Electrical Stimulation for Improving Balance in Diabetes
Phase: NA
Conditions: Diabetic Peripheral Neuropathy
Sponsor: University of Texas Southwestern Medical Center

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Electrical Stimulation for Improving Balance in Diabetes
NCT02337218
October 12, 2015

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Electrical Stimulation for Improving Balance in Diabetes
Principal Investigator:
Lawrence A. Lavery, DPM, MPH
Co-Investigators:
Javier La Fontaine, DPM
Suzanne van Asten, MD
Sponsor:
Qatar National Priority Research Program
NPRP No.: NPRP 5 - 117 - 3 - 028

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1. Introduction and Purpose:
Our long-term goal is to provide a convenient, low-cost therapeutic device and treatment
protocol for diabetic patients with high risk of falling. Eventually, we plan for this to be an approach
that can be used by patients at home. We will use preliminary data from this study to plan and
implement a randomized clinical study in high risk diabetics to evaluate long-term clinical outcomes,
specifically a reduction of falls, foot ulcers and amputations in patients that use the electrical
stimulation treatment.
This study will be a double-blind randomized clinical trial design consisting of two groups of
forty (40) patients with diabetic peripheral neuropathy and some level of postural instability. The
study consists of a 12 weeks treatment phase and two weeks of retention. Subjects will be asked to
wear a comfortable electrical stimulation device (SENSUS™ Pain Management System,
Neurometrix, Inc., Waltham, MA) during night time on daily basis for duration of 8 hours. The
proposed dosage regiment was used in our preliminary studies and no related adverse event was
reported while a significant improvement in skin perfusion was observed. The objective of this
proposed study is threefold:
Aim1: To compare postural control in subjects assigned to use the active Electrical Stimulation
(intervention group) and subjects assigned to non-functional stimulator (sham group). Balance will
be assessed for both groups at baseline and at monthly intervals. Study hypotheses are:
H1: Electrical Stimulation will improve postural coordination and helps to reduce body sway during
standing in the treatment group compared to the sham group as well as compared to the baseline.
H2: Electrical Stimulation will improve gait, gait initiation, and gait inter-cycle variability compared
to the sham group as well as compared to the baseline.
Aim2: To compare changes in skin perfusion in patients treated with Electrical Stimulation compared
to sham therapy.
H3: Electrical Stimulation will improve dorsal and plantar perfusion compared to the control group
and compared to baseline.
Aim3: To evaluate changes in quality of life in high risk diabetes who received Electrical Stimulation
compared to sham therapy.
H4: Plantar stimulation will improve subject quality of life in the intervention group assessed using
SF36.
H5: Plantar stimulation will improve spontaneous daily physical activity. More specifically, the
duration of walking and standing as well as activity organization (i.e. day-to-day activity fluctuation)
will be improved.
H6: The risk and fear of falling during activity of daily life will be improved.

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2. Background:
This project builds on the results from our previous studies and is designed to translate basic
science findings into protocols and methods of therapeutic value. In the following the most relevant
studies to the purpose of this project have been summarized:
Study 1: A novel body worn sensor technology for assessing postural control and
postural compensation strategy:
Human body motion is traditionally captured using standard optic, magnetic or sonic
technologies (Najafi, Aminian et al. 2003; Aminian and Najafi 2004). However, in recent years,
body- wearable sensor technology based on electro-mechanical sensors has provided a new
avenue for accurately detecting and monitoring body motion and physical activity of an individual
under free conditions (Aminian and Najafi 2004; Zijlstra and Aminian 2007; Najafi, Helbostad et al.
2009; Najafi, Horn et al. 2010; Najafi, Miller et al. 2010). In particular, combinations of multiple
accelerometers and angular-rate sensors (gyroscopes) show a promising design for a hybrid
kinematic sensor module for measuring the 3D kinematics of different body segments (Najafi
2003; Zijlstra and Aminian 2007).
Body-wearable sensors offer the key advantages of low cost and use in all environments—
since they don’t require installation of any particular infrastructure. These benefits are important in
developing a suitable tool for clinical applications, as they enable physicians to (1) improve the
evaluation of patient gait and postural control; and (2) help patients care for themselves. Body-
worn sensors incorporated with high-speed data acquisition system enable the measurement and
recording of 3D body segment motion with sample frequencies much higher than is possible with
camera-based systems. The high sample frequency is essential to creating an altered dynamic
environment to evaluate the postural response against alteration. In addition, a real-time
processing is highly beneficial to the creation a bio-feedback signal from body segment motion or
COM for both rehabilitation and evaluation of gait and postural control mechanisms. (Najafi 2003;
Aminian and Najafi 2004).
In a recent study, our bioengineer collaborator in the USA, has designed and validated a
biosensor technology named BalanSens™. (Najafi, Horn et al. 2010) This system is based on
widely-available kinematic sensors (i.e. accelerometer, gyroscope and magnetometer). The system
measures ankle and hip motion in three dimensions (3D)-figure 1. We have also integrated the
resulting data into a two- link biomechanical model of the human body for estimating the 2D sway
of the center of mass (COM) in anterior-posterior (AP) and medial-lateral (ML) directions (Fig. 2).
To evaluate the best postural strategy for maintaining balance, a reciprocal compensatory index
(RCI) was defined which quantifies how the movement around hip could compensate the
movement around ankle for
reducing the variation of COM. (Najafi, Horn et al. 2010; Najafi and
Wrobel 2010). RCI values near zero represent a good postural control strategy (i.e. negative
correlation between hip and ankle movements), RCI values more than one represent inappropriate
postural control strategy (i.e. positive correlation between hip and ankle movements leading to
increase the variation of COM and ankle, and hip in real time using a two-link biomechanical model
of a human body.

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The validity and reliability of the suggested system were examined by several measurements.
(Najafi, Horn et al. 2010) First, the COM estimated using BalanSens was compared with COP
measured using a standard pressure platform in 21 healthy subjects. Results suggested a relatively
high correlation (r=0.92) between two measurements during both eyes-open and eyes-closed
conditions. Interestingly, measuring COM seems to be more than 12 times more sensitive than
measuring COP (i.e. 12 times higher range of sway for COM compared to range of sway for COP,
see Fig 3). We also examined the sensitivity of the device for screening balance deterioration by
comparing the output of the system among several conditions where both visual and somatosensory
feedback was altered. Results demonstrated that this system is highly sensitive to detect balance
alterations due to challenges in visual (eyes-closed condition) and somatosensory feedback (standing
on a soft surface). (Najafi, Wu et al. 2009; Najafi, Horn et al. 2010) Finally, the clinical validity of the
system was assessed by comparing balance control of healthy subjects with a group of 17 diabetic
patients suffering from lack of somatosensory feedback. (Najafi, Horn et al. 2010) Results
demonstrated that DPN patients exhibit significantly greater COM sway than healthy subjects for
both EO and EC conditions (p<0.005) –Figure 4. The difference becomes highly pronounced while
eyes are closed (197±44cm2 vs. 68±56cm2). Furthermore, the results showed that postural
compensatory strategy assessed using RCI is significantly better in healthy subjects compared to
DPN subjects for both EO and EC conditions as well as in both medial-lateral and anterior-posterior
directions (p<0.05). Interestingly, alteration in somatosensory feedback in healthy subjects via asking
them to stand on a soft surface resulted in diminished RCI values that were similar to those seen in
the DPN subjects (p>0.05). These results suggest that a low cost technology based on inertial
sensors similar to those sensors used in new generation of iPhone® can provide accurate
Figure 3 – the validation results
compared to force-platform
Figure 1 –Assessing Balance:  two sensors were attached, one to the
subject’s lower back and one to the shin. These sensors allow
measuring three-dimensional angles of ankle and hip joints. Software
was developed to estimate the trajectory of COM
Figure 2 – Two-link biomechanical
model of human body for
estimating COM trajectory

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information about patient’s balance without using an elaborate gait lab infrastructure. This strategy
also appears to be more sensitive and responsive as the changes are approximately 12 times larger
than using traditional center of pressure techniques. This degree of discrimination could detect
clinically subtle yet meaningful changes in a patient’s balance.
Figure 4: The area of sway for (A) COM, (B) hip joint, and (C) ankle joint for healthy subjects while
standing on a hard surface (healthy SOM feedback), DPN subjects (distorted SOM feedback), and
healthy subjects while standing on a soft surface (distorted SOM feedback)
Study 2 & 3: The benefit of the electrical stimulation device on wound healing:
In a preliminary study, we have employed electrical stimulation on six patients, three men
and three women, with an average age of 57.1 ± 9.3 years, all with type II diabetes of a mean
14.7 ± 5.9 years’ duration. All wounds evaluated were plantar, five beneath the first metatarsal
head, one beneath the fifth metatarsal head, with a mean area of 5.1 ± 1.1 cm2. All wounds were
grade 1A (non- infected, full thickness skin not involving tendon, capsule, or bone) using the
University of Texas wound grading system. These wounds were present for a mean 77.3 ± 55.1
days prior to institution of electrical stimulation. All healed uneventfully in a mean 4.1 ± 2.3 weeks.
There were no known complications to electrical stimulation during the period of review. The
wound healing rate was between 33% and 50% faster than previously reported studies using
similar patient populations.(Mueller, Diamond et al. 1989; Armstrong, Lavery et al. 1996).
In a subsequent study(Peters, Lavery et al. 2001), we explored the benefit of pulse-
galvanic electric stimulation as an adjunct to healing diabetic foot ulcers. This study was
designed as a 12-week, double-blind, randomized, placebo-controlled clinical trial. Forty patients
with diabetic foot ulcers consecutively sampled (Table I). Twenty patients each assigned to
treatment and placebo groups. We used the Micro-Z™stimulator (see Section 4, Fig 11), that
delivers current via a microcomputer to a Dacron-mesh silver nylon stocking to provide nocturnal
electric stimulation to patients randomly assigned to the treatment group. The total program
was designed to run at night for an 8-hour period. The placebo group used identical functioning
units that delivered no current. Both the treatment and placebo group received traditional wound

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care consisting of debridement, topical hydrogel, and off-loading with removable cast walkers.
Patients were followed for 12 weeks or until healing, whichever occurred first. Outcomes included
the proportion of patients with complete wound healing in 12 weeks, the rate of wound healing, and
complications such as infection or need for amputation.  Sixty-five percent of the patients healed in
the group treated with stimulation, whereas 35% healed with placebo (P= .058). After stratification
by compliance (Fig 5), a significant difference was identified among compliant patients in the
treatment group (71% healed), noncompliant patients in the treatment group (50% healed),
compliant patients in the placebo group (39% healed), and noncompliant patients in the placebo
group (29% healed, linear-by-linear association =4.32, p= .038). There was no significant
difference in compliance between the 2 groups. We believe these preliminary data are very
promising and warrant further study.
Table I: Characteristics of Patients Who Received Placebo and Electric Stimulation
PLACEBO GROUP
TREATMENT GROUP
History of diabetes (years)
17.0 ±
16.4 ± 11.6
Ulcer duration (months)
5.5 ±
5.0 ± 6.4
Age (years)
59.9 +
54.4 + 12.4
Gender
16 male, 4 female
18 male, 2 female
Glycosylated Hemoglobin(%)
9.5 ± 2.4
9.2 ± 2.1
Peak Plantar Pressure (Ncm2)
81.5 +
91.1 + 15.7
Transcutaneous Oxygen
43.4 +
47.1 + 13.0
Semmes-Weinstien Monofilament
1.9 + 2.4
3.2 +
Vibratory Perception Threshold (volts)
41.5 +
38.5 +
Percentage with neuropathy
100%
100%
Compliance per week (hours)
27.9
30.2 + 11.9
Figure 5: Results of electric
stimulation on wound healing,
stratified by compliance. Patients who
used electric stimulation for 20 hours
or more a week were more likely to
heal than those who used the devices
less than 20 hours a week or patients
who used the placebo device:  (X2 for
trend=4.35, p=.037).

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70
60
50
40
30
20
10
Study 4: Electrical stimulation and increased perfusion:
The purpose of this study (Peters, Armstrong et al. 1998) was to evaluate the effect of galvanic
electrical stimulation on vascular perfusion in diabetic patients. Nineteen subjects with diabetes were
enrolled. Eleven subjects (57.9%) were diagnosed with impaired peripheral perfusion based upon
their initial transcutaneous oximetry values (< 40 mm Hg). The subjects were studied over a 2-day
period. On the 1st day, one foot was electrically stimulated for four 60-minute periods by an external
electrical stimulation device (Micro- Z™ stimulator, Fig 11). Vascular perfusion of both
feet was assessed before and after the sessions of electrical stimulation. On the 2nd day, no
electrical stimulation was applied and noninvasive vascular measurements were repeated. For
the 1st hour, transcutaneous oxygen pressure was measured continuously during stimulation at
the lateral aspect of the leg. Subsequently, perfusion between the periods of stimulation was
measured on the dorsum of the foot with both transcutaneous oximetry and laser Doppler
flowmetry after each stimulation period. In the group with impaired peripheral perfusion, a
significant rise in tissue oxygenation as compared to the control measurements was measured
during the first 5 minutes of stimulation (p < .040, Fig 6). For those without vascular disease
(TcpO2 > 40 mm Hg) however, there was not a significant increase compared to baseline (p =
.280). After the periods of stimulation, the stimulated feet did not show any higher perfusion levels
than the control feet. Patterns in perfusion during the day, as measured by laser Doppler flowmetry,
were similar in the tested feet and in the controls. These data suggest that external sub-sensory
electrical stimulation induces a transient rise in skin perfusion in persons with diabetes and impaired
peripheral perfusion.
Figure 6: Average changes in
transcutaneous oxygen pressure
after usage of plantar stimulation.
Treatment
Baseline
Treatment
Day 2t+5m
Control
Baseline
Control Day
2t+5m
P
V
D
No
P
V
D
TCP02 real time 95%Cl

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Study 5: Postural control improvement post recovery loss of mechanical sensitivity
using a novel Plantar Stimulation technology- A Double-Blinded, Randomized Study.
Many patients with diabetic peripheral neuropathy (DPN) experience a marked loss of
mechanical sensitivity, a condition that puts them at risk for the formation of dangerous skin ulcers
and postural instability. The purpose of this pilot research (Najafi, Crews et al. 2011) was to test
whether a specific form of subcutaneous electrical stimulation improves postural control in patients
suffering from DPN.
Fifty subjects with type 1 or type 2 diabetes and mild to moderate peripheral sensory neuropathy
(insensate to 10 gram monofilament at 1-3 of the following locations: hallux, 1st metatarsal head, 3rd
metatarsal head, and 5th metatarsal head) were enrolled. The study consisted of a six week
treatment phase with five treatments per week followed by 26 weeks of follow-up. Subjects were
randomized in to either sham or active stimulation. Both groups soaked their feet for five 30-minute
sessions per week in identical stimulator baths named WaveRx® (Fig. 7) that were connected to
electrical stimulators. The active group received continuous stimulation in the bath during the
soaking sessions, while the active group’s stimulators were non-functional and provided no
stimulation. Patients were instructed at the initiation of each treatment to gradually increase the
stimulator’s power to 40% or until the patient felt a comfortable tingling sensation. If the device was
active it would deliver 120 Hz pulsed current waveforms up to a maximum of 50 miliamperes.
Postural control was assessed in a sub-sample of thirteen subjects at baseline and every two weeks
during the treatment phase as well as in 3 and 6 months later. Postural control was quantified by
measuring the area of center of mass sway (COM) using the body worn sensor
technology explained in the preliminary study #1 (Fig 8).
Figure 7: WaveRx Electrical Stimulation System
Figure 8: Balance was quantified by measuring
the area of Sway for COM

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A significant improvement in postural control was observed in the active group (ANOVA, p<0.05)- Fig 9.
The area of COM sway was significant reduced on average 36% on treatment week two.
Figure 9 Aqueous treatment of DPN using
stimulator plantar stimulation technology
significantly improved postural control in
Active group compared to baseline as well
as sham group.
Figure 10 Patients with poor
hyperglycemia control (higher A1C
level) has weaker postural control

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3. Concise Summary of Project:
This is a double-blind randomized clinical trial. Both patients and the study coordinator who
collects data with the subject will be blinded to electrical stimulation application. The Study Physicians
(PI/Sub-!) will evaluate and monitor study subjects. The Physicians (PI/Sub-I) will not be blinded to the
treatment the subject receives and determine the status of active treatment versus sham treatment. This
documentation will be only in the PI/Sub-I possession. The manufacturer of the units will be asked to
not inform which patient received which unit. Each unit will be coded with a unique identification
number, and the manufacturer units revealed their status, placebo or electric stimulation, only at the
end of data collection for the last patient. Subsequently, the investigators could match the status of
the identification numbers with the corresponding units to start analyzing the data. Patients that
receive an activated electrical stimulation unit will receive a standard dose of
50 volts as described above.
Since most patients that participate in this project will have moderate to severe peripheral
Figure 11
SENSUS™ Pain Management System

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sensory neuropathy, they will not be able to “feel” if they are receiving electrical stimulation. Placebo
controls will have an electrical stimulation unit programmed not to provide any electrical current.
However, all the other lights and programming indicators will be functional. Both active and inactive
electrical stimulation units will be programmed to download the period that they are used on a
weekly basis in order to verify that the units are used for the prescribed time period. A sealed
randomization schedule envelope will be held at the coordinating center (UT Southwestern). Except
in a medical emergency, subjects will remain blinded with regard to group assignment until
crossover opportunity or such time that all source documentation is complete, e.g., transcription into
the CRFs has been completed, CRFs have been signed by the Principal Investigator, and the
database has been closed.
We will enroll a cohort of 80 diabetes (type II) patients with peripheral neuropathy (see section
6 for sample size justification). The diagnosis of diabetes mellitus will be based on World Health
Organization criteria.(World-Health-Organization 1999). The inclusion and exclusion criteria are
described in table III. The clinical assessments are described in table IV. The investigator will
discuss the study design, duration, and its risks with potential subjects asked to participate. We will
then provide the participant with a consent form to read at their leisure. The investigator will be
available to answer questions or provide more explanation as requested by potential participants
and their family.
Subjects will be recruited from two clinical centers: 1) Wound and Diabetic Foot center at the Hamad
Medical Corporation (HMC-Doha-Qatar) under supervision of Dr Talal (contact-LPI) and 2) the
University of Texas Southwestern Medical Center (UT Southwestern), Dallas, Texas under
supervision of Prof. Lavery (Lead-PI).
4. Study Procedures:
There will be a total of five study visits required for each patient. There will be one scheduled
visit for baseline evaluation and four additional visits at 2 weeks, 4 weeks, 6 weeks during treatment
and 8 weeks (2 weeks post stopping the treatment). The baseline visit will involve completion of a
standardized intake form, which will include pertinent demographics such as age, height,   weight,
education level, occupation, and comorbidities of the study patient (see Table IV). Several clinical
assessments will be performed at baseline as well as at each study visit to evaluate severity of
neuropathy and skin perfusion as described in the table IV.
5. Sub-Study Procedures:
N/A
Table IV: Clinical Assessments

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Baseline
Medical History: This will include: duration and type of diabetes, type of
diabetes medication (insulin, oral, combination therapy, diet), previous history
of foot ulcers, previ o us hi story of  fal l s, amputation (toe, foot), lower
extremity bypass, lower extremity angioplasty, Coronary
artery bypass
surgery, 
cardiac 
angioplasty, 
arthritis, 
liver 
disease, 
osteoporosis,
malignancy, and bone tumors. We will use the Kaplan co-morbidity index to
record disease severity. We will use the New York Heart Association
criteria to classify
congestive heart failure, and the National Kidney
Foundation Disease Outcomes Quality Initiative Clinical Practice Guidelines
for chronic kidney disease to stage kidney disease. We will document all
prescription and over-the-counter medications. We will measure height and
weight to determine body mass index (BMI). We will record prescription and
over-the-counter medications.
Baseline
Social Factors: We will evaluate the following factors: marital status, years
of education, type of work, tobacco history (pack years, current smoker,
current use of chewing tobacco, previous smoker, no tobacco history), drug
history (current, previous history, no drug history), education, occupation, and
alcohol history.
Foot questionnaire and foot exam
Baseline
Questionnaires
Screening Test for frailty assessment: Fried Frailty Criteria: Weight loss >10
pounds in preceding year; Grip strength; Low levels of physical activity; 15 foot
walk time; Exhaustion[13]
* Screening for cognitive problem: Folstein Mini-Mental State Exam score
[15]
* Foot questionnaire and foot exam
* Barthel ADL Index
* Depression Assessment
* Fear of Falling Scale
* Mobility Tiredness Scale
* Pain Assessment Scale
* SF-12 (at baseline and 6 week time points)

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Baseline  &  each
2- week follow-up
(week 2, week 4,
week 6, and week
8)
+ 2 day visit
window for each
protocol related
visit starting at
Week 2.
Peripheral Neuropathy:  We will evaluate Vibration Perception Threshold
(VPT) Testing to evaluate large fiber neuropathy
We will also use Semmes-Weinstein monofilaments, and the Modified
Neuropathy Disability Score. (Armstrong and Lawrence 1998) We will
assess light touch and pressure sensation at nine sites on each foot using 4,
10, 26, and 60 Semmes-Weinstein gram monofilaments. (Diamond, Mueller et
al. 1989) The Modified Neuropathy Disability Score is a scored clinical
examination that includes Achilles deep tendon reflex, pressure, vibration
sensation and temperature sensation in both feet. (Abbott, Carrington et al.
2002; Caselli, Spallone et al. 2006).
Pain: Visual Analogue Scale
Gait test: 8 sensors will be attached to the legs and lower back using
comfortable straps and will be asked to walk 20 meters on a flat surface, two
times. A third 20 meter walk will be performed with an additional distractive
cognitive task (counting -1). The 4th test will be fast walking. Walking
performance (e.g., speed, cadence, and stability) and spatio-temporal
parameters of gait (e.g., velocity, stride time, gait inter-cycle variability, double
support, and gait initiation) will be measured.
Balance test: The BalanSensTM kinematic sensor will be attached to the legs
and lower back and will be used to measure the variation of subject’s center of
mass measured by the Romberg protocol including double stance, semi-
tandem, and full-tandem tests. Patients will be asked to stand straight, feet
together, hands crossed for 30 seconds, 20 seconds, and 15 seconds
respectively for double stance test, semi-tandem, and full tandem tests with
eyes open and closed.
Baseline and 6
weeks follow-up
Activity Monitoring: Spontaneous daily physical activity will be monitored in
home environment for 2 days using PAMSysTM
Removal log: participants will be asked to note the time off, time on, and
reason for removal if the PAMSysTM is removed during the 2 day collection
period. Refer to Activity Monitoring Log for times of use and removal.
Quality of life questionnaire: SF12 will be administered.
Other assessment
Fall log: participant will receive a log and agree to call the study overseer in
the event of a fall during the 4 weeks study period.
Other patient information: if it was available patients record including medical
history, neurological exam results, and physical examination may be gathered
from patient record after authorization of the subject (see form T504a). In
addition, subject photograph or video during experiment may be taken after
subject’s authorization.

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Baseline  &  each
2- week follow-up
Vascular Assessment: We will assess perfusion of the macro-circulation with
arterial Doppler studies and micro-circulation with Skin Perfusion Pressure
measurements and transcutaneous oxygen measurements. Ankle Brachial
Index (ABI), Toe Pressures and Waveforms (pulse volume recordings) will be
measured on both extremities. If the ankle is too painful to perform a Doppler
examination, we will get Doppler measurements once the patient is in the
operating room and under anesthesia. ABI’s have been reported to be reliable
measurements for diagnosing peripheral vascular disease. ABI’s have a 95%
sensitivity in detecting angiographically positive disease in an ABI of less than
0.9. Non-compressible foot vessels will be defined as ABI’s >1.30. Peripheral
arterial occlusive disease will be defined as an ABI<0.90. Monckebergʹs medial
calcific sclerosis or calcification of the media of the arteries can limit the
effectiveness of using ABI’s in persons with diabetes. Therefore, we will use
the SensiLase system (Väsamed) to measure Skin Perfusion Pressure (SPP)
in mmHg and records PVR waveforms with its laser Doppler sensor and
computer-automated cuff. This technique has high sensitivity and high positive
and negative predictive value to predict amputation.(Castronuovo, Adera et al.
1997; Yamada, Ohta et al. 2008) In addition we will measure transcutaneous
oxygen measurements ar 2 sites on the foot and two sites on the lower leg
during the course of therapy.
Specific Aim 1: Our first goal is to compare postural control in subjects assigned to use the active
Electrical Stimulation (intervention group) and subjects assigned to non-functional stimulator (sham
group). Balance will be assessed for both groups at baseline and at bi-weekly intervals. Static
balance and postural compensatory strategy will be assessed using the body worn sensor
technology (BalanSens™) explained in the preliminary study #1. The duration of assessment is
approximately five minutes. The test includes quiet upright standing for a period of at least 30
seconds under two conditions: eyes-open and eyes-closed. Postural control will be quantified by
measuring the range of motion of center of mass (COM) in medial-lateral and anterior-posterior
direction. COM is estimated using an innovative and validated technology based on wearable
sensors as explained in our preliminary study #1 – Figure 12. The key advantage of this
technology is that balance is assessed outside of gait laboratory and directly in our podiatric
center. Additionally, it allows measuring directly COM instead of center of pressure (COP). Our
recent study suggests that measuring COM is 12 times more sensitive to assess postural
instability than COP (Figure 3) (Najafi, Horn et al. 2010).

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Figure 12: Balance will be assessed
according Romberg protocol and will
quantified using a validated technology
based on body worn sensors
Figure 13: An innovative device
based on body worn sensors
allows measuring spatio-
temporal parameters of gait and
gait initiation in free condition
including outside of a gaitlab.

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To examine postural compensatory strategy, we will use RCI (reciprocal compensatory index)
introduced in our previous study-see preliminary study #1(Najafi, Horn et al. 2010). This index
represents how the movement around ankle joint is compensated by the reciprocal movement
around hip joint to reduce the variation of COM. (Najafi, Horn et al. 2010) By comparing the balance
control and postural compensatory strategy between DPN and control group, we will explore
whether and how neuropathy may impact balance and during which conditions (e.g. closing eyes ).
The data is coded so the investigators involved in the data analysis are blind to the subject group
(i.e. Sham v. Intervention group). We assumed at baseline there is no significant difference for the
static postural control between two groups. But during treatment, balance will be significantly
improved in the intervention group while it will be deteriorated or remained the same in the sham
group (Hypothesis 1).
For assessing spatio-temporal parameters of gait as well as dynamic balance during walking,
we will use an innovative wearable technology developed and validated by Prof. Najafi (PI) and his
team in previous studies.(Aminian, Najafi et al. 2002; Aminian and Najafi 2004; Aminian, Trevisan
et al. 2004; Lindemann U., Najafi B. et al. 2008; Najafi, Helbostad et al. 2009; Najafi, Crews et al.
2010; Najafi, Miller et al. 2010) This wearable technology comprises miniaturized motion sensors
placed on the front of each lower leg and thigh and held in place with elastic Velcro straps, and a
lightweight data logger worn on a belt around the person’s waist (Fig 13). The sensors attached to
lower-limbs are a triaxial gyroscope, triaxial accelerometers, and triaxial magnetometer that allow
measuring of three-dimensional rotation of body segment using a quaternion scheme. (Najafi, Horn
et al. 2010; Wrobel and Najafi 2010; Wrobel, Edgar et al. 2010 (In Press)) Another sensor attached
to the lumbar region permits measuring the range of motion of center of mass (COM) for each gait
stride in both the anterior-posterior and medial-lateral directions. (Najafi, Helbostad et al. 2009;
Najafi, Miller et al. 2010) Signals from sensors are digitized (16 bit) at a sampling rate of 200 Hz by
the light portable data logger and stored for off-line analysis on a Secure Digital (SD) memory card.
This configuration allows measuring spatiotemporal parameters of gait, dynamic balance, and
kinematics of lower limbs during walking as well as obstacle crossing. The method for calculating
spatiotemporal parameters of gait has been described in detail and validated in previous
publications.(Aminian, Najafi et al. 2002; Aminian and Najafi 2004; Najafi, Helbostad et al. 2009) To
summarize, the gait phases are determined from the precise moments of heel-strike (initial foot
contact) and toe-off (terminal foot contact). These moments are extracted from gyroscopes attached
to each shank through a local minimal peak detection scheme. (Aminian, Najafi et al. 2002) The key
advantage of this technology is the ability to extract gait and balance parameters outside of a gait
laboratory and directly our clinical centers. Additionally, it allows extracting enough number of steps
which is of key importance to increase the accuracy of gait estimation as well as assessing inter-
cycle gait variability. Recent studies suggested that inter-cycle gait variability (or gait unsteadiness)
is a sensitive parameter to assess risk of falling.(Dubost, Beauchet et al. 2002; Beauchet, Kressig
et al. 2003; Beauchet, Aminian et al. 2005; Dubost, Kressig et al. 2006; Dubost, Annweiler et al.
2008; Beauchet, Annweiler et al. 2009; Beauchet, Annweiler et al. 2009)
For the purpose of gait analysis, subjects will be asked to walk at their habitual speed in a
distance of approximately 20 meters while wearing the gait analyzer sensors (Fig 13). The system
allows extracting over 30 spatio-temporal parameters of gait including stride velocity, stride length,
stride time, stance, double support time, COM in medial-lateral and anterior-posterior, and gait
initiation(Najafi, Helbostad et al. 2009; Najafi, Miller et al. 2010). We assumed that the performance
of gait and dynamic balance will be improved in the intervention group after treatment compared to
baseline and compared to sham group (Hypothesis 2). Additionally, we anticipate that the inter-cycle
gait variability and gait initiation will be improved after treatment in the active group compared to

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baseline and compared to sham group.
Specific Aim 2: Our second aim is to compare changes in skin perfusion in patients treated with
Electrical Stimulation (ESTIM) compared to sham therapy. We anticipate that electrical Stimulation
will improve dorsal and plantar perfusion compared to the control group and compared to baseline
(Hypothesis 3). As described in the clinical assessment (Table IV), we will assess perfusion of the
macro-circulation with arterial Doppler studies and micro-circulation with Skin Perfusion Pressure
measurements and transcutaneous oxygen measurements.
Specific Aim 3: Our last aim us to evaluate changes in quality of life in high risk diabetes that
receive Electrical Stimulation compared to sham therapy. Our hypotheses and methods of
assessment described in the following:
Hypothesis 4: We assume that plantar electrical stimulation will improve subject quality of life in the
intervention group. Quality of life will be assessed using SF-12 questionnaire (Melville, Lari et al.
2003) at the baseline visit and at week 6.
Hypothesis 5: We also anticipate that plantar electrical stimulation will improve spontaneous daily
physical activity. More specifically, the duration of walking and standing as well as activity
organization (i.e. day-to-day activity fluctuation) will be improved. Spontaneous daily physical
activity will be assessed using PAMSys™ designed and validated by Prof. Najafi (PI) and his
team with collaboration of Biosensics LLC. Participants will wear PAMSys embedded in a
lightweight breathable tank top worn under clothing for 2 consecutive days at baseline and each
study visit (Fig 14). This device uses a combination of miniaturized kinematic sensors housed in a
single portable sensor attached to the chest. It can detect body posture (sitting, standing, and
lying), as well as provide an accurate assessment of periods of locomotion (e.g., walking,
postural transition). The validity of this approach has been established i n  3  s e p a r a t e
p i l o t s studies, and by  benchmarking the results with independent analysis by an optical
motion system.(Najafi, Aminian et al. 2002; Najafi, Aminian et al. 2003; Najafi, Wrobel et al. 2008;
Najafi, Crews et al. 2010)  These studies demonstrate that the PAMSys™ has an overall
sensitivity of 99% for detecting the time of various postural transitions (e.g., sit-to-stand or stand-
to-sit) and more than 87% sensitivity and specificity for identifying the transition type. This fine-
grained analysis of human movement represents a tremendous leap in technology over what is
presently available. Thus, this measurement technique will provide unique data, not previously
acquired, on actual participation in daily life.

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Hypothesis 6: Finally, we assumed that risk and fear of falling in the intervention group will be
reduced compared to baseline and compared to sham group. To evaluate the fear of falling, we will
use Fall Efficacy Scale (FES) questionnaire (Bula, Martin et al. 2006; De Bruin, Najafi et al. 2007).
The risk of falling will be assessed using test timed Up&Go (Shumway-Cook, Brauer et al. 2000) as
well as the duration required for rising or sitting on a chair as described by Najafi et al.(Najafi,
Aminian et al. 2002)
6. Criteria for Inclusion of Subjects:
Inclusion
Men or women (non pregnant) 18 years old or above
Diagnosed for Diabetes Mellitus (type 2)*
and ADA criteria Diabetes (World-Health-Organization
Evidence of peripheral neuropathy on neurologic
examination
Identified by our clinical staff examination and based
on the criteria explained in ADA statement (Boulton et
al, 2005)
Agreed to participate in this study and comply with
instruction
Figure 14- (A) The ambulatory device for measurement of physical
activity during everyday life (PAMSys). This device designed to be
worn unobtrusively by the subject. (B) Physical activity measured by
ambulatory activity monitor for typical subject during 48 hours. (C)
Same data reported as the time percentage of each major posture –
walking covers a very low portion (3.5%) of the subject’s physical
activity

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May have a toe amputation
7. Criteria for Exclusion of Subjects:
Exclusion
Amputation and active ulcers or infection
Cognitive deficits.
MMSE score of 24 or lower
Unable to stand for more than 5 minutes
(including symptomatic orthostatic
hypotension or pain)
Any clinically significant orthopedic, muscular,
or peripheral vascular disorders that affect
Alcohol or substance abuse within 6 months
or major psychiatric disorder.
Significant vision problem
Less than 20/100 vision after correction
Any other neurological or medical disorders
that may significantly affect balance based on
clinical judgment (e.g. CVA, asymmetric
th
t )
Refusing or lacking medical decisional capacity
to provide informed consent.
Use of medications that is likely to affect
cognition or balance (based on physician
review) within 14 days
8. Sources of Research Material:
Demographic information (age, gender, ethnicity), medical and social history, results of examinations
of the feet, balance testing, responses to questionnaires, use of the electrical stimulation device,
adverse events and treatment.
9. Recruitment Methods and Consenting Process:
Subjects will be recruited from the investigator's patient population at the Parkland ASC Clinic and the
UTSW Wound Clinic. The Lead Coordinator or another member of the research team will identify
potential subjects during a standard care visit and asked if they are interested in participation in this
research. Subjects who express interest will be given a copy of the Consent to take home, read and
discuss with family/friends. The Lead Coordinator will schedule a Screening Visit.
Subjects will be given ample time to read and consider the Consent and allowed to bring a family
member or friend to the screening visit. Alternatives to participation will be presented and discussed.

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The subject will also be told that a decision not to participate in the research will not affect his/her
treatment relationship with the physician/investigator.
A member of the research team will review the Consent with the subject and answer any questions.
If the subject agrees to participate, he/she will sign the Consent and HIPAA Authorization.  He/She
will receive copies of the signed documents.  The consent process will be documented in the source
file.
10. Potential Risks:
Study Intervention
In previous clinical research, no risks have been identified with the SENSU (Neurometrix, Inc. ;
http://www.sensusrx.com/ ) That is, no previous subjects have experienced any adverse events (side
effects) from wearing thedevice.
Loss of Confidentiality
Any time information is collected; there is a potential risk of loss of confidentiality.
Other Risks
There may possibly be other side effects that are unknown at this time.
11. Subject Safety and Data Monitoring:
The principal investigator will monitor the experience of the subjects at least monthly and the conduct
of the protocol, including:
· Study accrual rate
· Experience of study participants
· Study attrition including participant withdrawals/dropouts
· Patterns of AEs and/or unanticipated events
· Patterns of protocol deviations and/or violations
· Changes in risk/benefit
12. Procedures to Maintain Confidentiality:
All study procedures will be conducted in the private treatment areas at UT Southwestern.
For participants who are screened but not eligible for participation in the study, their essential
documents will be securely maintained and placed in a locked cabinet with all of the hard copies of
the essential documents obtained during this research. For participants who are screened and then
enrolled in the study, their essential documents will be filed with the individual’s research file. The
HIPAA Authorization covers all PHI collected through the course of the participation in the study in
addition to that which is covered through the screening process.

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Hard copy documents (source files) will be kept in locked cabinets in the locked research office.
Electronic data will be stored on a dedicated research drive that is password-protected with access
limited to members of the research team.  No identified data will leave the campus.  Presentations,
papers and publications from this research will use only aggregate data and no personally identifiable
information.
13. Potential Benefits:
Wearing the Sensus stimulator may improve balance, circulation (blood flow), and quality of life, but
this cannot be guaranteed.
We hope the information learned from this study will benefit others with diabetic peripheral
neuropathy in the future.  Information gained from this research could lead to better treatment.
14. Biostatistics:
Power & Sample Size Estimation: The sample size for the study was designed to achieve 85%
power when comparing the change in the actively treated group to the change in the sham treated
group, using assumed rates of 50% and 10% improvement, respectively. A two-sided test of
results in evaluable subjects (qualified for analyses of efficacy on vibration perception threshold and
on structured S-W monofilament testing) will provide the specified power at a 5% significance
level. Sample size calculations resulted in a requirement for a total of twenty-seven (27) subjects
in each group. The sample size was also estimated using our pilot data in which we explored the
benefit of plantar stimulation for improving balance (Study 5). At baseline, the area of sway for
center of mass (COM) was 5.23±2.81 cm2 and 5.41±1.14cm2
respectively for the sham and
intervention groups. After week two of treatment, the area of COM sway was 4.94±3.42cm2 for the
sham and 3.49±1.25 cm2 for the intervention group. Using  the same criteria explained above, to
observe  a significant improvement in the intervention group receiving active stimulation compared
to sham group (with nonfunctional stimulator), twenty seven subjects per group is required.
Assuming 10% drop out, therefore, 40 subjects per group (a total of 80 subjects) should be enough
for the purpose of this study.
No suitable alternative treatments exist for patients with loss of protective sensation due to diabetic
peripheral neuropathy, so a statistically detected difference in improvement between groups may be
considered a clinically meaningful result. However, the study was designed to detect a sufficiently
large difference to account for an anticipated “placebo effect” in the sham treated group.
Analysis Plan:
P-values of 0.05 or less will be considered statistically significant based on a two-sided test
unless otherwise noted. All variables will be tabulated descriptively at each scheduled time point. For
each continuous variable, the analyses will include the mean, standard deviation, minimum and
maximum. For each categorical variable, the summary will include frequencies and percentages.
Each variable will be analyzed using all available data. Baseline variables will be summarized using
descriptive statistics. Between-group differences for primary and secondary endpoints will be
explored at the time of the last treatment visit (weeks 12) and every two weeks of treatment.
Additionally, the retention of potential benefit will be assessed at the time of follow-up visit following
the completion of treatment (two weeks post termination of treatment). The frequency of subjects

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with adverse events (AEs) will be tabulated. AEs will also be tabulated by severity and, when
appropriate, by relationship to study treatment. The difference in the occurrence of adverse events
between the study groups will be compared descriptively.
To determine whether gait, balance, and physical activity variables change significantly across
different study visit epochs, within-subject analyses of variance (ANOVA’s) will be employed. We
assume that plantar electrical stimulation is helpful to improve subjects gait, balance, and physical
activity. Then sensor-derived movement variables should change substantially from baseline to the
end of the study for the active group with no significant change in placebo group. For example, the
range of motion of COM and RCI values should be reduced and gait velocity should be increased.
Next, for all continuous variables, pretreatment scores will be regressed on post-treatment scores to
form residualized change scores (e.g. VPT, monofilament test, pain intensity, A1C, etc). Correlations
will then be generated among these scores to determine whether changes in sensor-derived
movement factors are related appropriately with increases in (clinically assessed) functional
capacities and self-report measures of activities, mood, socializing, etc. ANOVA test will be used to
examine significant difference between intervention and sham group at baseline for age and BMI as
well as the indicated outcomes (e.g. gait, balance, VPT, ABI,. Etc). We assumed there is no
significant difference between sham and intervention group at baseline for the indicated variables.
The same test will be repeated for the week 12. We assumed that the outcomes of study will be
improved in the intervention group compared to the sham group. Paired- sample t-test will be used to
examine the retention of the electrical stimulation therapy at two weeks post stopping the therapy
compared to week-12. We assumed the benefit of the electrical stimulation therapy will be retained at
least for two weeks. Additional analyses will examine the degree to which early-treatment changes in
cognitive variables and functional capacity variables (representing functional restoration processes)
predict late-treatment changes in moving ability post plantar electrical stimulation therapy. Such
analyses will also allows to elucidate the relative contributions fear of falling (assessed using FES
score); and/or and range of motion (assessed using body worn sensors) made to bringing about
clinically meaningful changes in gait balance control. Moderator effects will also be examined for
exploratory purposes. Using gender as an example, mixed design ANOVA’s will be conducted to
determine whether gait and balance factors change over the course of treatment at different rates or
with different patterns for men and women as well as for patients with high or low severity of
neuropathy and peripheral vascular disease. We assume those who have higher peripheral vascular
problem will receive maximum benefit from electrical stimulation. Additional analyses will test whether
changes in gait and balance variables predict changes in clinically important outcome factors (e.g.,
fear of falling (FES) , quality of life (SF12), adverse events, foot ulcer, etc) depending on gender.