Wireless Nerve Stimulation Device To Enhance Recovery After Stroke

NCT04534556 | Enrolling By Invitation DMC FDA Device

• 2 other identifiers: 020-392UG3NS109497
• Study Type: interventional
• Target: 42
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Stroke; Chronic Stroke; Upper Extremity Paresis; Ischemic Stroke; Hemorrhagic Stroke

Keywords

Vagus Nerve Stimulation (VNS); Rehabilitation; Targeted Plasticity Therapy

Outcome Measures

Primary Outcomes (1)

• 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 implant date or final session of rehabilitation (whichever comes second)

Secondary Outcomes (6)

• ReStore Stimulation Successes

  Weeks 6-11, during follow-on intervention visits 2-13, 14-25, and 25-36

• Upper-Extremity Fugl-Meyer Assessment (UEFM)

  Weeks 1, 3, 10, 17

• Wolf Motor Task Functional Ability Scale

  Weeks 1, 3, 10, 17

• Action Research Arm Test

  Weeks 1, 5, 12, 19, 20, 24, 32

• Modified Rankin Scale

  Weeks 1, 5, 12, 19, 20, 24, 32

Study Arms (3)

Immediate Start Vagus Nerve Stimulation group

EXPERIMENTAL

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

Delayed Start Vagus Nerve Stimulation group

PLACEBO COMPARATOR

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

Follow-On Study Group

EXPERIMENTAL

The Follow-On Study group will receive up to 112 rehabilitation sessions with active VNS over the course of approximately 36 weeks after completion of Phase II. Participants will be provided with a system of rehabilitative devices to utilize at home.

Device: Active Vagus Nerve Stimulation

Interventions

Active Vagus Nerve Stimulation DEVICE

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.

Also known as: VNS, vagus nerve stimulation, paired VNS

Follow-On Study Group; Immediate Start Vagus Nerve Stimulation group

Placebo Vagus Nerve Stimulation DEVICE

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.

Also known as: placebo, control

Delayed Start Vagus Nerve Stimulation group

Eligibility Criteria

• Age: 22 Years - 79 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Baylor Research Institute: lead
• The University of Texas at Dallas: collaborator
• University of Texas Southwestern Medical Center: collaborator
• National Institute of Neurological Disorders and Stroke (NINDS): collaborator

Study Sites (1)

Baylor Scott & White Institute for Rehabilitation

Dallas, Texas, 75246, United States

Location

Related Publications (20)

• Engineer ND, Kimberley TJ, Prudente CN, Dawson J, Tarver WB, Hays SA. Targeted Vagus Nerve Stimulation for Rehabilitation After Stroke. Front Neurosci. 2019 Mar 29;13:280. doi: 10.3389/fnins.2019.00280. eCollection 2019.

  PMID: 30983963 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.

  PMID: 23954448 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.

  PMID: 24553102 BACKGROUND

• Hays SA, Khodaparast N, Ruiz A, Sloan AM, Hulsey DR, Rennaker RL 2nd, Kilgard MP. The timing and amount of vagus nerve stimulation during rehabilitative training affect poststroke recovery of forelimb strength. Neuroreport. 2014 Jun 18;25(9):676-82. doi: 10.1097/WNR.0000000000000154.

  PMID: 24818637 BACKGROUND

• Hays SA, Khodaparast N, Hulsey DR, Ruiz A, Sloan AM, Rennaker RL 2nd, Kilgard MP. Vagus nerve stimulation during rehabilitative training improves functional recovery after intracerebral hemorrhage. Stroke. 2014 Oct;45(10):3097-100. doi: 10.1161/STROKEAHA.114.006654. Epub 2014 Aug 21.

  PMID: 25147331 BACKGROUND

• Hays SA, Ruiz A, Bethea T, Khodaparast N, Carmel JB, Rennaker RL 2nd, Kilgard MP. Vagus nerve stimulation during rehabilitative training enhances recovery of forelimb function after ischemic stroke in aged rats. Neurobiol Aging. 2016 Jul;43:111-8. doi: 10.1016/j.neurobiolaging.2016.03.030. Epub 2016 Apr 7.

  PMID: 27255820 BACKGROUND

• Khodaparast N, Kilgard MP, Casavant R, Ruiz A, Qureshi I, Ganzer PD, Rennaker RL 2nd, Hays SA. Vagus Nerve Stimulation During Rehabilitative Training Improves Forelimb Recovery After Chronic Ischemic Stroke in Rats. Neurorehabil Neural Repair. 2016 Aug;30(7):676-84. doi: 10.1177/1545968315616494. Epub 2015 Nov 4.

  PMID: 26542082 BACKGROUND

• Pruitt DT, Schmid AN, Kim LJ, Abe CM, Trieu JL, Choua C, Hays SA, Kilgard MP, Rennaker RL. Vagus Nerve Stimulation Delivered with Motor Training Enhances Recovery of Function after Traumatic Brain Injury. J Neurotrauma. 2016 May 1;33(9):871-9. doi: 10.1089/neu.2015.3972. Epub 2015 Aug 5.

  PMID: 26058501 BACKGROUND

• Ganzer PD, Darrow MJ, Meyers EC, Solorzano BR, Ruiz AD, Robertson NM, Adcock KS, James JT, Jeong HS, Becker AM, Goldberg MP, Pruitt DT, Hays SA, Kilgard MP, Rennaker RL 2nd. Closed-loop neuromodulation restores network connectivity and motor control after spinal cord injury. Elife. 2018 Mar 13;7:e32058. doi: 10.7554/eLife.32058.

  PMID: 29533186 BACKGROUND

• Meyers EC, Solorzano BR, James J, Ganzer PD, Lai ES, Rennaker RL 2nd, Kilgard MP, Hays SA. Vagus Nerve Stimulation Enhances Stable Plasticity and Generalization of Stroke Recovery. Stroke. 2018 Mar;49(3):710-717. doi: 10.1161/STROKEAHA.117.019202. Epub 2018 Jan 25.

  PMID: 29371435 BACKGROUND

• Engineer ND, Riley JR, Seale JD, Vrana WA, Shetake JA, Sudanagunta SP, Borland MS, Kilgard MP. Reversing pathological neural activity using targeted plasticity. Nature. 2011 Feb 3;470(7332):101-4. doi: 10.1038/nature09656. Epub 2011 Jan 12.

  PMID: 21228773 BACKGROUND

• Kimberley TJ, Pierce D, Prudente CN, Francisco GE, Yozbatiran N, Smith P, Tarver B, Engineer ND, Alexander Dickie D, Kline DK, Wigginton JG, Cramer SC, Dawson J. Vagus Nerve Stimulation Paired With Upper Limb Rehabilitation After Chronic Stroke. Stroke. 2018 Nov;49(11):2789-2792. doi: 10.1161/STROKEAHA.118.022279.

  PMID: 30355189 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.

  PMID: 26645257 BACKGROUND

• Kilgard MP, Rennaker RL, Alexander J, Dawson J. Vagus nerve stimulation paired with tactile training improved sensory function in a chronic stroke patient. NeuroRehabilitation. 2018;42(2):159-165. doi: 10.3233/NRE-172273.

  PMID: 29562561 BACKGROUND

• Darrow MJ, Mian TM, Torres M, Haider Z, Danaphongse T, Rennaker RL Jr, Kilgard MP, Hays SA. Restoration of Somatosensory Function by Pairing Vagus Nerve Stimulation with Tactile Rehabilitation. Ann Neurol. 2020 Feb;87(2):194-205. doi: 10.1002/ana.25664. Epub 2020 Jan 7.

  PMID: 31875975 BACKGROUND

• Meyers EC, Kasliwal N, Solorzano BR, Lai E, Bendale G, Berry A, Ganzer PD, Romero-Ortega M, Rennaker RL 2nd, Kilgard MP, Hays SA. Enhancing plasticity in central networks improves motor and sensory recovery after nerve damage. Nat Commun. 2019 Dec 19;10(1):5782. doi: 10.1038/s41467-019-13695-0.

  PMID: 31857587 BACKGROUND

• Darrow MJ, Torres M, Sosa MJ, Danaphongse TT, Haider Z, Rennaker RL, Kilgard MP, Hays SA. Vagus Nerve Stimulation Paired With Rehabilitative Training Enhances Motor Recovery After Bilateral Spinal Cord Injury to Cervical Forelimb Motor Pools. Neurorehabil Neural Repair. 2020 Mar;34(3):200-209. doi: 10.1177/1545968319895480. Epub 2020 Jan 22.

  PMID: 31969052 BACKGROUND

• Heck C, Helmers SL, DeGiorgio CM. Vagus nerve stimulation therapy, epilepsy, and device parameters: scientific basis and recommendations for use. Neurology. 2002 Sep 24;59(6 Suppl 4):S31-7. doi: 10.1212/wnl.59.6_suppl_4.s31.

  PMID: 12270966 BACKGROUND

• Agnew WF, McCreery DB, Yuen TG, Bullara LA. Histologic and physiologic evaluation of electrically stimulated peripheral nerve: considerations for the selection of parameters. Ann Biomed Eng. 1989;17(1):39-60. doi: 10.1007/BF02364272.

  PMID: 2537589 BACKGROUND

• Hays SA, Adehunoluwa EA, Epperson JD, Malley KM, Porter AL, Gallaway HL, Swank C, Carrera AJ, Stevens C, Gillespie J, Arnold D, Kian S, Bynum ZS, Meyers EC, Bleker N, Naftalis RC, Foreman ML, Hamilton RG, Rennaker RL, Kilgard MP, Wigginton JG. Closed-Loop Vagus Nerve Stimulation Delivered With a Miniaturized System Produces Lasting Recovery in Individuals With Chronic Stroke. Stroke. 2026 Jan;57(1):38-49. doi: 10.1161/STROKEAHA.125.052937. Epub 2025 Oct 7.

  PMID: 41054846 DERIVED

MeSH Terms

Conditions

Stroke; Paresis; Ischemic Stroke; Hemorrhagic Stroke

Interventions

Vagus Nerve Stimulation

Condition Hierarchy (Ancestors)

Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Electric Stimulation Therapy; Therapeutics

Study Officials

• Michael Kilgard, PhD

  The University of Texas at Dallas

  PRINCIPAL INVESTIGATOR

• Robert Rennaker, PhD

  The University of Texas at Dallas

  PRINCIPAL INVESTIGATOR

• Seth Hays, PhD

  The University of Texas at Dallas

  STUDY DIRECTOR

• Jane Wigginton, MD

  University of Texas Southwestern Medical Center

  PRINCIPAL INVESTIGATOR

• Rita Hamilton, DO

  Baylor Scott & White Institute for Rehabilitation

  PRINCIPAL INVESTIGATOR

• Michael Foreman, MD, FACS

  Baylor Health Care System

  STUDY DIRECTOR

• Richard Naftalis, MD, FAANS, FACS

  Baylor Health Care System

  STUDY DIRECTOR

• Mark Powers, PhD

  Baylor Health Care System

  STUDY DIRECTOR

• Ann Marie Warren, PhD

  Baylor Health Care System

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: DEVICE FEASIBILITY
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Prospective, double blind, randomized placebo controlled, plus open-label extension

Study Record Dates

• First Submitted: August 18, 2020
• First Posted: September 1, 2020
• Study Start: September 1, 2021
• Primary Completion (Estimated): February 25, 2027
• Study Completion (Estimated): February 25, 2027
• Last Updated: April 23, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)