An interventional study of TENS - high-dose and TENS - low-dose in Postacute Sequelae of Sars-CoV-2, Post-Acute COVID-19 Syndrome and Widespread Chronic Pain, sponsored by Baylor College of Medicine. Completed at 1 site in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2024-07-16.
Sponsored by Baylor College of Medicine · Not applicable, Interventional, and Supportive care
The purpose of the pilot study is to examine acceptability and proof of concept effectiveness of a wireless TENS technology to address PASC associated FM. Sample size (n=30) is convenient and designed to explore acceptability and feasibility. 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 high-dose devices (Intervention group, IG); the other group will utilize TENS low-dose 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 IG will keep their high-dose TENS device and the PG group will switch from a low-dose TENS to a high-dose TENS device. Both groups will continue to deliver 3-5 hour of stimulation daily, until their final 8th week follow up visit (8W). The primary outcome will be pain. Secondary outcomes include fatigue, limb strength and perfusion, gait assessment (cadence, stride time, double support), 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.
Postacute Sequelae of Sars-CoV-2 (PASC) 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 PASC. 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 PASC. 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 PASC 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 PASC, 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.
520 studies on the registry are indexed under Post-Acute COVID-19 Syndrome; 186 are open to participants now.
This study's enrollment of 30 is below the median of 60 across 361 interventional studies indexed under Post-Acute COVID-19 Syndrome.
Browse Post-Acute COVID-19 Syndrome studies →Baylor College of Medicine is the lead sponsor of 734 studies on the registry; 110 are open to participants now.
Of its 83 completed or terminated interventional studies of FDA-regulated products, 44 (53%) have results posted.
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Exclusion Criteria:
The IG will be undergoing Transcutaneous Electrical Nerve Stimulation (TENS) therapy with a functional device during a blinded period of 4 weeks. The functional device elicits 1 hour of TENS per session. Each session lasts 1 hour (100% of dose). 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: TENS - high-dose
The PG will be undergoing Transcutaneous Electrical Nerve Stimulation (TENS) therapy with a placebo device during a blinded period of 4 weeks. The placebo device is identical to the functional device in all respects except that it delivers 6 minutes of TENS therapy per session (10% out of 60 minutes).
Device: TENS - low-dose
After 4 weeks, the IG will be unblinded, and will continue to receive high-dose TENS with a functional device for additional 4 weeks until completing 8 weeks. The functional device elicits 1 hour of TENS per session. Each session lasts 1 hour (100% of dose). 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: TENS - high-dose
After 4 weeks, the PG will be unblinded and will switch to a high-dose TENS with a functional device for additional 4 weeks until completing 8 weeks. The functional device elicits 1 hour of TENS per session. Each session lasts 1 hour (100% of dose). 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: TENS - high-dose
Subjects will receive a functional TENS device (delivers 100% of the dose) to wear for 3-5 hours per day.
Also known as: functional, commercial
Subjects will receive a placebo TENS device (delivers 10% of the dose) to wear for 3-5 hours per day.
Also known as: placebo, sham
Mean Change in Functional Interference From Pain From Baseline to 4 Weeks (Blinded Phase)
Pain will be assessed with a validated questionnaire called Brief Pain Inventory interference composite score (BPI-I). The maximum score is 10, meaning pain completely interferes, while the minimum score is zero, meaning pain does not interfere.
Time frame: baseline to 4 weeks
Mean Change in Pain Severity From Baseline to 4 Weeks (Blinded Phase)
Pain severity will be assessed using the Brief Pain Inventory questionnaire composite score for severity. The maximum score is 10, meaning pain as bad as one can imagine, while the minimum score is zero, meaning no pain.
Time frame: Baseline to 4 weeks
Mean Change in Functional Interference From Fatigue From Baseline to 4 Weeks (Blinded Phase)
Functional interference from fatigue will be assessed calculating the Global Fatigue Index (GFI) obtained from a validated questionnaire called Multidimensional Assessment Fatigue, which has a minimum score of 0 (no fatigue) and a maximum sore of 100 (severe fatigue).
Time frame: Baseline to 4 weeks
Stride Time at 4 Weeks During a Simple Walking Task (Blinded Phase)
Stride time will be measured with wearable sensors (LEGSys, BioSensics, MA) during a free walking task (single task) using normal pace for 30 ft. Stride time is defined as the period elapsed between the first contact of two consecutive footsteps of the same foot expressed in seconds.
Time frame: at 4 weeks
Cadence at 4 Weeks During a Simple Walking Task (Blinded Phase)
Cadence will be measured with wearable sensors (LEGSys, BioSensics, MA) during a free walking task (single task) using normal pace for 30 ft. Cadence is defined as rate of number of steps per minute.
Time frame: at 4 weeks
Double Support Phase at 4 Weeks During a Simple Walking Task (Blinded Phase)
Double Support Phase will be measured with wearable sensors (LEGSys, BioSensics, MA) during a free walking task (single task) using normal pace for 30 ft. Double support phase is defined as percentage time when both feet are simultaneously in contact with the ground during a single stride.
Time frame: at 4 weeks
Cadence at 4 Weeks During a Dual Walking Task (Blinded Phase)
Cadence will be measured with wearable sensors (LEGSys, BioSensics, MA) during a dual walking task (participants asked to count backwards by two while walking) using normal pace for 30 ft. Cadence is defined as rate of number of steps per minute.
Time frame: at 4 weeks
Cadence at 4 Weeks During a Fast Walking Task (Blinded Phase)
Cadence will be measured with wearable sensors (LEGSys, BioSensics, MA) during a fast walking task (participants asked to walk at a slightly faster pace) for 30 ft. Cadence is defined as rate of number of steps per minute.
Time frame: at 4 weeks
Stride Time at 4 Weeks During a Dual Walking Task (Blinded Phase)
Stride time will be measured with wearable sensors (LEGSys, BioSensics, MA) during a dual walking task (participants asked to count backwards by two while walking) using normal pace for 30 ft. Stride time is defined as the period elapsed between the first contact of two consecutive footsteps of the same foot expressed in seconds.
Time frame: at 4 weeks
Stride Time at 4 Weeks During a Fast Walking Task (Blinded Phase)
Stride time will be measured with wearable sensors (LEGSys, BioSensics, MA) during a fast walking task (participants asked to walk at a slightly faster pace) for 30 ft. Stride time is defined as the period elapsed between the first contact of two consecutive footsteps of the same foot expressed in seconds.
Time frame: at 4 weeks
Gastrocnemius Muscle Endurance (Muscle Sustained Contraction) in Response to Electrical Stimulation at 4 Weeks (Blinded Phase)
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).
Time frame: at 4 weeks
Frailty at 4 Weeks (Blinded Phase)
Frailty will be measured with a upper-extremity wearable sensor (Frailty meter, BioSensics, MA) which enables a frailty index score based on a validated algorithm. Patients with frailty index \>0.27 is considered are considered as frail. Patients with a frailty index \<0.27 are considered as non-frail. The higher the frailty index, the higher the level of frailty. The frailty index ranges from 0-1.
Time frame: up to 4 weeks
Sural Nerve Conduction Velocity at 4 Weeks (Blinded Phase)
Sural nerve conduction will be assessed with a DPN Check device (Neurometrix Inc, MA). The device elicits a electrical stimulation upon contact with the skin on the ankle area and returns values that can range from a minimum of 20 m/s to a maximum of 60m/s. Measurements will be obtained at 4 weeks and value will be compared between groups.
Time frame: 4 weeks
Ankle Strength at 4 Weeks (Blinded Phase)
Ankle strength will be assessed with an ankle dynamometer. Participants will be asked to perform 3 maximum voluntary contractions (MVC) sustaining ankle dorsiflexion for 5 seconds with 30 seconds of resting in between MVCs. The average of the 3 MVCs will then be calculated per lower extremity.
Time frame: up to 4 weeks
Plantar Tissue Oxygen Saturation at 4 Weeks (Blinded Phase)
Percentage of tissue oxygen saturation (SatO2) will be measured using a validated near-infrared (NIR) camera (Snapshot NIR, KENT Imaging Inc., Calgary, AB, Can) that detects an approximate value of real-time SatO2 level in superficial tissue. The metatarsus area including the five toes will be traced.
Time frame: up to 4 weeks
Mean Daily Step Count at 4 Weeks (Blinded Phase)
Step count obtained with the mean 90 percentile will be will be measured over the course of the 4 weeks using a smart watch (Vivosmart 4, Garmin, US)
Time frame: up to 4 weeks
Sleep Duration at 4 Weeks (Blinded Phase)
Daily sleep duration in hours obtained with the mean 90 percentile will be measured over the course of the 4 weeks using a smart watch (Vivosmart 4, Garmin, US)
Time frame: up to 4 weeks
Sural Nerve Amplitude at 4 Weeks (Blinded Phase)
Sural nerve amplitude will be assessed with a DPN Check device (Neurometrix Inc, MA). The device elicits a electrical stimulation upon contact with the skin on the ankle area and returns values that can range from a minimum of 0 microVolts to a maximum of 32 microVolts. Measurements will be obtained at 4 weeks.
Time frame: at 4 weeks
Mean Change in Functional Interference From Pain at 8 Weeks (Unblinded Phase)
Pain will be assessed with a validated questionnaire called Brief Pain Inventory interference composite score (BPI-I). The maximum score is 10, meaning pain completely interferes, while the minimum score is zero, meaning pain does not interfere. This outcome assesses the difference between the mean BPI interference composite score at week 8 and week 4.
Time frame: from week 4 to week 8
Mean Change in Pain Severity From 4 Weeks to 8 Weeks (Unblinded Phase)
Pain severity will be assessed using the Brief Pain Inventory questionnaire composite score for severity. The maximum score is 10, meaning pain as bad as one can imagine, while the minimum score is zero, meaning no pain. This outcome assesses the difference between the mean BPI severity composite score at week 8 and week 4.
Time frame: 4 weeks to 8 weeks
Mean Change in Functional Interference From Fatigue From 4 Weeks to 8 Weeks (Unblinded Phase)
Functional interference from fatigue will be assessed calculating the Global Fatigue Index (GFI) obtained from a validated questionnaire called Multidimensional Assessment Fatigue, which has a minimum score of 0 (no fatigue) and a maximum sore of 100 (severe fatigue). This outcome assesses the difference between the mean global fatigue index at week 8 and week 4.
Time frame: 4 weeks to 8 weeks
Stride Time at 8 Weeks During a Simple Walking Task (Unblinded Phase)
Stride time will be measured with wearable sensors (LEGSys, BioSensics, MA) during a free walking task (single task) using normal pace for 30 ft. Stride time is defined as the period elapsed between the first contact of two consecutive footsteps of the same foot expressed in seconds.
Time frame: at 8 weeks
Gastrocnemius Muscle Endurance (Muscle Sustained Contraction) in Response to Electrical Stimulation at 8 Weeks (Unblinded Phase)
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).
Time frame: at 8 weeks
Frailty at 8 Weeks (Unblinded Phase)
Frailty will be measured with an upper-extremity wearable sensor (Frailty meter, BioSensics, MA) which enables a frailty index score based on a validated algorithm. Patients with frailty index \>0.27 is considered are considered as frail. Patients with a frailty index \<0.27 are considered as non-frail. The higher the frailty index, the higher the level of frailty. The frailty index ranges from 0-1.
Time frame: at 8 weeks
Sural Nerve Conduction Velocity at 8 Weeks (Unblinded Phase)
Sural nerve conduction will be assessed with a DPN Check device (Neurometrix Inc, MA). The device elicits a electrical stimulation upon contact with the skin on the ankle area and returns values that can range from a minimum of 20 m/s to a maximum of 60m/s. Measurements will be obtained at 8 weeks and value will be compared between groups.
Time frame: at 8 weeks
Ankle Strength at 8 Weeks (Unblinded Phase)
Ankle strength will be assessed with an ankle dynamometer. Participants will be asked to perform 3 maximum voluntary contractions (MVC) sustaining ankle dorsiflexion for 5 seconds with 30 seconds of resting in between MVCs. The average of the 3 MVCs will then be calculated per lower extremity.
Time frame: at 8 weeks
Plantar Tissue Oxygen Saturation at 8 Weeks (Unblinded Phase)
Percentage of tissue oxygen saturation (SatO2) will be measured using a validated near-infrared (NIR) camera (Snapshot NIR, KENT Imaging Inc., Calgary, AB, Can) that detects an approximate value of real-time SatO2 level in superficial tissue. The metatarsus area including the five toes will be traced.
Time frame: at 8 weeks
Mean Daily Step Count at 8 Weeks (Unblinded Phase)
Step count obtained with the mean 90 percentile will be will be measured starting from 4 weeks up to 8 weeks using a smart watch (Vivosmart 4, Garmin, US)
Time frame: Starting at 4 weeks up to 8 weeks
Sleep Duration at 8 Weeks (Unblinded Phase)
Daily sleep duration in hours obtained with the mean 90 percentile will be measured starting from 4 weeks up to 8 weeks using a smart watch (Vivosmart 4, Garmin, US)
Time frame: Starting at 4 weeks up to 8 weeks
Sural Nerve Amplitude at 8 Weeks (Unblinded Phase)
Sural nerve amplitude will be assessed with a DPN Check device (Neurometrix Inc, MA). The device elicits a electrical stimulation upon contact with the skin on the ankle area and returns values that can range from a minimum of 0 microVolts to a maximum of 32 microVolts. Measurements will be obtained at 8 weeks.
Time frame: up to 8 weeks
Double Support Phase at 4 Weeks During a Dual Walking Task (Blinded Phase)
Double Support Phase will be measured with wearable sensors (LEGSys, BioSensics, MA) during a dual walking task (participants asked to count backwards by two while walking) using normal pace for 30 ft. Double support phase is defined as percentage time when both feet are simultaneously in contact with the ground during a single stride.
Time frame: at 4 weeks
Double Support Phase at 4 Weeks During a Fast Walking Task (Blinded Phase)
Double Support Phase will be measured with wearable sensors (LEGSys, BioSensics, MA) during a fast walking task (participants asked to walk at a slightly faster pace) for 30 ft. Double support phase is defined as percentage time when both feet are simultaneously in contact with the ground during a single stride.
Time frame: at 4 weeks
Double Support Phase at 8 Weeks During a Simple Walking Task (Unblinded Phase)
Double Support Phase will be measured with wearable sensors (LEGSys, BioSensics, MA) during a free walking task (single task) using normal pace for 30 ft. Double support phase is defined as percentage time when both feet are simultaneously in contact with the ground during a single stride.
Time frame: at 8 weeks
Double Support Phase at 8 Weeks During a Dual Task (Unblinded Phase)
Double Support Phase will be measured with wearable sensors (LEGSys, BioSensics, MA) during a dual walking task (participants asked to count backwards by two while walking) using normal pace for 30 ft. Double support phase is defined as percentage time when both feet are simultaneously in contact with the ground during a single stride.
Time frame: at 8 weeks
Stride Time at 8 Weeks During a Dual Task (Unblinded Phase)
Stride time will be measured with wearable sensors (LEGSys, BioSensics, MA) during a dual walking task (participants asked to count backwards by two while walking) using normal pace for 30 ft. Stride time is defined as the period elapsed between the first contact of two consecutive footsteps of the same foot expressed in seconds.
Time frame: at 8 weeks
Stride Time at 8 Weeks During a Fast Walk Task (Unblinded Phase)
Stride time will be measured with wearable sensors (LEGSys, BioSensics, MA) during a fast walking task (participants asked to walk at a slightly faster pace) for 30 ft. Stride time is defined as the period elapsed between the first contact of two consecutive footsteps of the same foot expressed in seconds.
Time frame: at 8 weeks
Cadence at 8 Weeks During a Simple Walking Task (Unblinded Phase)
Cadence will be measured with wearable sensors (LEGSys, BioSensics, MA) during a free walking task (single task) using normal pace for 30 ft. Cadence is defined as rate of number of steps per minute.
Time frame: at 8 weeks
Cadence at 8 Weeks During a Dual Task (Unblinded Phase)
Cadence will be measured with wearable sensors (LEGSys, BioSensics, MA) during a dual walking task (participants asked to count backwards by two while walking) using normal pace for 30 ft. Cadence is defined as rate of number of steps per minute.
Time frame: at 8 weeks
Cadence at 8 Weeks During a Fast Walking Task (Unblinded Phase)
Cadence will be measured with wearable sensors (LEGSys, BioSensics, MA) during a fast walking task (participants asked to walk at a slightly faster pace) for 30 ft. Cadence is defined as rate of number of steps per minute.
Time frame: at 8 weeks
| Milestone | Active Group (AG) Blinded Phase | Placebo Group (PG) Blinded Phase | Active Group (AG) Unblinded Phase | Placebo Group (PG) Unblinded Phase |
|---|---|---|---|---|
| Started | 15 | 15 | 0 | 0 |
| Completed | 12 | 13 | 0 | 0 |
| Not completed | 3 | 2 | 0 | 0 |
| Withdrew: Lost to follow-up | 3 | 2 | 0 | 0 |
| Milestone | Active Group (AG) Blinded Phase | Placebo Group (PG) Blinded Phase | Active Group (AG) Unblinded Phase | Placebo Group (PG) Unblinded Phase |
|---|---|---|---|---|
| Started | 0 | 0 | 12 | 13 |
| Completed | 0 | 0 | 10 | 10 |
| Not completed | 0 | 0 | 2 | 3 |
Pain will be assessed with a validated questionnaire called Brief Pain Inventory interference composite score (BPI-I). The maximum score is 10, meaning pain completely interferes, while the minimum score is zero, meaning pain does not interfere.
| score on a scale | Intervention Group | Placebo Group |
|---|---|---|
| Mean Change in Functional Interference From Pain From Baseline to 4 Weeks (Blinded Phase) | 0.454 ± 0.503 | 0.198 ± 0.503 |
Pain severity will be assessed using the Brief Pain Inventory questionnaire composite score for severity. The maximum score is 10, meaning pain as bad as one can imagine, while the minimum score is zero, meaning no pain.
| score on a scale | Intervention Group at 4 Weeks (Blinded Phase) | Placebo Group at 4 Weeks (Blinded Phase) |
|---|---|---|
| Mean Change in Pain Severity From Baseline to 4 Weeks (Blinded Phase) | 1.184 ± 0.815 | 0.289 ± 0.255 |
Functional interference from fatigue will be assessed calculating the Global Fatigue Index (GFI) obtained from a validated questionnaire called Multidimensional Assessment Fatigue, which has a minimum score of 0 (no fatigue) and a maximum sore of 100 (severe fatigue).
| score on a scale | Active Group (AG) | Placebo Group (PG) |
|---|---|---|
| Mean Change in Functional Interference From Fatigue From Baseline to 4 Weeks (Blinded Phase) | 2.821 ± 1.504 | 2.231 ± 3.207 |
Stride time will be measured with wearable sensors (LEGSys, BioSensics, MA) during a free walking task (single task) using normal pace for 30 ft. Stride time is defined as the period elapsed between the first contact of two consecutive footsteps of the same foot expressed in seconds.
| seconds | Active Group (AG) | Placebo Group (PG) |
|---|---|---|
| Stride Time at 4 Weeks During a Simple Walking Task (Blinded Phase) | 1.13 ± 0.03 | 1.16 ± 0.03 |
Cadence will be measured with wearable sensors (LEGSys, BioSensics, MA) during a free walking task (single task) using normal pace for 30 ft. Cadence is defined as rate of number of steps per minute.
| steps/min | Active Group (AG) | Placebo Group (PG) |
|---|---|---|
| Cadence at 4 Weeks During a Simple Walking Task (Blinded Phase) | 106.42 ± 10.35 | 105.90 ± 10.13 |
Double Support Phase will be measured with wearable sensors (LEGSys, BioSensics, MA) during a free walking task (single task) using normal pace for 30 ft. Double support phase is defined as percentage time when both feet are simultaneously in contact with the ground during a single stride.
| percentage of time | Active Group (AG) | Placebo Group (PG) |
|---|---|---|
| Double Support Phase at 4 Weeks During a Simple Walking Task (Blinded Phase) | 22.84 ± 3.98 | 22.64 ± 4.08 |
Cadence will be measured with wearable sensors (LEGSys, BioSensics, MA) during a dual walking task (participants asked to count backwards by two while walking) using normal pace for 30 ft. Cadence is defined as rate of number of steps per minute.
| steps/min | Active Group (AG) | Placebo Group (PG) |
|---|---|---|
| Cadence at 4 Weeks During a Dual Walking Task (Blinded Phase) | 103.40 ± 17.36 | 103.40 ± 14.84 |
Cadence will be measured with wearable sensors (LEGSys, BioSensics, MA) during a fast walking task (participants asked to walk at a slightly faster pace) for 30 ft. Cadence is defined as rate of number of steps per minute.
| steps/min | Active Group (AG) | Placebo Group (PG) |
|---|---|---|
| Cadence at 4 Weeks During a Fast Walking Task (Blinded Phase) | 122.57 ± 15.87 | 122.57 ± 14.80 |
Stride time will be measured with wearable sensors (LEGSys, BioSensics, MA) during a dual walking task (participants asked to count backwards by two while walking) using normal pace for 30 ft. Stride time is defined as the period elapsed between the first contact of two consecutive footsteps of the same foot expressed in seconds.
| seconds | Intervention Group at 4 Weeks (Blinded Phase) | Placebo Group at 4 Weeks (Blinded Phase) |
|---|---|---|
| Stride Time at 4 Weeks During a Dual Walking Task (Blinded Phase) | 1.19 ± 0.21 | 1.19 ± 0.20 |
Stride time will be measured with wearable sensors (LEGSys, BioSensics, MA) during a fast walking task (participants asked to walk at a slightly faster pace) for 30 ft. Stride time is defined as the period elapsed between the first contact of two consecutive footsteps of the same foot expressed in seconds.
| seconds | Intervention Group at 4 Weeks (Blinded Phase) | Placebo Group at 4 Weeks (Blinded Phase) |
|---|---|---|
| Stride Time at 4 Weeks During a Fast Walking Task (Blinded Phase) | 1.00 ± 0.13 | 1.00 ± 0.12 |
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).
| Hertz | Intervention Group at 4 Weeks (Blinded Phase) | Placebo Group at 4 Weeks (Blinded Phase) |
|---|---|---|
| Gastrocnemius Muscle Endurance (Muscle Sustained Contraction) in Response to Electrical Stimulation at 4 Weeks (Blinded Phase) | 150.93 ± 7.44 | 154.44 ± 8.07 |
Frailty will be measured with a upper-extremity wearable sensor (Frailty meter, BioSensics, MA) which enables a frailty index score based on a validated algorithm. Patients with frailty index \>0.27 is considered are considered as frail. Patients with a frailty index \<0.27 are considered as non-frail. The higher the frailty index, the higher the level of frailty. The frailty index ranges from 0-1.
| frailty index | Intervention Group at 4 Weeks (Blinded Phase) | Placebo Group at 4 Weeks (Blinded Phase) |
|---|---|---|
| Frailty at 4 Weeks (Blinded Phase) | 0.18 ± 0.04 | 0.21 ± 0.05 |
Sural nerve conduction will be assessed with a DPN Check device (Neurometrix Inc, MA). The device elicits a electrical stimulation upon contact with the skin on the ankle area and returns values that can range from a minimum of 20 m/s to a maximum of 60m/s. Measurements will be obtained at 4 weeks and value will be compared between groups.
| m/s | Active Group (AG) | Placebo Group (PG) |
|---|---|---|
| Sural Nerve Conduction Velocity at 4 Weeks (Blinded Phase) | 54.96 ± 1.16 | 55.96 ± 1.40 |
Ankle strength will be assessed with an ankle dynamometer. Participants will be asked to perform 3 maximum voluntary contractions (MVC) sustaining ankle dorsiflexion for 5 seconds with 30 seconds of resting in between MVCs. The average of the 3 MVCs will then be calculated per lower extremity.
| kg | Active Group (AG) | Placebo Group (PG) |
|---|---|---|
| Ankle Strength at 4 Weeks (Blinded Phase) | 7.78 ± 0.82 | 7.93 ± 1.09 |
Percentage of tissue oxygen saturation (SatO2) will be measured using a validated near-infrared (NIR) camera (Snapshot NIR, KENT Imaging Inc., Calgary, AB, Can) that detects an approximate value of real-time SatO2 level in superficial tissue. The metatarsus area including the five toes will be traced.
| percentage of oxygen saturation | Active Group (AG) | Placebo Group (PG) |
|---|---|---|
| Plantar Tissue Oxygen Saturation at 4 Weeks (Blinded Phase) | 67.46 ± .78 | 66.31 ± .62 |
Step count obtained with the mean 90 percentile will be will be measured over the course of the 4 weeks using a smart watch (Vivosmart 4, Garmin, US)
| steps/day | Active Group (AG) | Placebo Group (PG) |
|---|---|---|
| Mean Daily Step Count at 4 Weeks (Blinded Phase) | 4988.11 ± 3396.20 | 4887.59 ± 3594.30 |
Daily sleep duration in hours obtained with the mean 90 percentile will be measured over the course of the 4 weeks using a smart watch (Vivosmart 4, Garmin, US)
| hours/day | Active Group (AG) | Placebo Group (PG) |
|---|---|---|
| Sleep Duration at 4 Weeks (Blinded Phase) | 9.2 ± 1.39 | 9.3 ± 1.2 |
Sural nerve amplitude will be assessed with a DPN Check device (Neurometrix Inc, MA). The device elicits a electrical stimulation upon contact with the skin on the ankle area and returns values that can range from a minimum of 0 microVolts to a maximum of 32 microVolts. Measurements will be obtained at 4 weeks.
| microVolts | Intervention Group at 4 Weeks (Blinded Phase) | Placebo Group at 4 Weeks (Blinded Phase) |
|---|---|---|
| Sural Nerve Amplitude at 4 Weeks (Blinded Phase) | 14.4 ± 6.23 | 16.04 ± 12.1 |
Pain will be assessed with a validated questionnaire called Brief Pain Inventory interference composite score (BPI-I). The maximum score is 10, meaning pain completely interferes, while the minimum score is zero, meaning pain does not interfere. This outcome assesses the difference between the mean BPI interference composite score at week 8 and week 4.
| score on a scale | Intervention Group at 8 Weeks (Unblinded Phase) | Placebo Group at 8 Weeks (Unblinded Phase) |
|---|---|---|
| Mean Change in Functional Interference From Pain at 8 Weeks (Unblinded Phase) | 0.29 ± 2.03 | -0.87 ± 1.27 |
Pain severity will be assessed using the Brief Pain Inventory questionnaire composite score for severity. The maximum score is 10, meaning pain as bad as one can imagine, while the minimum score is zero, meaning no pain. This outcome assesses the difference between the mean BPI severity composite score at week 8 and week 4.
| score on a scale | Intervention Group at 8 Weeks (Unblinded Phase) | Placebo Group at 8 Weeks (Unblinded Phase) |
|---|---|---|
| Mean Change in Pain Severity From 4 Weeks to 8 Weeks (Unblinded Phase) | 0.53 ± 1.09 | -0.43 ± 1.24 |
Functional interference from fatigue will be assessed calculating the Global Fatigue Index (GFI) obtained from a validated questionnaire called Multidimensional Assessment Fatigue, which has a minimum score of 0 (no fatigue) and a maximum sore of 100 (severe fatigue). This outcome assesses the difference between the mean global fatigue index at week 8 and week 4.
| score on a scale | Intervention Group at 8 Weeks (Unblinded Phase) | Placebo Group at 8 Weeks (Unblinded Phase) |
|---|---|---|
| Mean Change in Functional Interference From Fatigue From 4 Weeks to 8 Weeks (Unblinded Phase) | -0.39 ± 7.91 | 2.14 ± 5.88 |
Stride time will be measured with wearable sensors (LEGSys, BioSensics, MA) during a free walking task (single task) using normal pace for 30 ft. Stride time is defined as the period elapsed between the first contact of two consecutive footsteps of the same foot expressed in seconds.
| seconds | Intervention Group at 8 Weeks (Unblinded Phase) | Placebo Group at 8 Weeks (Unblinded Phase) |
|---|---|---|
| Stride Time at 8 Weeks During a Simple Walking Task (Unblinded Phase) | 1.15 ± 0.10 | 1.16 ± 0.10 |
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).
| Hertz | Intervention Group at 8 Weeks (Unblinded Phase) | Placebo Group at 8 Weeks (Unblinded Phase) |
|---|---|---|
| Gastrocnemius Muscle Endurance (Muscle Sustained Contraction) in Response to Electrical Stimulation at 8 Weeks (Unblinded Phase) | 148.90 ± 6.60 | 148.52 ± 6.09 |
Frailty will be measured with an upper-extremity wearable sensor (Frailty meter, BioSensics, MA) which enables a frailty index score based on a validated algorithm. Patients with frailty index \>0.27 is considered are considered as frail. Patients with a frailty index \<0.27 are considered as non-frail. The higher the frailty index, the higher the level of frailty. The frailty index ranges from 0-1.
| frailty index | Intervention Group at 8 Weeks (Unblinded Phase) | Placebo Group at 8 Weeks (Unblinded Phase) |
|---|---|---|
| Frailty at 8 Weeks (Unblinded Phase) | 0.19 ± 0.07 | 0.19 ± 0.07 |
Sural nerve conduction will be assessed with a DPN Check device (Neurometrix Inc, MA). The device elicits a electrical stimulation upon contact with the skin on the ankle area and returns values that can range from a minimum of 20 m/s to a maximum of 60m/s. Measurements will be obtained at 8 weeks and value will be compared between groups.
| m/s | Intervention Group at 8 Weeks (Unblinded Phase) | Placebo Group at 8 Weeks (Unblinded Phase) |
|---|---|---|
| Sural Nerve Conduction Velocity at 8 Weeks (Unblinded Phase) | 55.64 ± 5.02 | 56.04 ± 5.02 |
Ankle strength will be assessed with an ankle dynamometer. Participants will be asked to perform 3 maximum voluntary contractions (MVC) sustaining ankle dorsiflexion for 5 seconds with 30 seconds of resting in between MVCs. The average of the 3 MVCs will then be calculated per lower extremity.
| kg | Intervention Group at 8 Weeks (Unblinded Phase) | Placebo Group at 8 Weeks (Unblinded Phase) |
|---|---|---|
| Ankle Strength at 8 Weeks (Unblinded Phase) | 9.59 ± 5.11 | 9.79 ± 5.18 |
Percentage of tissue oxygen saturation (SatO2) will be measured using a validated near-infrared (NIR) camera (Snapshot NIR, KENT Imaging Inc., Calgary, AB, Can) that detects an approximate value of real-time SatO2 level in superficial tissue. The metatarsus area including the five toes will be traced.
| percentage of oxygen saturation | Intervention Group at 8 Weeks (Unblinded Phase) | Placebo Group at 8 Weeks (Unblinded Phase) |
|---|---|---|
| Plantar Tissue Oxygen Saturation at 8 Weeks (Unblinded Phase) | 67.82 ± 3.79 | 67.38 ± 3.38 |
Step count obtained with the mean 90 percentile will be will be measured starting from 4 weeks up to 8 weeks using a smart watch (Vivosmart 4, Garmin, US)
| steps/day | Intervention Group at 8 Weeks (Unblinded Phase) | Placebo Group at 8 Weeks (Unblinded Phase) |
|---|---|---|
| Mean Daily Step Count at 8 Weeks (Unblinded Phase) | 3545.86 ± 4569.65 | 4166.31 ± 3897.13 |
Daily sleep duration in hours obtained with the mean 90 percentile will be measured starting from 4 weeks up to 8 weeks using a smart watch (Vivosmart 4, Garmin, US)
| hours/day | Intervention Group at 8 Weeks (Unblinded Phase) | Placebo Group at 8 Weeks (Unblinded Phase) |
|---|---|---|
| Sleep Duration at 8 Weeks (Unblinded Phase) | 2.64 ± 1.83 | 10.53 ± 2.40 |
Sural nerve amplitude will be assessed with a DPN Check device (Neurometrix Inc, MA). The device elicits a electrical stimulation upon contact with the skin on the ankle area and returns values that can range from a minimum of 0 microVolts to a maximum of 32 microVolts. Measurements will be obtained at 8 weeks.
| microVolts | Intervention Group at 8 Weeks (Unblinded Phase) | Placebo Group at 8 Weeks (Unblinded Phase) |
|---|---|---|
| Sural Nerve Amplitude at 8 Weeks (Unblinded Phase) | 14.71 ± 7.47 | 14.71 ± 6.99 |
Double Support Phase will be measured with wearable sensors (LEGSys, BioSensics, MA) during a dual walking task (participants asked to count backwards by two while walking) using normal pace for 30 ft. Double support phase is defined as percentage time when both feet are simultaneously in contact with the ground during a single stride.
| percentage time | Intervention Group at 4 Weeks (Blinded Phase) | Placebo Group at 4 Weeks (Blinded Phase) |
|---|---|---|
| Double Support Phase at 4 Weeks During a Dual Walking Task (Blinded Phase) | 24.45 ± 8.47 | 24.45 ± 8.81 |
Double Support Phase will be measured with wearable sensors (LEGSys, BioSensics, MA) during a fast walking task (participants asked to walk at a slightly faster pace) for 30 ft. Double support phase is defined as percentage time when both feet are simultaneously in contact with the ground during a single stride.
| percentage time | Intervention Group at 4 Weeks (Blinded Phase) | Placebo Group at 4 Weeks (Blinded Phase) |
|---|---|---|
| Double Support Phase at 4 Weeks During a Fast Walking Task (Blinded Phase) | 17.87 ± 4.63 | 17.87 ± 4.57 |
Double Support Phase will be measured with wearable sensors (LEGSys, BioSensics, MA) during a free walking task (single task) using normal pace for 30 ft. Double support phase is defined as percentage time when both feet are simultaneously in contact with the ground during a single stride.
| percentage time | Intervention Group at 8 Weeks (Unblinded Phase) | Placebo Group at 8 Weeks (Unblinded Phase) |
|---|---|---|
| Double Support Phase at 8 Weeks During a Simple Walking Task (Unblinded Phase) | 20.69 ± 4.77 | 21.75 ± 4.13 |
Double Support Phase will be measured with wearable sensors (LEGSys, BioSensics, MA) during a dual walking task (participants asked to count backwards by two while walking) using normal pace for 30 ft. Double support phase is defined as percentage time when both feet are simultaneously in contact with the ground during a single stride.
| percentage | Intervention Group at 8 Weeks (Unblinded Phase) | Placebo Group at 8 Weeks (Unblinded Phase) |
|---|---|---|
| Double Support Phase at 8 Weeks During a Dual Task (Unblinded Phase) | 24.47 ± 3.24 | 24.51 ± 2.27 |
Stride time will be measured with wearable sensors (LEGSys, BioSensics, MA) during a dual walking task (participants asked to count backwards by two while walking) using normal pace for 30 ft. Stride time is defined as the period elapsed between the first contact of two consecutive footsteps of the same foot expressed in seconds.
| seconds | Intervention Group at 8 Weeks (Unblinded Phase) | Placebo Group at 8 Weeks (Unblinded Phase) |
|---|---|---|
| Stride Time at 8 Weeks During a Dual Task (Unblinded Phase) | 1.21 ± 0.15 | 1.27 ± 0.15 |
Stride time will be measured with wearable sensors (LEGSys, BioSensics, MA) during a fast walking task (participants asked to walk at a slightly faster pace) for 30 ft. Stride time is defined as the period elapsed between the first contact of two consecutive footsteps of the same foot expressed in seconds.
| seconds | Intervention Group at 8 Weeks (Unblinded Phase) | Placebo Group at 8 Weeks (Unblinded Phase) |
|---|---|---|
| Stride Time at 8 Weeks During a Fast Walk Task (Unblinded Phase) | 0.99 ± 0.11 | 1.04 ± 0.10 |
Cadence will be measured with wearable sensors (LEGSys, BioSensics, MA) during a free walking task (single task) using normal pace for 30 ft. Cadence is defined as rate of number of steps per minute.
| steps/min | Intervention Group at 8 Weeks (Unblinded Phase) | Placebo Group at 8 Weeks (Unblinded Phase) |
|---|---|---|
| Cadence at 8 Weeks During a Simple Walking Task (Unblinded Phase) | 105.36 ± 10.16 | 101.63 ± 5.77 |
Cadence will be measured with wearable sensors (LEGSys, BioSensics, MA) during a dual walking task (participants asked to count backwards by two while walking) using normal pace for 30 ft. Cadence is defined as rate of number of steps per minute.
| steps/min | Intervention Group at 8 Weeks (Unblinded Phase) | Placebo Group at 8 Weeks (Unblinded Phase) |
|---|---|---|
| Cadence at 8 Weeks During a Dual Task (Unblinded Phase) | 100.51 ± 12.56 | 96.04 ± 10.62 |
Cadence will be measured with wearable sensors (LEGSys, BioSensics, MA) during a fast walking task (participants asked to walk at a slightly faster pace) for 30 ft. Cadence is defined as rate of number of steps per minute.
| steps/min | Intervention Group at 8 Weeks (Unblinded Phase) | Placebo Group at 8 Weeks (Unblinded Phase) |
|---|---|---|
| Cadence at 8 Weeks During a Fast Walking Task (Unblinded Phase) | 122.80 ± 14.88 | 116.14 ± 12.59 |
Collected over AEs were collected from study start date (March 1 2022) to the study completion (December 1, 2023) in a non-systematic way. Per patient, AEs were collected up to 8 weeks after Baseline. During follow-ups, participants were asked if they experienced AEs. If participant missed a visit or had low adherence (assessed by monitoring device usage remotely) the coordinator called the participant and asked for AEs. AEs were also reported by the participants on a case-by-case basis when they occurred.. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Intervention Group at 4 Weeks (Blinded Phase) | 0/15 (0%) | 0/15 (0%) | 3/15 (20%) |
| Placebo Group at 4 Weeks (Blinded Phase) | 0/15 (0%) | 0/15 (0%) | 3/15 (20%) |
| Intervention Group at 8 Weeks (Unblinded Phase) | 0/12 (0%) | 0/12 (0%) | 0/12 (0%) |
| Placebo Group at 8 Weeks (Unblinded Phase) | 0/13 (0%) | 0/13 (0%) | 0/13 (0%) |
| Event | Intervention Group at 4 Weeks (Blinded Phase) | Placebo Group at 4 Weeks (Blinded Phase) | Intervention Group at 8 Weeks (Unblinded Phase) | Placebo Group at 8 Weeks (Unblinded Phase) |
|---|---|---|---|---|
| Minor AE due to device misuseProduct Issues | 3/15 | 3/15 | 0/12 | 0/13 |
| Age, Continuous(years) | Placebo Group (PG) | Active Group (AG) | Total |
|---|---|---|---|
| Mean | 43.38 ± 11.79 | 51.08 ± 12.32 | 45.28 ± 12.18 |
| Sex: Female, Male(Participants) | Placebo Group (PG) | Active Group (AG) | Total |
|---|---|---|---|
| Female | 9 | 10 | 19 |
| Male | 4 | 2 | 6 |
| Race/Ethnicity, Customized(Participants) | Placebo Group (PG) | Active Group (AG) | Total |
|---|---|---|---|
| Black | 1 | 2 | 3 |
| Hispanic | 2 | 3 | 5 |
| Asian | 2 | 0 | 2 |
| White | 6 | 6 | 12 |
| Unknown | 2 | 1 | 3 |
| Region of Enrollment(participants) | Placebo Group (PG) | Active Group (AG) | Total |
|---|---|---|---|
| United States | 13 | 12 | 25 |
| Body Mass Index (BMI)(kg/m^2) | Placebo Group (PG) | Active Group (AG) | Total |
|---|---|---|---|
| Mean | 27.76 ± 5.98 | 27.72 ± 7.92 | 27.74 ± 6.95 |
| High Blood Pressure(Participants) | Placebo Group (PG) | Active Group (AG) | Total |
|---|---|---|---|
| Count of participants | 3 | 2 | 5 |
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Baylor College of Medicine