Electrical Stimulation as an Adjunctive Therapy to Increase Vascular Perfusion in People With PAD or PVD
Phase: NA
Conditions: PAD - Peripheral Arterial Disease, PVD- Peripheral Vascular Disease
Sponsor: Stanford University

 
 
 
 
 
Electrical Stimulation as an Adjunctive Therapy to Increase Vascular 
Perfusion in People With PAD or PVD 
Study Protocol and Statistical Analysis Plan 
NCT04313985 
September 12, 2018 
 
 

Study Title 
Electrical stimulation as an adjunctive therapy to increase vascular perfusion and enhance 
healing in patients with chronic wounds associated with peripheral arterial disease: A 
prospective case-controlled double-blinded randomized cross-over pilot study. 
 
OBJECTIVES (Primary & Secondary Outcome measures) 
Primary Objective: 
This study is designed to test the effectiveness of the Tennant Biomodulator® PRO electrical 
stimulation device (Avazzia), which uses BEST™ (Bio-Electric Stimulation Technology), in 
enhancing short-term perfusion at the wound site in patients with chronic wounds associated 
with peripheral arterial disease. The perfusion will be examined using the HyperMed's 
HyperView device. 
 
Secondary Objectives: 
This study is also designed to test the effectiveness of Avazzia in reducing bacterial burden at 
the wound site, enhancing overall wound healing, and improving patient’s pain level. The 
bioburden and bacterial load will be assessed using quantitative deep tissue swabs from the 
wounds. Wound healing will be assessed by percentage decrease in wound size. Pain will be 
assessed using a numerical 0-10 visual scale. 
 
BACKGROUND 
Study Disease: 
Chronic cutaneous wounds are defined as wounds that have failed to proceed through an 
orderly and timely series of events to produce a durable structural and functional closure. The 
main etiologies include diabetes, pressure, venous insufficiency, and peripheral arterial disease. 
Those afflicted experience decreased quality-of-life, pain, restricted mobility, loss of limb, and 
loss of life. The incidence is on the rise due to aging population and growing prevalence of 
obesity and diabetes. Approximately, 2% of the population in developed countries suffer from 
chronic wounds, and the care costs in the United States alone exceed $50 billion annually. 
Peripheral arterial disease constitutes estimated 20% of the chronic wounds. Arterial ulcers, 
also referred to as ischemic ulcers, are caused by poor perfusion (delivery of nutrient-rich 
blood) to the lower extremities. The overlying skin and tissues are then deprived of oxygen, 
killing these tissues and causing the area to form an open wound. In addition, the lack of blood 
supply can result in minor scrapes or cuts failing to heal and eventually developing tissue 
necrosis and/or ulceration. The primary goal of the treatment for arterial ulcers is to increase 
circulation to the area, either surgically or medically. Surgical options range from 
revascularization in order to restore normal blood flow to amputation and rehabilitation in 
extreme cases. It is needless to say that the surgical options are invasive and associated with 
high risk. As for non-surgical measures, modifying contributing factors can slow or stop the 
progression of the local ischemia. Additionally, there are boots and pumps available to augment 
perfusion to the affected limb. There is an apparent lack of effective non-surgical modality to 
treat this crippling health condition. 
 

Study Devices: 
* Tennant Biomodulator PRO electrical stimulation device (Avazzia): This study is designed to 
test the effectiveness of the Avazzia device, which uses BEST™ (Bio-Electric Stimulation 
Technology), in enhancing short-term perfusion at the wound site. Avazzia device is a 
microcurrent transcutaneous electro-stimulation device with proprietary frequency sets 
specified by Jerry Tennant, MD within the BEST platform control options. It is an easy-to-use, 
hand-held, AA battery-operated portable device for use at home or clinic. It applies charge and 
power to the tissue through electrodes where maximum power delivered to the load is 
controlled and limited, and an automatic shut off is implemented. The user can passively place 
the electrodes where indicated and apply stimulation for a set period of time. The user controls 
the output by selecting the preset mode and power setting. BEST™ devices produce unique 
microcurrent impulses transmitted through the skin to interface with the internal peripheral 
nervous system for the purpose of therapeutic intervention. With each response, the electrical 
properties of the tissue change. These changes in the tissue characteristics result in changes in 
the output. The device detects changes and indicates relative tissue reaction responses in a 
cybernetic feedback loop. BEST products are controlled by a high-performance micro-computer 
chip, which uses Avazzia proprietary software. These hand-held devices are FDA-cleared for the 
symptomatic relief and management of chronic, intractable pain. Additionally, there is data to 
suggest their effect in improving perfusion, as well as their disinfectant properties. 
 
* We will examine perfusion using the HyperMed's HyperView device: HyperView is a handheld, 
battery operated, portable diagnostic imaging device that is used to assess tissue oxygenation 
without contacting the patient. Patented technology uses a proprietary spectrometer to 
measure light absorption in blood molecules to determine levels of oxyhemoglobin and 
deoxyhemoglobin and oxygen saturation in superficial tissue. The product is intended for use by 
physicians and healthcare professionals as a non-invasive tissue oxygenation measurement 
system that reports an approximate value of oxygen saturation (O2Sat), oxyhemoglobin level 
(Oxy), and deoxyhemoglobin level (Deoxy) in superficial tissue. The HyperView system displays 
two-dimensional, color-coded images of tissue oxygenation of the scanned surface. Images and 
data provide hyperspectral tissue oxygenation measurements for selected tissue regions. The 
product is indicated for use to determine oxygenation levels in superficial tissues for patients 
with potential circulatory compromise. 
 
For Clinicaltrials.gov Compliance: 
The devices used in our study are both FDA-cleared.  
 
Rationale: 
It has been proven that improving arterial supply in patients with peripheral arterial disease 
would enhance the healing process of the associated wounds in this patient population. The 
preliminary data suggests that electric stimulation may enhance vascularization. Therefore, we 
hypothesize that electric stimulation may be beneficial in healing the wounds associated with 
peripheral arterial disease. We hypothesize that, based on previous data, Avazzia would 
enhance short-term perfusion, decrease bioburden, decrease pain, and improve overall wound 
healing. The scientific premise is supported by previous literature including those published by 

Dr. Harikrishna K.R. Nair. 
 
Study Design: 
* The primary purpose for the study is “treatment”. 
* The interventional model is “cross-over” where participants will receive one of two 
alternative interventions during stage 1 and the other in stage 2. 
* There will be “two” intervention arms in this study. 
* The study will be masked in a “double-blind” fashion, as both parties will be unaware of 
intervention assignment. 
* The study will be “randomized”. 
* The primary outcome that the study is designed to evaluate is “efficacy”. 
 
Inclusion Criteria 
* Age above 18 years 
* Ankle Brachial Index (ABI) ≤ 0.7 
* Chronic wounds associated with peripheral arterial disease. 
* Failure to demonstrate clinically-significant healing after 4 weeks of conventional therapy. 
* Subjects must demonstrate ability to understand and the willingness to sign a written 
informed consent document. 
* Wound size ≤ 5cm diameter at widest point. 
* We will include patients with clinical malnutrition but subject this data to subgroup analysis. 
 
Exclusion Criteria 
* Age younger than 18 years 
* ABI > 0.7 
* Wound size > 5cm diameter at widest point 
* Active malignancy 
* Clinical signs of infection at the wound site. 
* Patients in need for immediate surgical revascularization including those with critical limb 
ischemia and/or wet gangrene.  
 
Informed Consent Process 
All participants will be provided a consent form describing the study with sufficient information 
for participants to make an informed decision regarding their participation. Participants must 
sign the IRB approved informed consent prior to participation in any study specific procedure. 
The participant will receive a copy of the signed and dated consent document. The original 
signed copy of the consent document will be retained in the research file. 
 
Randomization Procedures 
Upon enrollment, each patient will be randomized via sealed envelopes to one of the two study 
groups, treatment group and control group. The randomization process will be conducted by an 
independent clinic staff. Both patients and primary investigators will be blinded to the 
randomization status. 
 

Study Timeline 
Primary Completion: 
The study will reach primary completion 6 months from the time the study opens to accrual. 
 
Study Completion: 
The study will reach study completion 7 months from the time the study opens to accrual. 
 
TREATMENT PLAN 
Study Design 
To validate our hypotheses, we will conduct a prospective case-controlled double-blinded 
randomized cross-over pilot study. We plan to enroll total of 30 patients, 15 in the study group 
and 15 in the control group. All subjects will be assessed during the screening period for 
inclusion and exclusion criteria. Patients will be followed for total of two weeks. Patients will 
visit the wound clinic twice during the follow-up period for assessing outcomes, one week and 
two weeks after the initial enrollment. Study protocol consists of 5 steps: 
 
- Step 1 (Take BEFORE-treatment data): document the wound size; take perfusion data before-
treatment (using HyperView device); take a wound swab for bacterial measurement (tissue 
samples will not be retained and will not be used for future research); document the pain level; 
take a photograph of the wound.  
 
- Step 2 (Apply study treatment protocol therapy): First, test the device and equipment before 
treating the patient. Verify the device, conductive electrode pads, and lead wires connections 
by letting the patient feel what the stimulation will feel like by placing the electrode pads on 
the hands of the patient, powering on the device, and increasing the power until the 
stimulation is felt. Then, turn off the device and move the pads to the treatment area on the 
patient. Explain to the patient that it is normal for some patients to not feel the stimulation due 
to the chronic condition of their wound. It is also normal for some patient’s skin to become 
more sensitive during therapy so that while they may not feel the stimulation at first, it is 
possible that they will begin to feel it, and it may even become too strong and need to reduce 
the intensity power settings. The patients can do this themselves if the output becomes 
uncomfortable. Treat the patient’s wound area as the following. Place self-adhesive, conductive 
electrode pads on either side of the wound on the skin where the pads are not placed in the 
open wound itself, but rather in the surrounding area with one pad on each side of the wound. 
Connect the pads to the lead wire to the Avazzia device. There will be two different sets of lead 
wires marked as A or B where A is for “good” lead wires for therapy and B is for “broken” lead 
wires for the control group. Turn on the Avazzia device and change modes to the RSI mode. 
Allow to run unattended for 15 minutes. Change modes to Blue Stimulation mode without 
moving any of the pads. Allow to run unattended for 10 minutes. The total duration of each 
treatment session per day will be 25 minutes. 
 
- Step 3 (Take AFTER-treatment data): take perfusion data after-treatment; take a wound swab 
for bacterial measurement; document the pain level; take a photograph of the wound 
 

- Step 4: One week later, patient assigned groups will be switched. The study will be repeated 
with cross-over fashion so that the patients that had real treatment repeat the test, but with 
broken lead wires. And patients who had broken lead wires get treatment with good lead wires. 
 
- Step 5 (Take final data one week later): document the wound size; take perfusion data; take a 
wound swab for bacterial measurement; document the pain level; take a photograph of the 
wound 
 
Criteria for Removal from Study 
In the case of following events, the patient will be removed from the study and his or her usual 
care will be restored based on the conventional therapy: disease progression; unacceptable 
adverse events; patient withdrawal from study. 
 
Alternatives 
Patients in both study and control groups will continue to receive the standard-of-care wound 
therapy throughout the course of study. 
 
Potential Adverse Events 
Potential risks associated with Avazzia device is minimal, being limited to pain at the site of 
probe application, and/or temporary numbness of the peri-wound area. 
 
Potential risks associated with HyperView device is negligible. 
 
Potential risks associated with wound swabs is minimal, being limited to pain and/or minimal 
bleeding. 
 
STATISTICAL CONSIDERATIONS 
Assuming a 1-2% drop out, the estimated sample size is 30. The sample size will include a cross-
over study design. We recognize that this sample size may not be sufficient to validate all 
primary and secondary end-points but would be sufficient to estimate trend and determine a 
more-accurate sample size for the larger scale study. A sample size for long-term benefit has 
not been calculated yet. This is a pilot study assessing improved perfusion. If findings 
demonstrate favorable trend, Avazzia will consider a larger study with appropriate sample size 
calculations consistent with assessment of long-term benefits. 
 
Publication plans envisioned for this work 
Results will be disseminated in relevant conferences (e.g. Wound Healing Society Annual 
Meeting) and peer reviewed journals (e.g. Wound Repair and Regeneration)