Therapeutic Plantar Electrical Stimulation Intervention During Hemodialysis to Improve Balance and Mobility

Study Overview
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Brief Summary
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A high prevalence of diabetes has been reported in Qatar with nearly 23% population suffering from the pandemic, thereby increasing the associated healthcare cost. Low compliance with exercise and physical activity in patients with diabetes increases foot risk complications, deteriorates health, and further increases economic costs. This is particularly true among patients with diabetes who are undergoing hemodialysis (HD) process. Exercise interventions have been shown to improve mobility and balance, reduce the incidence of falls, and improve peripheral blood flow, which is essential to reduce foot problems and peripheral arterial disease. However, uptake of exercise programs for individuals who are undergoing HD treatment has been limited. The three main factors limiting uptake and adherence among HD patients are time availability, post-dialysis fatigue, and transportation to exercise programs, which are usually offered in rehabilitation departments or cardiovascular centers but not in nephrology departments or in free-standing dialysis clinics. Many of these patients visit clinics 3 times a week to receive hemodialysis, providing an optimal opportunity for intervention. Thus the investigators are proposing an innovative intervention based on plantar electrical stimulation treatment during HD (3 times per week) to enhance balance and quality of life while reducing the risk of peripheral arterial diseases and diabetic foot ulcers, which are highly prevalent among people with diabetes and chronic kidney disease. This interdisciplinary study is based on preliminary studies, in which the investigators demonstrated that regular plantar electrical stimulation is an effective and practical therapy to enhance motor performance and plantar sensation in patients with diabetes. The scientific premise of the proposed intervention has been also supported by literature as well as three systematic reviews suggesting the effectiveness of electrical stimulation to reduce pain, improve balance, improve skin perfusion, and improve plantar sensation. In the context of this study, the investigators propose to bring an innovative technology based on an FDA-cleared bio-electric stimulation technology (BEST®) microcurrent platform, named Tennant Biomodulator® (Avazzia Inc., Dallas, TX, USA), which is a transcutaneous electrical nerve stimulator (TENS) and has been designed for symptomatic relief and management of chronic pain. However, the system was modified to provide electrical stimulation to the plantar area via two electrodes placed on the hind and forefoot area instead of the leg. The device has a 60-minute run cycle after which it automatically turns off. In the context of a previous study funded by QNRF, the investigators developed and tested 50 electrical stimulation units (which will be used in the context of the study), including 25 active systems and 25 placebo systems. The placebo systems are similar to active systems in the appearance and functioning of lights and indicators. However, they were programmed not to provide any electrical current. In a preliminary study, the proof of concept of this revised technology was tested in the context of enhancing balance and skin perfusion in ambulatory patients with diabetes and peripheral neuropathy. In the context of this study, the investigators plan to translate this technology for routine treatment during HD sessions for patients with diabetes who are undergoing regular HD treatment. Using a double-blinded randomized-controlled model, the investigators will validate the effectiveness of this technology to enhance balance, reduce pain, and improve skin perfusion. One hundred (n=100) HD volunteers with diabetes will be recruited and randomized to either intervention (n=50) or control (CG: n=50) group for the purpose of this study. Plantar electrical stimulation will be provided during HD sessions, 3 times per week and for 12 weeks. Outcomes will be assessed at baseline, 6 weeks, and 12 weeks to examine the effectiveness of the proposed intervention to enhance balance, improve quality of life, and improve lower extremity skin perfusion among HD patients with diabetes. This proposal is in line with Qatar National Priorities Research goals and if successful the result will open new doors to managing diabetes and kidney failure. In a setting where no therapeutic agents or interventions effectively address poor balance and loss of protective sensation among HD patients with diabetes and where affected individuals life with a heightened risk of developing a debilitating foot ulcer and quite possibly a disabling amputation, the potential impact from the plantar electrical stimulation system may offer the potential for significant clinical benefit, with very low risk, and with ease of implementation in routine care application for patients who are undergoing HD treatment.

Detailed Description
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This interdisciplinary project (Technology Readiness Level 9, TRL 9) aims to translate and clinically validate the effectiveness of an innovative wearable electrical stimulator technology for improving balance, quality of life, and skin perfusion in patients with diabetes and chronic kidney failure. Around the world, more than 347 million people suffer from diabetes, with 90% of them having Type 2 diabetes. The most common factors contributing towards diabetes include excessive body weight and poor physical activity. Among other countries around the world, Qatar has also been a victim to the COVID-19 pandemic with a prevalence of nearly 23%, thereby increasing the associated healthcare cost. One of the common predictors of metabolic syndrome in Qatar was found to be increased body mass index, which is usually associated with dietary and sedentary behavior. Management of diabetes is therefore of utmost importance in Qatar in order to reduce the negative impact of complications related to diabetes. One big challenge is encouraging patients with diabetes to be active in particular those with poor balance control, which is unfortunately prevalent among patients with diabetes. Poor postural control is often the primary comorbidity that limits their ability to be engaged in daily physical activities and seems to have a significant impact on quality of life. Exercise is probably the best evidence-based intervention to enhance balance. But unfortunately exercising among patients with diabetes is limited in particular among older patients, who are also suffering from diabetic peripheral neuropathy, which impacts 60 to 70 percent of older patients with diabetes. In particular, the lack of mobility and poor adherence to exercise are major concerns among patients with diabetes and end-stage renal disease (ESRD) that require dialysis. Among patients with diabetes, 35% suffer from chronic renal disease and may require dialysis or kidney replacement over time. Patients, who are undergoing hemodialysis (HD) are known to have a decreased ability to perform physical exercise, with exercise capacity reported to be at 60-70% of age-expected level leading to impaired physical functioning, muscle wasting, frailty at an earlier age, and increased risk of falling. Moreover, a 4-hour conventional HD session immobilizes the patient, contributing directly to sedentary behavior that can further worsen their functional motor abilities. Unfortunately, exercise programs are not widely used in HD clinical practice. Several studies have demonstrated that exercise training can improve balance and gait, thereby reducing fall risk in older adults including HD patients. Recent evidence also suggests that exercise can increase joint mobility and peripheral blood flow, which reduces the risk of foot complications in patients receiving HD. However, uptake of exercise programs for HD patients has been limited. The three main factors limiting uptake and adherence among HD patients are time availability, post-dialysis fatigue, and transportation to exercise programs, which are usually offered in rehabilitation departments or cardiovascular centers but not in nephrology departments or in free-standing dialysis clinics. Conventional fall prevention exercise strategies, including physiotherapy, strength exercises, and tai chi, are not well suited for HD patients because even moderate conventional exercise regimes can easily overtax them. The selection of exercise modalities and intensities must also avoid excessive plantar loading, which can increase the risk of foot ulceration. Furthermore, because HD treatment often leaves patients feeling fatigued and thus, reluctant to engage in physical activity, any balance training intervention outside of HD treatment may not be practical. Thus, an alternative intervention, which may effectively address poor balance, may assist in encouraging HD individuals to become more active. Another key complication associated with diabetes is lower extremities problems. Recent studies suggest that the most common cause of hospitalization of diabetes population is foot-related complications including ulcers. Furthermore, in HD patients, the risk of foot complications and amputation is even more common, expensive, and devastating. Interestingly, even though the incidence of foot ulcers in patients with dialysis has been reported to be the same as with patients with a history of foot ulcers; dialysis patients have a significantly higher rate of foot amputation. Foot-related hospital admission rate is higher in HD patients; additionally, the prevalence of foot complications among HD patients with diabetes is 250% more than patients with diabetes without end-stage renal disease. With 10 times, higher incidence of lower extremity amputation; after amputation and post-operative mortality is also 3.5 times higher in HD patients compared to patients with diabetes not requiring dialysis. To address the above gaps, the investigators propose translating an innovative wearable electrical stimulation intervention, practical for therapy during HD sessions. The long-term goal is to provide a convenient, low-cost therapeutic device and treatment protocol for patients with diabetes who are undergoing the hemodialysis process. Eventually, the investigators plan for this to be an approach that can be used during HD sessions as a routine intervention program to enhance mobility and reduce the risk of diabetic foot problems and peripheral arterial diseases (PAD). This study will be a double-blind randomized clinical trial design consisting of two groups of fifty (n=50) HD patients with diabetes and some level of postural instability. The study consisted of a 12 weeks treatment phase (three interventions per week) and two weeks of retention. In addition, all subjects will be followed up for 12 months post-intervention to document any incidents of falls, diabetic foot ulcers, limb amputation, and diabetes-related complications. Subjects will be provided plantar electrical stimulation treatment for a duration of an hour while receiving HD treatment, 3 times per week. The plantar electrical stimulation will be delivered using an innovative wearable technology based on FDA cleared wearable electrical stimulation system, named Tennant Biomodulator® (Avazzia Inc., Dallas, TX, USA), which is a transcutaneous electrical nerve stimulator (TENS) and has been designed for the management of chronic pain. However, the system was modified by to provide electrical stimulation to the plantar area via two electrodes placed on the hind and forefoot area instead of the leg. The device has a 60-minute run cycle after which it automatically turns off for 60 minutes. The device is activated using a single button without the need for any electrical stimulation adjustment making it easier for the purpose of home therapy under unsupervised conditions and suitable for busy HD clinics. The proposed dosage regimen was used in a preliminary studies by the investigators and no related adverse events were reported while a significant improvement in skin perfusion and balance was observed. Sufficient disposable electrodes will be provided to participants for regular replacement.

Official Title
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Therapeutic Plantar Electrical Stimulation Intervention During Hemodialysis to Improve Balance and Mobility

Conditions
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Diabetes Mellitus, Hemodialysis Complication, Cardiovascular Complication, Quality of Life

Intervention / Treatment
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* Device: Tennant Biomodulator ®


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female patients with diabetes receiving dialysis who are >40 years old. Ambulatory (able to independently walk 20m with or without walking assistance). Willing and able to provide informed consent. Diabetes will be defined based on the American Diabetes Association (ADA) criteria (83). Evidence of peripheral neuropathy and its severity will be determined based on a neurologic examination using criteria explained in the ADA statement. Exclusion Criteria: Have an active foot ulcer, an active infection, Charcot neuroarthropathy, or major foot amputation. Patients with any clinically significant medical or psychiatric condition, or laboratory abnormality that would, in the judgment of the investigators, interfere with the ability to participate in the study. Patients concurrently participating in exercise training; major hearing/visual impairment; any patient with changes in psychotropic or sleep medications in the last 6 weeks. If they were unlikely to fully comply with the follow-up protocol (e.g., travel plans).

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Prospective cohort study with a double-blinded randomized control trial model.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Intervention group<br>The intervention group will take part in a 12-week plantar electrical stimulation intervention using the proposed technology 3 times per week during HD either in a sitting or supine position under the supervision of a research staff member. The duration of each treatment session will be one hour. Patients who receive an activated electrical stimulation unit will receive a standard dose of 30 milliamps as described in the following during each HD session (3 times per week for 12 weeks). | Device: Tennant Biomodulator ®<br>* Tennant Biomodulator ® (Avazzia, Inc., Texas, USA)(FDA Classification: 882.5890 Neurology, Biofeedback device) is FDA-cleared for symptomatic relief and management of chronic pain. The device is simply activated using device buttons and does not need to be adjusted or monitored once therapy begins, making it easy for the purpose of therapy under unsupervised conditions or for use in busy HD clinics. The device will be used with FDA-cleared TENS electrodes that will be connected to the device via wires, providing an electrically conductive interface between the device and the subject's skin.<br>* Other names: AVAZZIA;|
| Sham Comparator: Control group<br>Placebo controls will have an electrical stimulation unit programmed not to provide any electrical current, while all 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. | Device: Tennant Biomodulator ®<br>* Tennant Biomodulator ® (Avazzia, Inc., Texas, USA)(FDA Classification: 882.5890 Neurology, Biofeedback device) is FDA-cleared for symptomatic relief and management of chronic pain. The device is simply activated using device buttons and does not need to be adjusted or monitored once therapy begins, making it easy for the purpose of therapy under unsupervised conditions or for use in busy HD clinics. The device will be used with FDA-cleared TENS electrodes that will be connected to the device via wires, providing an electrically conductive interface between the device and the subject's skin.<br>* Other names: AVAZZIA;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in gait speed from baseline to 12 weeks | The investigators will quantify gait speed (meter/sec) using a validated wearable device (LEGSys, Biosensics, MA, USA) during walking under both habitual and fast speed conditions. | Baseline and12 weeks | 
| Change in balance from baseline to 12 weeks | Balance will be measured by assessing body sway area (cm^2) from the center of mass during upright standing for a duration of up to 30 seconds. The investigators will use a validated wearable device (BALANSense, Biosensics, MA, USA) to measure body sway. | Baseline and12 weeks | 
| Change in gait parameters from baseline to 12 weeks. | Gait parameters such as gait initiation and gait inter-cycle variability will be assessed using a validated wearable device (LEGSys, Biosensics, MA, USA). | Baseline and 12 weeks | 
| Change in skin perfusion from baseline to 12 weeks. | The investigators will assess skin perfusion by using an arterial Doppler. This will provide an ankle brachial index which will be used to categorize the level of ischemia/perfusion. | Baseline and 12 weeks | 
| Change in fear of falling | Changes in fear of falling will be assessed by a questionnaire (Short Falls Efficacy Scale International, FES-I). Score ranges from 16 to 64, with a higher score indicating increased concern for falling. | Baseline and 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in quality of life from baseline to 12 weeks. | Investigators will assess quality of life using a validated questionnaire (PROMIS Global-10) which is a 10-item patient-reported questionnaire in which the response options are presented as 5-point rating scale (and a single 11-point rating scale). The scores can range from 0 to 20, with a higher score indicating a better quality of life. | Baseline and 12 weeks | 
| Change in cognitive function | Investigators will assess cognitive function using the Montreal Cognitive Assessment (MoCA). Scores on MocA range from 0 to 30 with a score of 26 or greater indicating normal cognitive function. | Baseline and 12 weeks | 
| Change in pain | Investigators will assess pain using a visual analogue scale from 0 to 10 with 10 being the worst pain ever. | Baseline to 12 weeks | 
| Change in depression | Investigators will assess depression using Center of Epidemiologic Depression Scale (CES-D) questionnaire. CES-D scores range from 0 to 60 with high scores indicating greater depressive symptoms. | Baseline to 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Preventive supplements, Treatment of diabetes related complications, Health intervention, Lifestyle intervention