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The purpose of this study is to evaluate if multiple therapy sessions of Transcutaneous Vagus Nerve Stimulation (tVNS) combined with robotic arm therapy lead to a greater functional recovery in upper limb mobility after stroke than that provided by robotic arm therapy in a sham stimulation condition.
Promising new animal research suggests that vagus nerve stimulation paired with motor intervention induces movement-specific plasticity in the motor cortex and improves limb function after stroke. These results were recently extended to the first clinical trial, in which patients with stroke demonstrated significant improvements in upper limb function following rehabilitation paired with implanted VNS. Currently, vagus nerve stimulation is being used clinically to treat a number of human diseases including migraine headaches, epilepsy, and depression, and these investigations are expanding to deliver stimulation via a transcutaneous route to potentially improve intervention efficacy and decrease side effects. This pilot study will combine non-invasive transcutaneous stimulation of the vagus nerve with upper limb robotic therapy to investigate the potential of tVNS to augment improvements gained with robotic therapy in patients with chronic hemiparesis after stroke.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| active tVNS + robotic arm therapy | Experimental | Transcutaneous Vagus Nerve Stimulation (tVNS) will be delivered non-invasively via the ear (targeting the auricular branch of the vagus nerve) during robotic arm therapy sessions lasting ~60 minutes, 3x per week for 3 weeks. |
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| sham tVNS + robotic arm therapy | Sham Comparator | Sham (placebo) transcutaneous Vagus Nerve Stimulation (tVNS) will be delivered non-invasively via the ear (targeting the auricular branch of the vagus nerve) during robotic arm therapy sessions lasting ~60 minutes, 3x per week for 3 weeks. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Transcutaneous Vagus Nerve Stimulation (tVNS) | Device | tVNS is a non-invasive form of vagus nerve stimulation, activating the auricular branch of the vagus nerve transcutaneously through the cymba concha at the pinna of the ear. |
| Measure | Description | Time Frame |
|---|---|---|
| Median Absolute Change From Baseline in Electromyographic (EMG) Peak Amplitude of the Bicep/Tricep | The median absolute change in surface electromyographic (sEMG) peak amplitude of the bicep/tricep during gravity-eliminated, unassisted extensor movements was calculated from baseline to discharge at 3 weeks (immediately following the intervention) and again at 16 weeks (3 months follow-up from the intervention) in each training condition (sham tVNS + robotic arm training vs. active tVNS + robotic arm training). Bicep and tricep peak sEMG amplitude scores were calculated as a percentage of the maximal volitional contraction (MVC), with larger values indicating a greater absolute change (negative or positive) in bicep/tricep peak muscle activity during extensor movements. | baseline, discharge at 3 weeks (immediately following the intervention), and follow-up at 16 weeks (3 months after the intervention) |
| Measure | Description | Time Frame |
|---|---|---|
| Median Change From Baseline in Upper Extremity Fugl Meyer Assessment Score | The median change in Upper Extremity Fugl-Meyer Score will be calculated from baseline to discharge at 3 weeks (immediately following the intervention) and again at 16 weeks (3 months follow-up from the intervention) in each training condition (sham tVNS + robotic arm training vs. active tVNS + robotic arm training). The median change in Upper Extremity Fugl Meyer score is reported, with a range 0-66 points, and with higher values indicating better functional status. |
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Inclusion Criteria:
Exclusion Criteria:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Feinstein Institute for Medical Research | Manhasset | New York | 11030 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 26645257 | Background | Dawson J, Pierce D, Dixit A, Kimberley TJ, Robertson M, Tarver B, Hilmi O, McLean J, Forbes K, Kilgard MP, Rennaker RL, Cramer SC, Walters M, Engineer N. Safety, Feasibility, and Efficacy of Vagus Nerve Stimulation Paired With Upper-Limb Rehabilitation After Ischemic Stroke. Stroke. 2016 Jan;47(1):143-50. doi: 10.1161/STROKEAHA.115.010477. Epub 2015 Dec 8. | |
| 29375915 |
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| ID | Title | Description |
|---|---|---|
| FG000 | Active tVNS + Robotic Arm Therapy | Transcutaneous Vagus Nerve Stimulation (tVNS) will be delivered non-invasively via the ear (targeting the auricular branch of the vagus nerve) during robotic arm therapy sessions lasting ~60 minutes, 3x per week for 3 weeks. Transcutaneous Vagus Nerve Stimulation (tVNS): tVNS is a non-invasive form of vagus nerve stimulation, activating the auricular branch of the vagus nerve transcutaneously through the cymba concha at the pinna of the ear. |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jan 23, 2020 |
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This is a double-blind, sham controlled treatment study in which patients will have a 50/50 chance of receiving robotic arm therapy with either active transcutaneous vagus nerve stimulation (tVNS) or sham tVNS (placebo).
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Both the participants and investigators performing and analyzing clinical and objective outcome measures will remain blind to condition. Participants will be told that they have a 50-50 chance of receiving either active or sham stimulation, but they will not be told which condition they receive.
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| Sham Transcutaneous Vagus Nerve Stimulation (tVNS) | Device | tVNS is a non-invasive form of vagus nerve stimulation, activating the auricular branch of the vagus nerve transcutaneously through the cymba concha at the pinna of the ear. Sham tVNS means the patient is wearing the device, but it is turned off and not delivering current during the treatment. This is a placebo condition, which is used as a study control. |
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| baseline, discharge at 3 weeks (immediately following the intervention), and follow-up at 16 weeks (3 months after the intervention) |
| Capone F, Miccinilli S, Pellegrino G, Zollo L, Simonetti D, Bressi F, Florio L, Ranieri F, Falato E, Di Santo A, Pepe A, Guglielmelli E, Sterzi S, Di Lazzaro V. Transcutaneous Vagus Nerve Stimulation Combined with Robotic Rehabilitation Improves Upper Limb Function after Stroke. Neural Plast. 2017;2017:7876507. doi: 10.1155/2017/7876507. Epub 2017 Dec 10. |
| 24553102 | Background | Khodaparast N, Hays SA, Sloan AM, Fayyaz T, Hulsey DR, Rennaker RL 2nd, Kilgard MP. Vagus nerve stimulation delivered during motor rehabilitation improves recovery in a rat model of stroke. Neurorehabil Neural Repair. 2014 Sep;28(7):698-706. doi: 10.1177/1545968314521006. Epub 2014 Feb 18. |
| 23954448 | Background | Khodaparast N, Hays SA, Sloan AM, Hulsey DR, Ruiz A, Pantoja M, Rennaker RL 2nd, Kilgard MP. Vagus nerve stimulation during rehabilitative training improves forelimb strength following ischemic stroke. Neurobiol Dis. 2013 Dec;60:80-8. doi: 10.1016/j.nbd.2013.08.002. Epub 2013 Aug 15. |
| 26671658 | Background | Hays SA. Enhancing Rehabilitative Therapies with Vagus Nerve Stimulation. Neurotherapeutics. 2016 Apr;13(2):382-94. doi: 10.1007/s13311-015-0417-z. |
| 19752297 | Background | Volpe BT, Huerta PT, Zipse JL, Rykman A, Edwards D, Dipietro L, Hogan N, Krebs HI. Robotic devices as therapeutic and diagnostic tools for stroke recovery. Arch Neurol. 2009 Sep;66(9):1086-90. doi: 10.1001/archneurol.2009.182. |
| 34899170 | Derived | Chang JL, Coggins AN, Saul M, Paget-Blanc A, Straka M, Wright J, Datta-Chaudhuri T, Zanos S, Volpe BT. Transcutaneous Auricular Vagus Nerve Stimulation (tAVNS) Delivered During Upper Limb Interactive Robotic Training Demonstrates Novel Antagonist Control for Reaching Movements Following Stroke. Front Neurosci. 2021 Nov 25;15:767302. doi: 10.3389/fnins.2021.767302. eCollection 2021. |
| FG001 | Sham tVNS + Robotic Arm Therapy | Sham (placebo) transcutaneous Vagus Nerve Stimulation (tVNS) will be delivered non-invasively via the ear (targeting the auricular branch of the vagus nerve) during robotic arm therapy sessions lasting ~60 minutes, 3x per week for 3 weeks. Sham Transcutaneous Vagus Nerve Stimulation (tVNS): tVNS is a non-invasive form of vagus nerve stimulation, activating the auricular branch of the vagus nerve transcutaneously through the cymba concha at the pinna of the ear. Sham tVNS means the patient is wearing the device, but it is turned off and not delivering current during the treatment. This is a placebo condition, which is used as a study control. |
| COMPLETED |
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| NOT COMPLETED |
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| ID | Title | Description |
|---|---|---|
| BG000 | Active tVNS + Robotic Arm Therapy | Transcutaneous Vagus Nerve Stimulation (tVNS) will be delivered non-invasively via the ear (targeting the auricular branch of the vagus nerve) during robotic arm therapy sessions lasting ~60 minutes, 3x per week for 3 weeks. Transcutaneous Vagus Nerve Stimulation (tVNS): tVNS is a non-invasive form of vagus nerve stimulation, activating the auricular branch of the vagus nerve transcutaneously through the cymba concha at the pinna of the ear. |
| BG001 | Sham tVNS + Robotic Arm Therapy | Sham (placebo) transcutaneous Vagus Nerve Stimulation (tVNS) will be delivered non-invasively via the ear (targeting the auricular branch of the vagus nerve) during robotic arm therapy sessions lasting ~60 minutes, 3x per week for 3 weeks. Sham Transcutaneous Vagus Nerve Stimulation (tVNS): tVNS is a non-invasive form of vagus nerve stimulation, activating the auricular branch of the vagus nerve transcutaneously through the cymba concha at the pinna of the ear. Sham tVNS means the patient is wearing the device, but it is turned off and not delivering current during the treatment. This is a placebo condition, which is used as a study control. |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean | Full Range | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Region of Enrollment | Count of Participants | Participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Median Absolute Change From Baseline in Electromyographic (EMG) Peak Amplitude of the Bicep/Tricep | The median absolute change in surface electromyographic (sEMG) peak amplitude of the bicep/tricep during gravity-eliminated, unassisted extensor movements was calculated from baseline to discharge at 3 weeks (immediately following the intervention) and again at 16 weeks (3 months follow-up from the intervention) in each training condition (sham tVNS + robotic arm training vs. active tVNS + robotic arm training). Bicep and tricep peak sEMG amplitude scores were calculated as a percentage of the maximal volitional contraction (MVC), with larger values indicating a greater absolute change (negative or positive) in bicep/tricep peak muscle activity during extensor movements. | 30 patients completed 9 sessions (3x/week for 3 weeks) of robotic arm training + sham or active tVNS, and 3 month follow-up at 16 weeks. One patient in the sham condition had corrupted sEMG measures, so 29 participants were consequently included in the efficacy analysis. | Posted | Median | Inter-Quartile Range | percentage of MVC | baseline, discharge at 3 weeks (immediately following the intervention), and follow-up at 16 weeks (3 months after the intervention) |
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| Secondary | Median Change From Baseline in Upper Extremity Fugl Meyer Assessment Score | The median change in Upper Extremity Fugl-Meyer Score will be calculated from baseline to discharge at 3 weeks (immediately following the intervention) and again at 16 weeks (3 months follow-up from the intervention) in each training condition (sham tVNS + robotic arm training vs. active tVNS + robotic arm training). The median change in Upper Extremity Fugl Meyer score is reported, with a range 0-66 points, and with higher values indicating better functional status. | 30 patients completed 9 sessions (3x/week for 3 weeks) of robotic arm training + sham or active tVNS, and 3 month follow-up at 16 weeks. A total of 30 participants were consequently included in the efficacy analysis. | Posted | Median | Inter-Quartile Range | scores on a scale | baseline, discharge at 3 weeks (immediately following the intervention), and follow-up at 16 weeks (3 months after the intervention) |
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Adverse event data were collected for approximately 4 months, including the 3 week duration of the study intervention and the subsequent 3 month follow-up period.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Active tVNS + Robotic Arm Therapy | Transcutaneous Vagus Nerve Stimulation (tVNS) will be delivered non-invasively via the ear (targeting the auricular branch of the vagus nerve) during robotic arm therapy sessions lasting ~60 minutes, 3x per week for 3 weeks. Transcutaneous Vagus Nerve Stimulation (tVNS): tVNS is a non-invasive form of vagus nerve stimulation, activating the auricular branch of the vagus nerve transcutaneously through the cymba concha at the pinna of the ear. | 0 | 18 | 0 | 18 | 0 | 18 |
| EG001 | Sham tVNS + Robotic Arm Therapy | Sham (placebo) transcutaneous Vagus Nerve Stimulation (tVNS) will be delivered non-invasively via the ear (targeting the auricular branch of the vagus nerve) during robotic arm therapy sessions lasting ~60 minutes, 3x per week for 3 weeks. Sham Transcutaneous Vagus Nerve Stimulation (tVNS): tVNS is a non-invasive form of vagus nerve stimulation, activating the auricular branch of the vagus nerve transcutaneously through the cymba concha at the pinna of the ear. Sham tVNS means the patient is wearing the device, but it is turned off and not delivering current during the treatment. This is a placebo condition, which is used as a study control. | 0 | 18 | 0 | 18 | 2 | 18 |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| flu | Infections and infestations | Non-systematic Assessment | Subject suffered from the flu (unrelated to study intervention) and consequently missed repeated sessions. Subject was ultimately withdrawn from the study as a consequence. |
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| wrist fracture | Injury, poisoning and procedural complications | Non-systematic Assessment | Subject fractured wrist and was consequently unable to return for follow-up. |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Senior Research Coordinator | Feinstein Institutes for Medical Research at Northwell Health | 5165623646 | jchang14@northwell.edu |
| May 10, 2021 |
| Prot_SAP_000.pdf |
| ICF | No | No | Yes | Informed Consent Form | Jan 23, 2020 | May 10, 2021 | ICF_001.pdf |
| ID | Term |
|---|---|
| D020521 | Stroke |
| D010291 | Paresis |
| ID | Term |
|---|---|
| D002561 | Cerebrovascular Disorders |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D009461 | Neurologic Manifestations |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| Male |
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| Asian |
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| Native Hawaiian or Other Pacific Islander |
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| Black or African American |
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| White |
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| More than one race |
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| Unknown or Not Reported |
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| Median absolute change in bicep peak amplitude from baseline to 3 month follow-up |
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| Median absolute change in tricep peak amplitude from baseline to 3 month follow-up |
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| Wilcoxon (Mann-Whitney) | 0.445 | The Mann-Whitney Wilcoxon test was performed to compare median absolute change in tricep peak sEMG amplitude from baseline to 3 weeks (discharge) across two separate study conditions (active vs. sham tVNS). | U value | 87.000 | 2-Sided | Equivalence | Statistical analysis of the median absolute change in tricep peak sEMG amplitude from baseline to DC immediately following 3 weeks of training was measured in the active vs. sham tVNS conditions. Null hypothesis is that there is no difference in median absolute change in bicep peak sEMG amplitude between the active and sham tVNS conditions. A significance level of 0.05 was used (two-tailed). |
| Wilcoxon (Mann-Whitney) | 0.678 | The Mann-Whitney Wilcoxon test was performed to compare the median absolute change in bicep peak sEMG from baseline to 16 weeks (follow-up) across two separate study conditions (active vs. sham tVNS). | U value | 95.000 | 2-Sided | Equivalence | Statistical analysis of the median absolute change in bicep peak sEMG amplitude from baseline to week 16 (3 month follow-up after training) was measured in the active vs. sham tVNS conditions. Null hypothesis is that there is no difference in median absolute change in bicep peak sEMG amplitude between the active and sham tVNS conditions. A significance level of 0.05 was used (two-tailed). |
| Wilcoxon (Mann-Whitney) | 0.777 | The Mann-Whitney Wilcoxon test was performed to compare the median absolute change in tricep peak sEMG from baseline to 16 weeks (follow-up) across two separate study conditions (active vs. sham tVNS). | U value | 98.000 | 2-Sided | Equivalence | Statistical analysis of the median absolute change in tricep peak sEMG amplitude from baseline to week 16 (3 month follow-up after training) was measured in the active vs. sham tVNS conditions. Null hypothesis is that there is no difference in median absolute change in bicep peak sEMG amplitude between the active and sham tVNS conditions. A significance level of 0.05 was used (two-tailed). |
Sham (placebo) transcutaneous Vagus Nerve Stimulation (tVNS) will be delivered non-invasively via the ear (targeting the auricular branch of the vagus nerve) during robotic arm therapy sessions lasting ~60 minutes, 3x per week for 3 weeks.
Sham Transcutaneous Vagus Nerve Stimulation (tVNS): tVNS is a non-invasive form of vagus nerve stimulation, activating the auricular branch of the vagus nerve transcutaneously through the cymba concha at the pinna of the ear. Sham tVNS means the patient is wearing the device, but it is turned off and not delivering current during the treatment. This is a placebo condition, which is used as a study control.
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