, and triglycerides). hsCRP, 
insulin, non-esterified free fatty acids, IL-6, TNF, MCP-1, PAI-1, 
ICAM-1, VCAM-1, Adiponectin, IL-10 assessed before and after the 16-
week intervention. Lipids and hsCRP will be determined by standard 
analyses procedures employed by the CRC. Secondary variables of 
particular note include HDL-c, total cholesterol:HDL-c ratio and hsCRP.
o
Genetic Testing: A separate sample will be collected and stored for future 
analysis to assess genetics in relation to body composition and metabolism 
after spinal cord injury. 
A total of approximately 26 ml of blood (approximately 5 teaspoons) will be 
collected for all the aforementioned tests. 
•
Body Composition: Dual Energy X-Ray Absorptiometry (DXA): Total body and 
regional (lumbarspine, proximal femur, and forearm) dual-energy x-ray 
absorptiometry (DXA) scans will be performed using a Lunar iDXA bone 
densitometer at the Lynn Rehabilitation Center Physical Medicine and 
Rehabilitation (Lynn PM&R) Research Lab. DXA scans will be completed at 
screening, baseline, and at the midpoint and end of the study intervention to 
assess for changes in body composition. All scans will be performed and analyzed 
by a trained, certified DXA operator. A single trained investigator will analyze all 
scans. The DXA total bone mineral content measurements will be used to correct 
for the mineral fraction in the criterion body composition model (4-compartment 
model) [39]. Anthropometric measures (skinfolds, girths and circumferences) will 
be obtained for pilot data using a CRC adjunct proposal. Primary variables will 
include %BF, Absolute Fat Mass (FM), and Absolute FFM determined by DXA.
•
Weight: Subjects will be weighed at each visit to the Lynn PM&R Research Lab.
•
Lower Extremity bone mineral density (BMD) and bone mineral content 
(BMC): Lower extremity bone mineral density will be determined by dual-energy 
x-ray absorptiometry (DXA) using a Lunar iDXA (Lunar Inc., Madison, WI) bone 
densitometer at the Clinical Translational Research Site, 7th floor as described 
above. All scans will be performed and analyzed by a trained, certified DXA 
operator using the Lunar software version 13.4. A single trained investigator will 
analyze all scans. Secondary variables of particular note include femoral neck and 
proximal tibial BMD (areal density) and BMC.
•
BMR: Subjects will have their basal metabolic rate measured by indirect 
calorimetry using a canopy COSMED Quark RMR gas exchange measurement 
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system. They will be woken early in the day before eating or drinking and lie still 
for 20 minutes while the measurement is in progress.
•
IVGTT: An IVGTT will be used to determine insulin sensitivity and glucose 
effectiveness using standard protocols established at the University of Miami 
Towers: Clinical Translational Research Site, 7th floor. After a 10 to 16-hour fast, 
an indwelling catheter with an intravenous saline drip (0.9% NaCl) will be placed 
in an antecubital vein, and another intravenous line will be placed in a 
contralateral vein or hand vein between the hours of 0630 and 0800 to facilitate 
infusion of glucose and blood sampling during the IVGTT. Glucose samples will 
be taken at –6, -4, -2, 0, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 19, 22, 23, 24, 25, 27, 30, 
35, 40, 50, 60, 70, 80, 90, 100, 120, 140, 160, and 180 minutes after the rapid 
glucose injection (0.3 gm/kg IV over 30 seconds at time zero). In addition, 20 
minutes after the glucose injection a bolus of insulin (0.02 U/kg) will be injected 
to determine insulin sensitivity. Blood pressure and heart rate will be assessed at 
minutes 22, 23, and 24 of the protocol. Plasma glucose will be measured by the 
Autoanalyzer glucose oxidase method and plasma insulin concentrations will be 
determined by electrochemiluminescence (ECL). The Si (glucose disposal rate per 
unit of secreted insulin per unit time) and SG (glucose mediated glucose disposal 
rate) are calculated from a least-squares fitting of the temporal pattern of glucose 
and insulin throughout the IVGTT using the MINMOD program.[60, 104] 
Reproducibility studies from our group comparing entry (screening) IVGTT SI 
data with studies done following placebo treatment have indicated that the 
coefficient of variation is approximately 15% (Gater, unpublished results) The 
acute insulin response to IV glucose (AIRG) is calculated as the mean rise in 
plasma insulin above baseline at 3, 4 and 5 minutes after IV glucose 
administration. KG, a measure of glucose tolerance, is calculated as the least 
square slope of the natural log of absolute glucose concentration between 5 and 
20 minutes after the glucose bolus. Primary variables will include SI and SG. The 
total amount of blood drawn during the entire study is about 1/2 pint, which is less 
than donating a unit (1 pint) of blood.
•
Stress Test & Energy Expenditure: This procedure will be performed on all 
subjects at the UMH Echocardiography Laboratory under the supervision of Dr. 
Martin Bilsker. A dobutamine echocardiogram stress test will be performed prior 
to exercise to rule out significant cardiovascular disease and to establish peak 
heart rate that will be used to prescribe peak exercise intensity for the HBFES 
exercise intervention as per ACSM guidelines; this is a standard procedure at our 
SCI Center for persons desiring exercise. Before the administration of the 
dobutamine, epicardial adipose tissue will be measured. A post-intervention 
echocardiogram will also be performed to measure epicardial adipose tissue 
following the intervention [109]. The COSMED Quark RMR (Rome, Italy) gas 
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exchange measurement system will be used with canopy to determine basal 
metabolic rate (BMR) as described above, and exercise energy expenditure by 
mask indirect calorimetry during the aerobic exercise (in target heart rate zone) 
for exercise sessions 1, 41 and 80. BMR will be utilized to assess caloric needs 
for the dietary intervention proposed. Primary variables will include BMR and 
exercise energy expenditure.
•
Non-contrast CT images: Abdominal/pelvic/thigh scans will be performed at 
UM/Sylvester Department of Radiology, these will be obtained pre and post 
intervention using a 128-slice multidimensional whole body scanner before and 
after the intervention. Prior to undergoing the scan subjects will have their lower 
extremities ranged and stretched as described above. Images will be attained from 
the xiphoid process to the superior aspect of the patella. All images will be 
analyzed at a separate workstation using TeraRecon iNtuition imaging software. 
Images are automatically segmented into adipose tissue, skeletal muscle, and 
bone/background based on location and then their attenuation properties, with 
adipose having the lowest attenuation and bone/background having the highest 
attenuation. A CT attenuation range of -120 to -40 Hounsfield units (HU) will be 
used to encompass abdominopelvic adipose tissue, -190 to -30 HU will be used 
for IMF, and -29 to +150 HU will be used for skeletal muscle (needed for IMF 
quantification).71 Cross sectional area (CSA; cm2) will be automatically calculated 
by the software by summing the pixels of the tissue and multiplying it by the pixel 
surface area for each adipose tissue depot, while volume (cm3) will be computed 
by multiplying the CSA by the image slice thickness and inter-slice space. Visual 
distinction will be used to determine VAT versus SAT based on the anatomical 
locations of the tissues and CSA and volumes will be summed together from 
consecutive slices. Total VAT mass and total SAT mass (in grams) will be the 
product of the total volume and fat density (0.9196 g/cm3). For the CSA of IMF, 
the outer perimeter of the thigh muscle group will be traced and the femur will be 
excluded. A bimodal graph will be used to determine pixel differences between 
muscle (higher attenuation) and IMF (lower attenuation). To account for muscle 
size, IMF CSA will be normalized to muscle CSA. Volume of IMF will be 
calculated as described above.
•
Exercise Training Intervention: Within approximately two weeks of testing, 
subjects will be randomly assigned to either HBFES-LCE + Diet or Diet alone 
(Diet) group. Prior to each exercise bout, all participants will have lower 
extremities ranged and stretched according to a standard protocol (Appendix 5), to 
reduce risk of injury and to reduce spasticity and tone. The exercise protocol will 
include an initial accommodation period of 4 weeks, during which four 10-minute 
exercise bouts/day will be interspersed with 5 minutes of rest, gradually 
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lengthening bouts until at least continuous 40-minute sessions are tolerated. 
However, subjects will have the flexibility to advance through the 
accommodation period at their own pace, as tolerated. Exercise intensity during 
the remaining 12-week intervention will be set at 70% maximal heart rate 
(HRmax), as determined by the initial dobutamine stress test, or as close to that as 
tolerated / capable by the subject based on stimulation intensity and resistance 
(see below). Exercise training will consist of three to five, 40-67-minute sessions 
(200 minutes at target intensity) each week for a total of 16 weeks; 10-minute 
warm-up and cool-down sessions will accompany each exercise session. An 
intent-to-treat protocol will be employed, and thus all subjects randomized will be 
used in the final data analyses. FES leg cycle ergometry (LCE) training will be 
induced on the RT300 FES-LCE ergometer (Restorative Therapeutics, Inc., 
Baltimore, MD) through wires connected to silastic surface electrodes over 
bilateral quadriceps, hamstring and gluteal muscles. Electrodes will be placed on 
the skin of the following corresponding skeletal muscle groups. Quadriceps: One 
electrode will be placed on the skin approximately 3 finger widths above the 
superior aspect of the patella, and the other 4-5 finger widths from the inguinal 
crease. The Q-angle should be kept in mind when centering the electrodes over 
the quadriceps. Hamstrings: One electrode will be placed 2-3 finger widths above 
the popliteal fossa and the other electrode approximately 1 hand width apart but 
no further than 3-4 finger widths from the gluteal fold. Gluteus Maximus: Two 
electrodes will be placed parallel and on the bulk of the muscle belly with at least 
2 finger widths between electrodes. The medial electrode will be placed 
approximately 2-3 finger widths from and parallel to the gluteal cleft and the 
lateral electrode approximately 2-3 finger widths posterior to the greater 
trochanter. The above are guidelines and due to anatomical differences among 
subjects, slight modifications may be required at the discretion of the Physical 
Therapist in order to achieve optimal tetanic contraction. Subjects will be 
provided with a pictorial instructional guide on proper electrode placement. (FES 
Protocol for Patient and Families Appendix 6).
In the event of an unforeseen interruption or pause in a subject’s intervention due 
to illness or other personal reasons, the PI will manage the course of the 
remaining sessions at his discretion. This includes extending or restarting the 
intervention as appropriate with the goal of ensuring that subjects are able to 
experience the full intervention while also preserving data integrity. 
Accommodations to conduct the exercise sessions and other FES related activities 
at an alternative site (e.g., home, office, The Miami Project gym) may be made at 
the discretion of the PI and study team to mitigate any extreme unforeseen 
circumstance impacting the home-based sessions and facilitate the participation in 
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the protocol. The ability to make these accommodations will facilitate data 
collection and minimize transportation and caregiver burden for the subject. 
o
The RT300 FES-LCE computer sequences functional electrical 
stimulation impulses which induce contractions of the quadriceps, 
hamstrings, and gluteal muscles in an order that allows for the hip, knee, 
and ankle joints to combine to create the repetitive circular motion of 
pedaling. The RT300 has HIPAA Compliant internet connectivity that 
allows clinicians to follow results and make alterations to the exercise and 
cycle parameters remotely. Once a session is completed the performance 
data including time, distance, power, energy expenditure and the session 
parameters such as current amplitude, pulse width, current frequency, 
cycling speed and resistance are displayed and stored. The HIPAA 
compliant internet connectivity allows for the optimization of training and 
safety. The RT300 also allows the participant to cycle from his or her own 
wheelchair eliminating the need to transfer onto a cycle. Prior to starting 
home based FES-LCE, subjects will undergo 1-3 FES-LCE sessions in the 
Lynn PM&R Research Lab so that electrode application, ergometer 
function can be taught, and heart rate, blood pressure and possible 
autonomic dysreflexia symptoms could be monitored. A baseline blood 
pressure and heart rate reading will be obtained prior to beginning  an 
exercise session and then every 10 minutes thereafter (for a total of three 
readings) while monitoring for symptoms of autonomic dysreflexia. 
Subjects will continue to be assessed for symptoms of autonomic 
dysreflexia during the session. After completion of the laboratory trial 
without incident, the subject will be cleared to begin home based FES-
LCE. The PT and at least one other member of the research team  will 
assist with delivery and set-up of the RT300 ergometer, cardiovascular 
monitoring and audiovisual teleconference equipment in the subject’s 
home. The initial 1-2 sessions in-home will be monitored by in-person PT 
and/or RN, as well as by telemonitoring by research coordinator / graduate 
student in the lab and dietician on the CRC to ensure real-time audiovisual 
communication is intact. At any time during the 16-week intervention, 
should audiovisual monitoring equipment malfunction, telephone or Zoom 
communication initiated by a UM study team member) will allow for 
immediate home-evaluation of equipment by PT, RN and/or technicians. 
Study team members and participants will be protected from COVID-19 by 
observing standard precautions as is the practice when at the Lynn PM&R Lab. 
These include mask-wearing, handwashing,  the use of sanitizer and/or sanitizing 
wipes, additionally social distancing to the extent possible.  All subjects will be 
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asked to participate in 3-5 cycling sessions per week of 40-67 minutes for 
a total of 200 minutes/week in target intensity zone, plus 10-minute warm-
up and 10- minute cool-down. Sessions will be monitored by the research 
staff via internet connection and telemedicine VitelNet and web cam (HR 
& BP q 10 minutes). Cycle parameters will be individualized depending 
on the amount of current needed to perform the cycling activity and 
depending on the comfort of the participants. The cycling parameter 
ranges will include maximum values not to exceed the following: 140 mA 
for current amplitude, 500 µs for pulse width, and 100 Hz for frequency.  
Speed will be advanced between 30 and 50 rpm with an initial resistance 
of 0.5 Nm. The resistance will be set on automatic so that the RT300 cycle 
would vary the resistance to allow the set speed. For example, if the speed 
is set at 40 rpm and the resistance is at 1.0 Nm, if the participant cannot 
sustain the set speed at that resistance, the cycling system will 
automatically decrease the resistance to allow the participant to maintain 
the selected speed. Cycling duration will be increased over the 16-week 
period until a goal of between 40 and 67 minutes of continuous active FES 
cycling was attained. Subject and home assistants will be provided 
training concerning the placement of electrodes and the FES-LCE 
procedures. Medical guidelines proposed by Phillips will be employed at 
all sessions. [62] 
•
Dietary analyses will be completed through a comprehensive dietary assessment 
(Appendix 1) and by 24-hour (Appendix 2) and 72-hour recall on the CRC (Food 
Frequency Questionnaire) (Appendix 3) analyzed by NDS-R software, with 
immediate feedback provided by a registered dietician. An individualized, 
detailed dietary plan consistent with My Healthy Plate Dietary Guidelines of 
America (http://www.choosemyplate.gov/) (Appendix 4)will be used based on 
estimated caloric needs determined by indirect calorimetry (BMR) as described 
above; daily multivitamins will recommended for all subjects and additional 
supplements, e.g. Vitamin D will be prescribed as necessary to ensure a 
homogenous sample. Both groups (HBFES LCE + Diet and Diet alone) will 
receive daily (M-F) electronic dietary education, assessments and consultation via 
trained Nutrition Coaches using the MyFitnessPal dietary app, as well as weekly 
dietary assessments and consultation done with the Nutrition Coaches and RD via 
audiovisual teleconference. For the HBFES LCE + Diet group and the Diet alone 
group, once weekly dietary sessions will occur on a mutually agreed upon time 
over teleconference. In the event of a technical malfunction, telephone or Zoom 
communication will be used as an alternate method of communication.  Zoom 
will be initiated by a UM study team member. The HBFES LCE + Diet group will 
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have diet modified based on their energy expenditure during their exercise 
sessions. Diet modifications in both groups will be individualized to ensure 
appropriate nutrient/vitamin density and 200 Kcal/day energy deficit to yield ~1/2 
pound fat loss per week, i.e., ~ 8 lb. fat loss over the 4- month study, in accord 
with the PI’s previous work.[87, 90] Throughout the study, all subjects will be 
informed of high quality proteins and instructed on the importance of including 
protein throughout the day (at each meal). In addition to daily electronic and 
weekly telemedicine caloric and nutrient counseling (both groups), the Nutrition 
Coaches and registered dietician will provide health tips from the “choose my 
plate” website (Appendix 4) and individualize the subject’s diet for the desired 
weight loss.
•
Methods: Each subject will undergo a complete physical examination by a 
physiatrist board certified in SCI medicine, with 12-lead resting ECG and 
dobutamine echocardiogram stress test (reviewed by the cardiologist) and 
comprehensive dietary assessment prior to participation. Echocardiograms 
(transthoracic two-dimensional guided M-mode) will be performed by standard 
techniques with subjects in the left lateral decubitus position. The thickness of 
EAT will be measured perpendicular to the free wall of the right ventricle at the 
end of systole in three cardiac cycles using parasternal long-axis or short-axis 
view. Echocardiographically, EAT is identified as the echo lucent (echo-free) 
space between the superficial/external wall of the myocardium and the visceral 
layer of the serous pericardium. Measurement of EAT on right ventricle was 
chosen for two reasons: 1) this point is recognized as the greatest absolute 
epicardial fat layer thickness, and 2) parasternal long-and short-axis views allow 
the most accurate measurement of epicardial adipose tissue on the right ventricle 
with optimal cursor beam orientation in each view. The baseline measurement of 
EAT will precede the dobutamine stress echocardiogram. The physical 
examination by Dr. Gater will conclude with a surface neurostimulator trial to 
determine muscle response to electrical stimulation at bilateral gluteus maximus, 
vastus lateralis, and vastus medialis. During this visit, participants will also be 
screened for total body fat percentage by DXA. Screening labs will be obtained 
including fasting sodium, potassium, chloride, bicarbonate, BUN, creatinine, 
glucose and HgbA1c. Within approximately, two weeks, depending on subjects’ 
availability, eligible participants will return to the University of Miami medical 
campus. This visit will include the remaining DXA scans for estimation of body 
composition. After DXA completion, participants will be escorted to the UM 
Towers: Clinical Translational Research Site (CTRS), 7th floor and will be asked 
to remain in the CTRS overnight. At 6 am the following morning, the subject will 
be gently awakened for determination of basal metabolic rate (BMR) by indirect 
calorimetry using a canopy COSMED Quark RMR (Rome, Italy) gas exchange 
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measurement system for 20 minutes. The 3-hour intravenous glucose tolerance 
test (IVGTT) will be completed between the hours of approximately 7 and 11am. 
Once assigned to an intervention group, HBFES LCE + Diet subjects will begin 
monitored exercise (4-week initial accommodation described below), proceeding 
with a target heart rate @ 70% HRMax for 40 minutes, 5 times weekly for 16 
weeks. Energy expenditure for exercise sessions 1, 41 and 80 will be determined 
using by indirect calorimetry using a COSMED Quark RMR (Rome, Italy) gas 
exchange measurement system. Post-testing will ensure within approximately 1 
week of the last exercise bout, to optimize IVGTT responses. Both groups will 
receive daily (M-F) electronic dietary education, assessments and consultation via 
Nutrition Coaches, as well as via audiovisual remote teleconference weekly to 
maintain a daily 200 Kcal/d energy deficit.
Screening Visit (Week 1) 
The screening visit will take place Lynn PM&R Research Lab.  Potential participants will 
be encouraged to ask questions, thoroughly review the consent document and discuss the 
decision to participate with their family and caregivers. An additional visit will be 
scheduled to complete the screening procedures in the event the potential participant does 
not consent at the initial visit.
After obtaining written consent, subjects will undergo the following procedures: 
•
History and Physical Examination 
•
An ASIA exam for those who may not have had one within the last year 
•
Surface Neurostimulation 
•
Total body scan by DXA to determine total body fat percentage
•
ECG & Dobutamine Stress Echocardiogram
•
Pregnancy test for women of childbearing potential 
The aforementioned procedures will be completed at the Lynn PM&R Research Lab. The 
dobutamine echocardiogram/epicardial fat and adipose tissue measurements will be 
performed at the UHealth Tower. The dobutamine stress echocardiogram is intended to 
rule out any significant cardiovascular disease and to establish peak heart rate that will be 
used to prescribe peak exercise intensity for the HBFES-LCE exercise intervention. 
The Screening Visit and procedures are expected to take approximately 3 hours to 
complete and can be arranged at the subject’s convenience.
Baseline Assessment (Weeks 2-3) 
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Once the subject has completed the screening visit and their eligibility for continued 
participation has been confirmed, they will be asked to return for a baseline assessment. 
At this visit, subjects will undergo the following procedures:
•
Anthropometric measures performed at Lynn PM&R Research Lab) 
•
Remaining DXA scans (performed at Lynn PM&R Research Lab) 
•
CT (Abdomen/pelvis/thigh performed at UM/Sylvester Department of Radiology)
•
BMR (following an overnight stay at CTRS) 
o
A registered nurse will be available to stay with the subject during the 
overnight stay. A family member or caretaker will also be allowed to stay 
overnight. 
•
IVGTT (performed at CTRS)
A full electrolyte panel will be obtained (fasting sodium, potassium, chloride, 
bicarbonate), BUN, creatine, glucose and HgbA1c (performed at CTRS). Blood 
Lipids, hsCRP insulin, non-esterified free fatty acids, IL-6, TNF, MCP-1, PAI-1, 
ICAM-1, VCAM-1, adiponectin, IL-10 and a separate blood sample for genetic 
analysis (performed at CTRS) will also be obtained. This process is expected to 
take approximately 18 hours to complete and will require an overnight stay at the 
CTRS. This visit can be arranged at the subject’s convenience but must be 
scheduled within 2 weeks of the Screening Visit. 
•
COVID-19 PCR testing with a negative result within 48 of admission to CTRS for 
subjects and their caregiver if applicable
Randomization 
Directly after the baseline visit subjects will be randomly assigned to the HBFES LCE + 
Diet or Diet alone intervention groups using a random number generator.
Exercise Trial and Mask Indirect Calorimetry Session 1: (Week 4) 
HBFES LCE + Diet subjects will undergo at least 1 FES-LCE session in the Lynn PM&R 
Research Lab this week so that heart rate, blood pressure and possible autonomic 
dysreflexia symptoms can be monitored. Subjects’ energy expenditure during aerobic 
exercise will be measured at this time by mask indirect calorimetry. This assessment 
represents Session 1 of the intervention. If another session is required, the subject will 
return within 5 days to perform another FESLCE session. After completion of the 
laboratory trial without incident, the subject will be cleared to begin home based FES-
LCE. 
Accommodation Period (Weeks 5-8)
The FES-LCE subjects will have an accommodation period of 4 weeks, during which 
four 10-minute exercise bouts/day will be interspersed with 5 minutes of rest, gradually 
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lengthening bouts until at least continuous 40-minute sessions are tolerated. Both groups 
(HBFES LCE + Diet and Diet alone) will have weekly dietary assessments and 
consultation done with the RD via teleconference. For both groups, these weekly sessions 
will occur at a mutally agreed upon time.
Mask Indirect Calorimetry Sessions 21, 41 and 61 (Subject-Specific)
Exercise energy expenditure by mask indirect calorimetry during aerobic exercise will be 
measured additionally at Sessions 21, 41and 61 of the intervention. We anticipate the 
timing of these assessments will be subject-specific depending on the frequency of the 
weekly exercise routine established by each subject. They will occur at varying 
timepoints during the intervention as subjects work through their weekly exercise 
sessions. For example, subjects who maintain a 5-day/week schedule, exercise session 41 
will occur at about week 8 of the intervention. For those who exercise on a 3-day/week 
schedule, session 41 will occur later in the intervention at about week 13. Subjects will 
return to the Lynn PM&R Research Lab for this assessment. 
Exercise Intervention & Mask Indirect Calorimetry Session 80 (Weeks 9-20)
For the following 12 weeks the HBFES LCE + Diet subjects will exercise 3-5 times each 
week in order to achieve 200 minutes at target intensity. Both intervention groups will 
continue to meet with the RD via teleconference once per week. For both groups, these 
weekly sessions will occur at a mutually agreed upon time. Session 80 represents the 
conclusion of the exercise intervention and the timing of the final assessment of energy 
expenditure during aerobic exercise by mask indirect calorimetry. Subjects will perform 
their final FES-LCE session for this assessment at the Lynn PM&R Research Lab. 
End of Study Assessment (Week 21) 
All subjects will return to the Lynn PM&R Research Lab and CTRS within 1 week of 
study completion. At this visit subjects will repeat the same procedures they did during 
the baseline assessment: 
•
Anthropometric measures (performed at Lynn PM&R Research Lab) 
•
DXA (performed at Lynn PM&R Research Lab) 
•
BMR (overnight stay at CTRS) A registered nurse will be required to stay with 
the subject during the overnight stay. A family member or caretaker will also be 
allowed to stay overnight. 
•
IVGTT (performed at CTRS after overnight stay)
•
Blood Lipids, hs-CRP, insulin, non-esterified free fatty acids, IL-6, TNF, MCP-
1, PAI-1, ICAM-1, VCAM-1, adiponectin, IL-10 (performed at CTRS)
•
Echocardiogram (non-dobutamine, performed at UMH Echocardiography 
Laboratory)
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•
CT imaging - Abdomen/Pelvis/Thigh (performed at UM/Sylvester Department of 
Radiology)
•
COVID-19 PCR testing with a negative result within 48 of admission to CTRS for 
subjects and their caregiver if applicable
The End of Study Assessment is expected to take approximately 18 hours to complete 
and will require an overnight stay at the CTRS.
Subjects who were randomized to the Diet only cohort will be offered an opportunity to 
experience HBFES LCE by enrolling in the TEAM-SCI protocol #20220652 once they 
have completed their participation in SCIENCE.
9) Data and Specimen Banking
Genetic Testing 
As part of our baseline blood collection during the overnight stay at the CTRS, we will 
also obtain a sample for genetic testing. Subjects’ samples will be stored indefinitely for 
future analysis to assess genetics in relation to body composition and metabolism after 
spinal cord injury. Samples will be labeled via a deidentified mechanism but linked to the 
subject by a unique study ID that will be assigned to them when they enter the study. The 
link to each subject’s identity and/or other identifiable information will be maintained 
separately from the research data. 
The data will be kept at the Lynn PM&R Research Lab 3rd Floor located at 1611 NW 12th 
Avenue Miami, FL 33136. The blood samples for genetic testing will be kept frozen at 
the Biomarker and Immunoassay Laboratory located at the Diabetes Research Institute, 
1450 NW 10th Avenue, Room 3033 Miami, FL. 33136. Extracted samples will be 
analyzed at the Hussman Institute for Human Genomics (HIHG) Biorepository, 1501 NW 
10th Avenue Biomedical Research Building (BRB) Room 448 Miami, FL. 33136. 
Subjects may be contacted to inform them of their results.
10) Data Management
Sample size determination 
Sample size estimates were determined for the primary variables most important to the 
investigation, notably % Body Fat and the Insulin Sensitivity Index (SI) determined using 
Bergman’s Minimal Model to interpret IVGTT data. For the purpose of statistical 
analyses, we will assume a dropout rate of 15%, although we are optimistic that persons 
participating in the project will actually demonstrate a better compliance rate than usual, 
due to the Home-Based interventions. Sample size consideration for % Body Fat (%BF) 
as determined by DXA was based upon body composition changes noted by Bauman et al 
(1994) in response to a 12-week FES leg ergometry training. % BF (Mean± SE) 
decreased from 31.8± 2.3 to 28.5± 2.4 for the 12 subjects monitored. Assuming a similar 
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change in the %BF for our HBFES LCE + Diet group and a minimal change in %BF of -
0.06 for our Diet alone group, with an α = 0.05 significance level using a Mixed Linear 
Model (MLM) to fit a Repeated Measures ANOVA (RMANOVA) with one between 
subjects factor (Group), one within subjects factor (Time) and the interaction between 
Group and Time and assuming both a correlation of 0.70 between the Pre and Post 
measurements and a correlation of 0.50 between the Pre and Post measurements. In 
addition, simulations were performed with the variance seen in the pilot data as well as 
with this variance doubled; these results are presented in Table 3. In all scenarios 
considered a sample size of 20 subjects per group would provide over 80% power to 
detect a significant Group by Time interaction. Even if 5 subjects dropped out we would 
still have over 80% power to detect a significant Group by Time interaction in all but one 
scenario.
Power Calculation for BF%
α = 0.05
Var(Pre)=Var(Post)=6.250
Var(Pre)=Var(Post)=12.500
Sample Size
Empirical 
Power 
ρ=0.70
Empirical 
Power 
ρ=0.50
Empirical 
Power 
ρ=0.70
Empirical 
Power ρ=0.50
n=10 per group
95%
80%
76%
53%
n=15 per group
99%
95%
86%
67%
n=20 per group
100%
97%
95%
80%
The sample size consideration for IVGTT was based on group comparisons of changes in 
mean response levels of insulin sensitivity to exercise between the spinal cord injury 
group and the able-bodied group noted within our institution in response to an exercise 
regime in 13 subjects with spinal cord injury. Differential equations are employed to 
describe glucose kinetics (assuming a single compartment model for glucose distribution) 
and insulin effects (assuming a separate compartment, remote from plasma) using insulin 
and glucose concentrations determined during the IVGTT. The resulting information 
provides a good estimate of glucose effectiveness, i.e., the effect of glucose at basal 
insulin to enhance glucose disposal, and insulin sensitivity, i.e., whole body 
responsiveness to an insulin challenge.[145] In these 13 subjects insulin sensitivity 
increased 8.24 μU/ml with a calculated standard deviation of change of 19.74 μU/ml. A 
large part of both the mean chance and the variability in the 13 observed patients was 
attributable to two extreme responders. To be conservative we assumed both a “large” 
change in insulin sensitivity of 3.2 μU/ml and a “small” change of 1.6 μU/ml and a 
“large” standard deviation of 6 μU/ml and a small standard deviation of 3 μU/ml. Using a 
linear regression model to predict the change scores (post-score minus pre-score) with 
one between subjects factor (Group) and assuming both a correlation of 0.70 between the 
Pre and Post measurements and a correlation of 0.50 between the Pre and Post 
measurements and assuming both a correlation of 0.70 between the Pre and Post 
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measurements and a correlation of 0.50 between the Pre and Post measurements. The 
results of the power calculations based on the simulation is shown in table 4 (next page). 
In all but the most extreme scenarios considered (small mean change, large variance or 
low correlation) a sample size of 20 subjects per group would provide over 80% power to 
detect a significant Group by Time interaction. Even if 5 subjects dropped out we would 
still have over 80% power to detect a significant Group by Time interaction in all but the 
three extreme scenarios noted.
Statistical methods 
Forty subjects will be randomly assigned to either HBFES LCE + Diet or Diet alone. All 
tests will be two-sided at the α = .05 level of significance. Effects will be reported with a 
point estimate and 95% confidence intervals in addition to p-values. We will examine the 
distributions of all measures and identify possible outliers. Dependent variables that are 
found to be non-normally distributed will be transformed to more closely approximate 
normality before analysis. Outliers will be thoroughly checked for collection or data entry 
errors before being used in the analysis. A linear regression model will be used to fit a 
model to assess the effects of exercise training (independent variable) on the change 
scores (post-score minus pre-score) for body composition, insulin sensitivity, glucose 
effectiveness, serum lipids and lower extremity bone mineral density (dependent 
variables). The linear regression model will have one between subjects (independent) 
factor, Group (HBFES LCE + Diet or Diet alone). While this model is exactly the same 
as a two-sample t-test for the change scores it allows for the adjustment of other 
explanatory variables that might have an impact on the dependent variable (i.e. age, time 
since injury, etc.). While we anticipate that randomization will balance out the groups 
with respect to covariates that may have an impact on dependent variables, if this is not 
the case the linear regression model for the change scores will allow for the inclusion of 
these covariates to adjust for the Group predictor variable, which are the real variables of 
interest in the study. Specific variables for body composition will include per cent and 
absolute BF, as well as per cent and absolute FFM mass, as determined by 4-
compartment modeling. Insulin sensitivity (SI), glucose effectiveness (SG) will be the 
primary variables assessed from the IVGTT, and BMR will be assessed as a primary 
variable. Specific variables for serum lipids will include total cholesterol, HDL-C, LDL-
c, triglycerides; hsCRP will be measured separately. Areal density (BMD) and bone 
mineral content (BMC) will also be considered secondary variables of interest.
Power calculations for Insulin Sensitivity (Si)
Mean Diff(T2-T1) Group 1=0.0, Group 2=3.2
α = 0.05
Var(Time1)=Var(Time 2)=3.00
Var(Time1)=Var(Time 2)=6.00
Sample Size
Empirical 
Power ρ=0.70
Empirical 
Power ρ=0.50
Empirical 
Power ρ=0.70
Empirical 
Power ρ=0.50
n=10 per group
99%
98%
95%
79%
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n=15 per group
100%
100%
99%
90%
n=20 per group
100%
100%
100%
97%
Mean Diff(T2-T1) Group 1=0.0, Group 2=1.6
α = 0.05
Var(Time1)=Var(Time 2)=3.00
Var(Time1)=Var(Time 2)=6.00
Sample Size
Empirical 
Power ρ=0.70
Empirical 
Power ρ=0.50
Empirical 
Power ρ=0.70
Empirical 
Power ρ=0.50
n=10 per group
72%
49%
45%
31%
n=15 per group
88%
68%
57%
40%
All primary and secondary outcomes will be visually assessed (boxplots, histograms, etc.) 
for normality and/or continuous data will be examined with a Shapiro-Wilk test.  We will 
use a 2-way (group x time) mixed-model analysis of variance (ANOVA) to assess group 
interaction. Where significant interaction effects are observed, paired and independent t-
tests will be used to determine significant differences within and between groups. Alpha 
will be set at < 5%.
11) Provisions to Monitor the Data to Ensure the Safety of Subjects
Please refer to the attached document DSMB 0719
12) Withdrawal of Subjects
12.1 Criteria for removal from study 
Subjects will be removed from the study for the following reasons: 
•
Withdrawn Consent 
•
Non-compliance with study requirements 
•
Recurrent Autonomic Dysreflexia
12.2 Follow-up for withdrawn subjects
Subjects withdrawn from the study prior to the 16-week assessment will be asked to 
return to the lab for an End of Study visit. These subjects will be asked to complete all 
baseline assessments. Subjects may refuse any or all of the End of Study procedures. At a 
minimum, investigators will require subjects to return the exercise equipment. 
Subjects who are withdrawn early will not be replaced; we anticipate an Intent-to-Treat 
analysis of all subjects who complete screening and are randomized. 
Subjects removed from the study for adverse events or safety concerns will be followed 
for resolution of the event. No additional follow up of withdrawn subjects will be 
performed.
13)  Risks to Subjects
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•
Venous catheter Insertion may result in localized swelling, soreness, bruising, 
chance of infection, bleeding, pain, lightheadedness or possible fainting.
•
Insulin Sensitivity Tests may result in hypoglycemia (low blood sugar) with 
occasional dizziness, sweating, and nausea. Seizures, coma or death may 
occur, but are highly unlikely during medical monitoring.
•
Dobutamine echocardiogram may cause anxiety or dizziness.
•
Anthropometrics may cause discomfort or bruising.
•
Basal metabolic rate determination may cause anxiety or shortness of breath.
•
Functional electrical stimulation may result in a fracture of the lower 
extremity and cause redness and skin lesions affecting the areas of electrode 
placement. The severity of the lesions may range from mild skin irritation to 
lesions that require treatment. Adherence to the recommended protocol for 
treatment and prevention of skin lesions will be provided to subjects. This 
protocol is as follows: 
o
During the FES session in the first few weeks we will gradually 
increase amplitude while keeping a narrow pulse width. Pulse width 
will be gradually increased thereafter. 
o
After each FESLCE session participants will be instructed to 1) wash 
the areas with soap and warm water, 2) thoroughly dry and apply 
over-the-counter Neosporin or any other over-the-counter triple 
antibiotic ointment or cream to the affected areas, and 3) cessation of 
fabrifoam wraps. After each session, the research team will request 
photos of the skin where the electrodes are placed for a post-session 
skin assessment.
o
Prior to the start of the FES sessions and throughout the protocol we 
recommend that all participants clip their hair. 
o
When lesions begin to appear, stimulation will be decreased. 
•
DXA scan may cause anxiety and excessive exposure to radiation
•
CT Imaging may cause anxiety and some exposure to radiation
•
Exercise training may cause light-headedness, shortness of breath and altered 
heart rate and blood pressure. Muscle soreness at the neck, upper back, 
shoulders, arms and hands rarely occur. 
•
Autonomic dysreflexia may occasionally occur during functional electrical 
stimulation but will be closely monitored for, and stimulation diminished or 
stopped if unresolved with usual measures. 
•
Training may also cause pressure ulcers, but close monitoring during and after 
sessions should prevent such wounds. 
•
Extreme exercise may cause fainting, heart attack or (almost never) death.
14)  Potential Benefits to Subjects
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Potential benefits may include weight loss, improved body composition, improved 
glucose tolerance and lipid profiles, and improved mobility and self-efficacy and appear 
to largely outweigh the potential risks listed on the previous page. This population is 
especially at risk for metabolic dysfunction, obesity and metabolic syndrome including 
glucose intolerance, dyslipidemia, hypertension and vascular inflammation.
15) Vulnerable Populations
No vulnerable populations will be recruited or enrolled in the study.
Some subjects may present with a caregiver who assists them with certain activities such 
as completing and signing documents.  These subjects may have limited use of their 
upper extremities as a result of their spinal cord injury, making it difficult or impossible 
to sign for themselves.  It is usual and customary, in this scenario for the caregiver to sign 
on their behalf, e.g. the informed consent form, however these subjects will not have any 
cognitive deficits. 
16) Sharing of Results with Subjects
Overall study results are expected to be published in peer-reviewed scientific journals at 
the conclusion of the study. 
Clinically significant research results will be shared with subjects during the course of the 
study. Subjects will likely be self-aware of some study findings, such as weight loss, 
increased muscle mass. There are no plans to share overall study findings directly with 
subjects. 
If requested, results can be shared with a subject’s PCP and a note will be put in the 
patient’s EMR about their participation in the research study.
17) Setting
•
Activities related to recruitment, consent, and some baseline data collection will 
occur at the University of Miami .
•
Data collection and other related procedures will occur within the Department of 
Physical Medicine & Rehabilitation at the UM Miller School of Medicine (CTRS 
7th floor) or the Lynn PM&R Research Lab.
Data storage, administrative, and data analysis activities will occur in the offices of the 
PI, collaborators, and study staff at the UM Miller School of Medicine Department of 
Physical Medicine & Rehabilitation. 
18) Resources Available
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As PI, Eduard Tiozzo, PhD, MSCTI, FAHA will devote 30% of his time (6 calendar 
months) and have primary responsibility for project implementation. He has more than 10 
years of experience in clinical research trial implementation, particularly, in the role of 
Exercise Physiologist as it relates to exercise and nutrition interventions, and body 
composition assessment (DXA Certified) 
As Co-Investigator, Dr. Jose Ramon Vives-Alvarado will perform history and physical 
and ASIA examinations, admissions and discharges, intravenous glucose tolerance tests, 
provide medical supervision of all subjects, , presentations and manuscript submissions. 
Meghan Cochrane will also assist with performing history and physical and ASIA 
examinations, determination of eligibility and general medical supervision of subjects.
Other co-investigators are included on the project that fulfill several roles: clinical experts 
in SCI, and in pain management, research experts in SCI, and in pain measurement and 
assessment. The study staff also includes a Clinical Research Nurse (Dinorah Rodriguez, 
RN, BSN, CCRC), physical therapists (Cristina Segredo Thurston, PT, DPT, NCS and 
Thomas Pelaez DPT, CSCS), registered dietician Alicia Sneij, PhD, MS, RDN, nutrition 
coaches, named in the study team section of the IBIS application, research associate one  
postdoctoral associate (Gary J. Farkas, PhD), and research assistants, named in the study 
team section of the IBIS application. All staff that will participate in conducting the 
study, including recruitment, data collection, data review, etc., and their associated duties, 
are listed within the IRB application in IBIS. Regularly-scheduled meetings will be held 
with all study staff in order to ensure that all are up-to-date on study procedures, training, 
and oversight efforts.
Financial resources for this work, including study staff effort, device procurement, 
subject payments, and miscellaneous supplies are provided for as appropriate via grant 
funding obtained by the Department of Physical Medicine and Rehabilitation.
19) Prior Approvals
N/A
20) Recruitment Methods
20.1 Identification of subjects 
•
Subjects will be actively recruited from the South Florida Spinal Cord Injury 
Model System, a database of the Department of Physical Medicine and 
Rehabilitation under the Directorship of Elizabeth Felix, PhD. (ePROST 
#20100501). Subjects will also be recruited from the Miami Project to Cure 
Paralysis using a telephone script.  Participants enrolled in the Miami Project to 
Cure Paralysis database were recruited by word-of-mouth, casual contact, online 
advertisement on The Miami Project to Cure Paralysis website, and via phone or 
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email contact for those individuals who have filled out the intake form on the 
Miami Project to Cure Paralysis Website.  The intake form contains a provision 
for participants to opt in to receive updates on research projects. 
https://redcap.miami.edu/surveys/index.php?s=P9T87MYKH4
•
Through the intake form, The Miami Project maintains a database of persons who 
have volunteered their participation in research studies. This is a searchable 
database under the management of David McMillan Director of Education and 
Outreach. This database contains self-reported information, such as age, date of 
injury, level of injury, and impairment scale score that will allow us to screen 
potential participants. In addition to these two sources, we are also requesting a 
Waiver of Authorization for pre-screening for the purpose of reviewing subjects’ 
medical records. 
•
Direct response from subjects responding to the study flyer will be 
recruited/screened using a telephone script.
20.2 Recruitment process 
Potential subjects will be contacted via phone calls, and in the clinic to provide 
information for participation in this research study. Flyers and ads will be posted 
throughout the University of Miami campus as well as on the department’s website. As a 
result, subjects inquiring about this study may be offered participation in other PM&R 
studies for which they may be eligible. The Clinical Trials Search Tool will be used. 
20.3 Recruitment materials 
•
Flyers: posted at the University of Miami hospital, websites, clinic sites and 
community centers. 
•
Telephone Script 
•
Clinical Trials Search Tool – https://umiamihealthresearch.org
20.4 Eligibility/screening of subjects 
We anticipate most subjects will be known to us through the SCI database. Prior to 
consent, we will confirm with potential subjects, by review of the database or their 
medical chart the location and date of their SCI. All other screening assessments, 
physical exam, surface neurostimulation, lab tests, and body composition measurement, 
will be performed only after subject’s written consent has been obtained
20.5 Payment
Each subject will be paid $50 for completing the Baseline Assessments, and $50 for 
completing the final assessment for a total of $100. In addition, we will pay subjects $25 
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per completed CT scan, pre and post intervention for a total of $50.  If the Week 22 visit 
is not completed, there will be no pro-rated payments for the completion of the other 
visits. 
21) Local Number of Subjects
We anticipate that, over the recruitment period (Aug 2019 – Dec 2022) 40 subjects will 
participate in the study. To allow for a percentage of subjects who will not meet 
inclusion/exclusion criteria, it may be necessary to screen up to 60 subjects.  We will not 
consent more than 60 subjects without prior approval by the IRB. 
22)  Other Physical Medicine and Rehabilitation Research Studies 
Subjects will be offered participation in other PM&R studies for which they may be 
eligible (as described in the recruitment process above). The possibility of dual 
enrollment or partial overlap of participation in more than one study is conceivable. This 
could result in duplication of required assessments subjects would need to complete. 
However, in an attempt to simplify subjects’ participation, reduce the number of visits to 
our research lab, and mitigate testing redundancy, we may apply test results completed 
for one study to another in those cases.
23) Confidentiality
Check all that apply: 
  Data obtained or created for this research will be stored on an 
encrypted electronic device or system owned by the University of 
Miami or on a cloud storage system that has been approved by the 
University of Miami for storage or research data. 
 The Investigator (or research staff) will record (e.g. write 
down, abstract) data collected in a manner that does not include 
any indirect or direct identifiers and the recorded data will not be 
linked to the individual’s’ identity.  
 The investigator (or research staff) will record (e.g. write down, 
abstract) the data collected in a manner that does not include any 
direct identifiers of the subject. The investigator will assign a code 
to each subject and link the code to the subject’s identity.  The 
research team will maintain the link to the subject’s identity on a 
document separate from the research data.  Both documents will be 
stored in separate files on a University of Miami encrypted device 
or on a University of Miami approved cloud storage system. The 
research team will destroy the identifiers at the earliest 
opportunity.
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 The research team will maintain the research data for at least 
six years. 
  Bio-Specimens obtained for this research will be stored 
without any direct or indirect identifiers.  
 X Bio-Specimens obtained for this research will be stored in a de-
identified coded manner.  
X  When required to transport data or bio-specimens for this 
research, the research team will transport the data and bio-
specimens in a de-identified (or anonymous) manner with a link to 
the individual subject’s identity maintain separately from the data 
and/or bio-specimen.
Data that is collected on paper will be stored securely in a locked cabinet in a locked 
office that is accessible only to study staff as described in Section 23, Provisions to 
Protect the Privacy Interest of Subjects. Electronic data will be collected and stored on a 
secure server within the University of Miami network with access limited only to those 
personnel listed on the IRB application for this study.
24) Provisions to Protect the Privacy Interests of Subjects
For recruitment purposes, the study team physician(s) and approved staff will access 
information from medical records to assess eligibility for the study, therefore we are 
requesting a Waiver of Authorization.  These source documents will be retained and the 
information confirming inclusion and exclusion criteria will be noted in the subject’s 
study records/documents.
During the initial consenting procedures, a history and physical will be obtained as part 
of standard of care which may include questions sensitive in nature. Subjects will be 
ensured that they do not have to respond to all of these questions. If they are not 
comfortable answering, they may still participate in the study. Subjects will be reminded 
of this throughout assessment sessions as needed. Research staff will make every effort to 
provide a friendly atmosphere and assurances of privacy and confidentiality in any way 
possible. Paper documents for data collection will only include assigned subject ID 
numbers that cannot be easily linked to subject identity. A password-protected log of 
subject ID numbers associated with subject identity and contact information will be 
maintained only until all activities of the study are completed.
All study-related interviews or completion of questionnaires and assessments will be 
conducted in private areas where others will not be able to see or hear participant 
responses, and study staff will not discuss personal information with other study staff 
members unless they are in a private location where others cannot hear. Patients’ study-
related information will not be discussed or disclosed to anyone that is not a part of the 
research study unless indicated by law. 
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25)  Compensation for Research-Related Injury
If you are hurt or get sick due to being in this study, treatment will be available in 
most cases.  If you are hurt because of a correctly done study procedure the Sponsor 
will pay for the cost of treating the injury.  The University of Miami and the 
sponsor are not planning to pay for pain, lost wages, and other costs you incur 
because you were hurt. You do not give up any of your legal rights to obtain 
payment for an injury if you sign this consent document. If the sponsor pays any of 
your medical expenses, we may be required to give the sponsor your name, date of 
birth, and Medicare ID or social security number.
26) Economic Burden to Subjects
The subjects will not be responsible for any costs due to participation in the research 
study.
27) Consent Process
26.1 Obtaining Informed Consent 
•
Subjects will complete the consent process at the Lois Pope Life Center, Christine 
Lynn Rehabilitation Hospital, or the Clinical Research Center (CRC) in a private 
room during a time that is convenient for them.
•
Subjects will be given plenty of time to consider participation and to ask any and 
all questions they have. They will have the opportunity to take the consent form 
home and consider it further if needed. The subjects will be assured that 
participation is voluntary, that they may withdraw from participation at any time, 
and that current and future health care will not be affected by the participants’ 
choice to participate or not. 
•
Waiver of Authorization is requested to review medical records for eligibility 
prior to the subject signing informed consent for participation. 
26.2 Consent Documentation 
•
Written documentation of consent will be completed for each subject. For 
subjects who are unable to sign as a result of their spinal cord injury, verbal 
consent will be obtained from the subject and the consent form will be signed 
by the subject’s legally authorized representative. The consent document will 
be included in this submission. 
26.3 Consent – Other Considerations 
•
Cognitively Impaired Adults 
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o
Capability of Providing Consent: Not Applicable 
o
Adults Unable to Consent: Not Applicable 
o
Assent of Adults Unable to Consent: Not Applicable 
•
Subjects who are not yet adults (infants, children, teenagers) 
o
Parental Permission: Not Applicable 
o
Assent of subjects who are not yet adults: Not Applicable
28) Process to Document Consent in Writing
The subject’s consent to participate in this research study will be documented in writing 
according to standard UM IRB SOP (HRP-091). 
29) Authorization for Use and Disclosure of Protected Health 
Information (HIPAA)
Type of Request:
 Waiver of Authorization for access to medical record for subject 
identification/recruitment.
 Waiver of Authorization for access to medical record to obtain data for the 
research.
Confirm that you will destroy or de-identify the information you collect at the 
earliest opportunity. 
  I confirm
Confirm that the information you collect will not be reused or disclosed to any other 
person or entity, except as required by law, for authorized oversight of the research 
study or for other research for which the use or disclosure of PHI is permissible.          
   I confirm        
30) Drugs or Devices
The devices used in this study do not require an IDE. Please refer to 9.) Procedures 
Involved for information about the devices and where they will be held. 
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77. Groah SL, Nash MS, Ljungberg IH, Libin A, Hamm LF, Ward E, Burns PA, Enfield G: 
Nutrient Intake and Body Habitus After Spinal Cord Injury: An Analysis by Sex and Level of 
Injury. Journal of Spinal Cord Medicine 2009, 32:25-33.
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87. Gorgey AS, Gater DR: Regional and relative adiposity patterns in relation to carbohydrate 
and lipid metabolism in men with spinal cord injury. Applied Physiology Nutrition and 
Metabolism-Physiologie Appliquee Nutrition Et Metabolisme 2011, 36:107-114.
88. Gorgey AS, Mather KJ, Gater DR: Central adiposity associations to carbohydrate and lipid 
metabolism in individuals with complete motor spinal cord injury. Metabolism-Clinical and 
Experimental 2011, 60:843-851.
89. Clasey JL, Janowiak AL, Gater DR: Relationship between regional bone density 
measurements and the time since injury in adults with spinal cord injuries. Arch Phys Med 
Rehabil 2004, 85:59-64.
90. Creasey GH, Ho CH, Triolo RJ, Gater DR, DiMarco AF, Bogie KM, Keith MW: Clinical 
applications of electrical stimulation after spinal cord injury. J Spinal Cord Med 2004, 27:365-
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91. Gater DR, Dolbow D, Tsui B, Gorgey AS: Functional electrical stimulation therapies after 
spinal cord injury. Neurorehabilitation 2011, 28:231-248.
92. Gater DR, McDowell SM, Abbas JJ: Electrical stimulation: a societal perspective. Assist 
Technol 2000, 12:85-91.
93. Gorgey AS, Black CD, Elder CP, Dudley GA: Effects of Electrical Stimulation Parameters on 
Fatigue in Skeletal Muscle. Journal of Orthopaedic & Sports Physical Therapy 2009, 39:684-692.
94. Gorgey AS, Poarch HJ, Gater DR: Effects of Resistance Training on Muscle Cross-sectional 
Area and Body Composition after Spinal Cord Injury. Medicine and Science in Sports and 
Exercise 2010, 42:66-66.
95. Triolo RJ, Bailey SN, Miller ME, Rohde LM, Anderson JS, Davis JA, Abbas JJ, DiPonio LA, 
Forrest GP, Gater DR, Yang LJ: Longitudinal Performance of a Surgically Implanted 
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98. Gorgey AS, Shepherd C: Skeletal Muscle Hypertrophy and Decreased Intramuscular Fat 
After Unilateral Resistance Training in Spinal Cord Injury: Case Report. Journal of Spinal Cord 
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99. Dolbow DR, Gorgey AS, Moore JR, Gater DR: Report of practicability of a 6-month home-
based functional electrical stimulation cycling program in an individual with tetraplegia. Journal 
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101. Gater DR, Gater DA, Uribe JM, Bunt JC: Effects of arginine/lysine supplementation and 
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103. Khalil RE, Gorgey AS, Janisko M, Dolbow DR, Moore JR, Gater DR: The Role of Nutrition 
in Health Status after Spinal Cord Injury. Aging and Disease 2013, 4:14-22.
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104. Bergman RN: Toward Physiological Understanding of Glucose-Tolerance - Minimal-Model 
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by Ehrman J, Gordon P, Visich P, Keteyian S. Champaign, IL: Human Kinetics; 2013: 489-510
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