Electrical Stimulation for Post Acute COVID-19 Syndrome

Study Overview
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Brief Summary
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The purpose of the pilot study is to examine acceptability and proof of concept effectiveness of a wireless TENS technology to address PACS associated FM. Sample size (n=40) is convenient and designed to explore acceptability and feasibility. Eligible participants will be screened at the BCM Post-COVID-19 Clinic for inclusion criteria. Participants, who satisfy the inclusion and exclusion criteria and sign the informed consent form will be randomly assigned with ratio of 1:1 into two groups. One group will utilize TENS functional devices (Active group, AG); the other group will utilize TENS non-functional devices (Placebo group, PG). The baseline measurements will be performed, and the patients will take the programmed device home for a duration of 4 weeks. Then, the patients will come back after four weeks (4W). At this 4th week visit, both groups will be unblinded and the AG will keep their functional device and the PG group will receive a functional device. Both groups will continue to deliver 3-5 hour of stimulation daily, until their final 8th week follow up visit (8W). The primary outcomes will be pain symptoms, sleep and fatigue. Secondary outcomes include limb strength and perfusion, gait assessment (gait speed, stride length, double stance, and gait steadiness), balance, pulse oximetry, and quality of life. The coordinator will utilize a weekly spreadsheet showing utilization (therapy sessions/day, logged in the Quell health Cloud) so compliance can be monitored and those that are not using the device can be encouraged.

Detailed Description
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Postacute COVID-19 syndrome (PACS) is an emerging entity that has been clearly recognized by musculoskeletal pain, fatigue, cognitive, and sleep disturbances, among other symptoms, in patients who have recovered from severe Sars-CoV-2 infection. Hospitalized survivors have reported a significant excess burden of many of these symptoms up to 8 months after discharge. Particularly in the lower extremity, musculoskeletal illness has been associated with prolonged immobilization, high-risk comorbidities, and the use of glucocorticoids that is commonly administered to these patients. These manifestations are the cardinal symptoms of fibromyalgia (FM), a condition thought to be caused by hyperactive sensory signaling due to central sensitization as well as deficient endogenous pain inhibition, triggered among others, by viral infections. Consequently, FM sequelae are one of the most common long-term complications seen in PACS. Thus, it is expected to impose a serious burden on different medical specialties in a near future. In a population that has persistent lack of symptom resolution such as FM, adherence to therapy could be challenging. Patients with constant pain, fatigue, and sleep disturbances, are difficult to keep motivated, especially those pain-medication dependents that often present low quality of life. One practical solution to address the symptomatology characteristic of FM is the use of transcutaneous electrical stimulation therapy (TENS). Studies have demonstrated its ability to manage pain and fatigue in patients with peripheral neuropathy and FM, and has shown to effectively improve lower-extremity perfusion and oxygen delivery in patients with ischemic lesions. However, TENS has not yet been explored for PACS. Since this technology is dose-dependent, the investigators propose a practical daily-basis therapy that patients with persistent associated FM due to previous COVID-19 infection could apply at home, thus, addressing PACS without relying only on medication. In this matter, Neurometrix Inc. (Woburn, MA, USA) has created a wireless TENS device (Quell®) to address pain, gait, sleep, and fatigue. This technology is placed in the lower-extremity and works through the stimulation of nerves that carry non-painful sensations (A-beta fibers) by closing a neurological gate in the spinal cord, thus, reducing transmission from pain nerves (A-delta and C fibers) to the brain. This device utilizes a wireless technology manageable through a smart phone application (Quell App) that also tracks symptom-status. Moreover, Baylor College of Medicine has created the Post-COVID-19 Clinic (McNair Campus, BCM St Luke's, Houston, TX, USA) supervised by specialists in critical and pulmonary care. This Clinic has a high volume of patients that present with PACS, particularly those with associated FM (i.e., persistent muscle pain, fatigue, weakness, atrophy, sleep problems, and/or anxiety). Therefore, the investigators believe Baylor institution is a suitable place to perform this pilot study.

Official Title
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Transcutaneous Electrical Nerve Stimulation For Lower Extremity In Patients With Post Acute Covid-19 Syndrome - A Proof Of Concept Randomized Clinical Trial

Conditions
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COVID-19, Muscle Weakness, Muscle Pain, Fatigue

Intervention / Treatment
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* Device: Electrical Stimulation - Active
* Device: Electrical Stimulation - Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Previous COVID-19 infection Persistent symptoms of pain, fatigue, weakness, or poor gait and balance after infection assessed by critical care clinicians on the initial consultation Willing to attend clinic for assessments Exclusion Criteria: Severe cognitive decline reduces their ability to interact with the TENS mobile app Major visual or hearing weakness reduces the ability to interact with TENS mobile app Unable to walk independently for a distance of 10 meter Major foot problems such as active lower extremity wounds, major foot deformity (e.g., Charcot Foot), previous major amputations, and claudication Demand-type cardiac pacemaker, implanted defibrillator, or other implanted electronic devices; and any conditions that may interfere with outcomes or increase the risk of the use TENS based on the judgement of clinicians

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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: Crossover Assignment
Interventional Model Description: Participants, who satisfy the inclusion and exclusion criteria and sign the informed consent form will be randomly assigned with ratio of 1:1 into two groups. One group will utilize TENS functional devices (Active group, AG); the other group will utilize TENS non-functional devices (Placebo group, PG). Both groups will receive their respective devices at the initial visit (BL) and will be asked to return in 4 weeks for follow-up assessment (4W visit). At this 4 week visit, study participants will be unblinded and the active group will keep their commercial (active) device, while the placebo group will receive a commercial (active) device. Study participants will return for a final in-person visit at the 8th week (8W), which will include the assessments described above. Throughout this 8-week period the participants may receive follow-up phone calls assessing their compliance. All subjects will keep their commercial (active) device after completion of the 8-week study.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active Group (AG)<br>Active group (AG). The AG (n=20) will be undergoing TENS therapy with an active device during 4 weeks. To deliver TENS, a band strap with hydrogel pads will be placed around the calf muscle of one lower-extremity alternating to the other side in a weekly basis. | Device: Electrical Stimulation - Active<br>* Subjects will receive an active electrical stimulation device (delivers 100% of the dose) to wear for 1 hour daily for up to 4 weeks.<br>|
| Placebo Comparator: Placebo Group (PG)<br>Placebo Group (PG) The PG (n=20) will be undergoing TENS therapy with a sham device as described in the AG. The sham device is identical to the active device in all respects except that it stimulates for 6 minutes during each therapy session instead of 60 minutes, and is therefore 10% of the dose. | Device: Electrical Stimulation - Placebo<br>* Subjects will receive a placebo electrical stimulation device (delivers 10% of the dose) to wear for 1 hour daily for up to 4 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in pain scores at 4 weeks | Pain will be assessed with a validated questionnaire called Brief Pain Inventory, which has a score from 0 (no pain) to 10 (the worst pain). | 4 weeks from baseline | 
| Change from baseline in Fatigue at 4 weeks | Fatigue will be assessed with a validated questionnaire called Multidimensional Assessment Fatigue, which has a score from 0 (no fatigue) to 100 (severe fatigue). | 4 weeks from baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline Gastrocnemius muscle strength at 4 weeks | Lower extremity strength will be assessed with an ankle dynamometer and surface electromyography (Delsys Trino Wireless EMG System, MA, US). | 4 weeks from baseline | 
| Change from baseline Gastrocnemius Muscle Endurance (Muscle Sustained Contraction) in Response to Electrical Stimulation at 4 weeks | Gastrocnemius muscle endurance in response to 5 minutes of electrical stimulation therapy will be assessed with surface electromyography using a validated non-invasive device (Delsys Trino Wireless EMG System, MA, US). | 4 weeks from baseline | 
| Change from baseline in Gait assessment at 4 weeks | Gait speed and static balance will be measured with a 6-minute walk test and wearable sensors (Legsys, Balansens, Pampsys). | 4 weeks from baseline | 
| Change from baseline in Lower extremity peripheral nephropathy at 4 weeks | Peripheral Nephropathy will be assessed with a DPN Check device that measures the signal nerve velocity of a determined nerve section. | 4 weeks from baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Electrical Stimulation, Limb Perfusion