Wireless Nerve Stimulation Device To Enhance Recovery After Stroke

Study Overview
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Brief Summary
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Texas Biomedical Device Center (TxBDC) has developed an innovative strategy to enhance recovery of motor and sensory function after neurological injury termed targeted plasticity therapy (TPT). This technique uses brief pulses of vagus nerve stimulation to engage pro-plasticity neuromodulatory circuits during rehabilitation exercises. Preclinical findings demonstrate that VNS paired with rehabilitative training enhances recovery in multiple models of neurological injury, including stroke, spinal cord injury, intracerebral hemorrhage, and traumatic brain injury. Recovery is associated with neural plasticity in spared motor networks in the brain and spinal cord. Moreover, two initial studies and a recently completed Phase 3 clinical trial using a commercially available device demonstrates that paired VNS with rehabilitation is safe and improves motor recovery after stroke. The purpose of this study is to extend these findings and evaluate whether VNS delivered with the new device paired with rehabilitation represents a safe and feasible strategy to improve recovery of motor and sensory function in participants with stroke.

Official Title
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Wireless Nerve Stimulation Device To Enhance Recovery After Stroke

Conditions
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Stroke, Chronic Stroke, Upper Extremity Paresis, Ischemic Stroke, Hemorrhagic Stroke

Intervention / Treatment
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* Device: Active Vagus Nerve Stimulation
* Device: Placebo Vagus Nerve Stimulation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: In order to be eligible to participate in this study, an individual must meet all of the following criteria: Provision of signed and dated informed consent form Stated willingness to comply with all study procedures and availability for the duration of the study Adult, aged 22-79 Ischemic or hemorrhagic stroke that occurred ≥ 12 months prior to enrollment UEFM score of 20 to 50 Modified Rankin Score of 2, 3, or 4 Right vocal cord has normal movement when assessed by laryngoscopy Women of reproductive potential must use contraceptive protection Meets all clinical criteria for the surgical VNS implantation as determined by the PI, surgeon, and anesthesiologist Exclusion Criteria: An individual who meets any of the following criteria will be excluded from participation in this study: Deficits in language or attention that interfere with study participation Severe spasticity (Modified Ashworth ≥ 3) Medical or mental instability that would likely interfere with study protocol Receiving any therapy (medication or otherwise) that would interfere with VNS, such as drugs that perturb neurotransmitter action (anticholinergics, adrenergic blockers, etc.) Presence of any other implanted electrical stimulation device Prior injury to vagus nerve Lactating, pregnant, or plan to become pregnant Participation in another interventional clinical trial Clinical complications that hinder or contraindicate the surgical procedure Abusive use of alcohol and/or illegal substances use Participants with sickle cell, lupus, clotting disorders or active neoplastic disease. Participants with any any medical condition or other circumstances that might interfere with their ability to return for follow-up visits in the judgment of the Investigator. Any condition which, in the judgment of the Investigator, would preclude adequate evaluation of device's safety and performance. Recent history of syncope Recent history of dysphagia Current or anticipated requirement for diathermy Uncontrolled hypertension Diagnosed with Cerebral amyloid angiopathy

Ages Eligible for Study
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Minimum Age: 22 Years
Maximum Age: 79 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: Device Feasibility
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Prospective, double blind, randomized placebo controlled, plus open-label extension
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Immediate Start Vagus Nerve Stimulation group<br>The Immediate Start VNS group will receive rehabilitation and active stimulation for 18 in-office sessions over the course of approximately six weeks during Phase 1. For Phase 2, all subjects will be provided with the option to participate in an open-label extension consisting of an additional 18 sessions of in-office rehabilitation with active VNS over the course of approximately six weeks. Additionally, participants may be provided with a system of rehabilitative devices to utilize at home. | Device: Active Vagus Nerve Stimulation<br>* Stimulation of the vagus nerve that is paired with upper limb rehabilitation. VNS stimulation as described in the current study consists of 0.5 second trains of 0.8 mA; 100 µsec biphasic pulses at 30 Hz. Stimulation trains are delivered only during rehabilitation.<br>* Other names: paired VNS;|
| Placebo Comparator: Delayed Start Vagus Nerve Stimulation group<br>The Delayed Start VNS group will receive equivalent rehabilitation with placebo stimulation for 18 in-office sessions over the course of approximately six weeks during Phase 1. For Phase 2, all subjects will be provided with the option to participate in an open-label extension consisting of an additional 18 sessions of in-office rehabilitation with active VNS over the course of approximately six weeks. Additionally, participants may be provided with a system of rehabilitative devices to utilize at home. | Device: Placebo Vagus Nerve Stimulation<br>* During Phase 1 of the study, the placebo group will receive a minimal amount of stimulation that fails to sufficiently activate the nerve, unknown to the participant and therapists. All participants will receive active stimulation during the Phase 2 open-label portion of the study.<br>* Other names: control;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Adverse Events [Device Safety] | Review of adverse events reported throughout the trial will be used to inform the potential risks associated with the ReStore system and provide a better understanding of risk/benefit analysis | From Week 1 through study follow-up, approximately two years after the final session of rehabilitation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ReStore Stimulation Successes | The percentage of stimulation attempts classified as 'Success' from the total number of stimulation attempts made will be calculated for each participant and the mean percent of successful attempts across all participants will be used as the outcome measure. | Weeks 6-11 | 
| Upper-Extremity Fugl-Meyer Assessment (UEFM) | The UEFM Assessment is a sixty-six point assessment of mobility administered by a therapist designed to facilitate consistent collection and reporting of basic upper extremity findings. The endpoint will be: estimate the shift in UEFM assessment following active VNS | Weeks 1, 5, 12, 19, 20, 24, 32 | 
| Wolf Motor Task Functional Ability Scale | The Wolf Motor Task Functional Ability Scale (WMFT-FAS) is a quantitative measure of upper extremity motor ability through timed and functional tasks. The task includes evaluation of dexterity, strength, and upper extremity function. Functional ability is measured on a 6-point ordinal scale (0-5) with a maximum total score of 75. The endpoint will be: estimate the shift in WMFT-FAS assessment following active VNS | Weeks 1, 5, 12, 19, 20, 24, 32 | 
| Action Research Arm Test | The ARAT is a nineteen-item observational assessment of upper limb function. The areas of assessment include activities of daily living, coordination, dexterity, and upper extremity function. The endpoint will be: Estimate the shift in ARAT assessment following active VNS | Weeks 1, 5, 12, 19, 20, 24, 32 | 
| Modified Rankin Scale | The Modified Rankin Scale (MRS) is a single item global outcomes rating scale that categorizes level of functional independence. The measure reflects ability to perform activities of daily living and functional mobility. The MRS is a 6 point scale with 0 being no disability and 5 being severe disability. A score of 6 indicates that the patient has expired. The endpoint will be: Estimate the shift in MRS assessment following active VNS | Weeks 1, 5, 12, 19, 20, 24, 32 | 
| Quantitative Force and Range of Motion Assessment | The Quantitative Force and Range of Motion Assessment form is a physical assessment of upper limb changes in force/torque as a result of VNS paired rehabilitation. The endpoints will be: 10% increase in finger pinch and flexion force following active VNS; 10% increase in wrist flexion and extension force following active VNS; 10% increase in wrist pronation and supination force following active VNS | Weeks 1, 5-20, 24, 32 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Vagus Nerve Stimulation (VNS), Rehabilitation, Targeted Plasticity Therapy