A Trial of Rehabilitation Paired with VNS for Motor Function in Patients with Stroke (Repair Study)

A Multi-Center, Triple-Blind, Randomized, Sham-Controlled Trial Assessing the Efficacy and Safety of Rehabilitation Paired with Vagus Nerve Stimulation for Upper Extremity Motor Function in Patients with Ischemic Stroke (Repair Study)

The goal of this clinical trial is to investigate the efficacy and safety of vagus nerve stimulation (VNS) paired with rehabilitation for enhancing upper extremity motor function after ischemic stroke.

Researchers will compare the outcomes of active VNS paired with rehabilitation against sham VNS (the actual intensity is 0 mA) also paired with rehabilitation, in order to assess improvements in arm motor function post-stroke.

Participants in this study will undergo a surgical procedure to implant the VNS system and will subsequently recieve a 6 weeks in-clinic therapy, followed by an additional 6 weeks home exercise. During the final 6 weeks, participants will either recieve in-clinic therapy or maintain their home exercise, depending on their assigned group.

Study Overview

• Status: Recruiting
• Conditions: Ischemic Stroke; Upper Extremity Paresis
• Intervention / Treatment: Device: VNS; Other: Rehabilitation; Device: Sham VNS

Detailed Description

There are 6 follow-up timepoints in this trial:

1. Screening follow-up timepoint (V1): All participants will sign the informed consent form and receive pre-implant evaluation, including physical examination, brain magnetic resonance imaging, FMA-UE, WMFT, modified Ashworth sacle, BDI, ect.
2. Surgery follow-up timepoint (V2):All participants will be implanted with the VNS system, including the G115R IPG and L312 lead.
3. Baseline follow-up timepoint (V3): There is a baseline evaluation 7 to 14 days after the surgery, then participants will be randomly assigned to VNS group or Control group. The randomization will be stratified by baseline FMA-UE (20 to 35, 36 to 50), age (<50, ≥50) and research center (south centers, north centers).
4. Clinic rehabilitation follow-up timepoint (V4): Participants will receive standard clinic rehabilitation 3 days per week and lasting 6 weeks. Active VNS (VNS group) or sham VNS (Control group) will be paired with rehabilitation. Participants will be evaluated at the last day of this follow-up timepoint.
5. Home exercise follow-up timepoint (V5): Participants will take standard home exercise everyday in 6 weeks. Active VNS (VNS group) or sham VNS (Control group) will be paired with rehabilitation. At the last day, after evaluating, group assignment is unblinded.
6. Unmasking follow-up timepoint (V6): In this 6 weeks, all participants will receive active VNS. Participants in VNS group will still take standard home exercise, and participants in Control group will receive standard clinic rehabilitation again. Participants will be also evaluated at the last day of this follow-up timepoint.

• Study Type: Interventional
• Enrollment (Estimated): 99
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Jianguang Sun; Phone Number: 010-60736388; Email: sunjianguang@pinsmedical.com
• Study Contact Backup: Name: Baichuan He; Phone Number: 18310971061; Email: hebaichuan@pinsmedical.com

Study Locations

• China
  • Anhui
    • Hefei, Anhui, China, 230022
      • Not yet recruiting
      • The First Affiliated hospital of USTC
  • Beijing
    • Beijing, Beijing, China, 100000
      • Recruiting
      • Beijing Tiantan Hospital, Capital Medical University
      • Contact: Yingchuan Chen; Phone Number: 18612257476
    • Beijing, Beijing, China, 100039
      • Not yet recruiting
      • Chinese People's Liberation Army General Hospital
  • Chongqing
    • Chongqing, Chongqing, China, 400037
      • Not yet recruiting
      • The Xin Qiao Hospital of Army Medical University
  • Fujian
    • Fuzhou, Fujian, China, 350004
      • Recruiting
      • The First Affiliated Hospital of Fujian Medical University
  • Guangdong
    • Guangzhou, Guangdong, China, 510260
      • Recruiting
      • Zhujiang Hospital of Southern Medical University
  • Guangxi
    • Nanning, Guangxi, China, 530012
      • Recruiting
      • Jiangbin Hospital of Guangxi Zhuang Autonomous Region
  • Hubei
    • Wuhan, Hubei, China, 430030
      • Recruiting
      • Tongji Hospital Tongji Medical College Of Hust
      • Contact: Min Lu; Phone Number: 13971268939
      • Contact: Feng Hu; Phone Number: 18871495411
  • Hunan
    • Changsha, Hunan, China, 410000
      • Not yet recruiting
      • Brain Hospital of Hunan Province The Second People's Hospital of Hunan Province
  • Jiangsu
    • Nanjing, Jiangsu, China, 210008
      • Not yet recruiting
      • Nanjing Drum Tower Hospital The Affiliated Hospital of Nanjing University Medical School
  • Jiangxi
    • Nanchang, Jiangxi, China, 330006
      • Not yet recruiting
      • The First Affiliated Hospital of NanChang University
  • Jilin
    • Changchun, Jilin, China, 130021
      • Recruiting
      • The First Bethune Hospital of Jilin University
  • Shandong
    • Jinan, Shandong, China, 250012
      • Not yet recruiting
      • Qilu Hospital of Shandong University
  • Shanghai
    • Shanghai, Shanghai, China, 200040
      • Recruiting
      • Huashan Hospital, Fudan University
      • Contact: Qi Yue; Phone Number: 16628702867
  • Sichuan
    • Chengdu, Sichuan, China, 618099
      • Not yet recruiting
      • West China Hospital, Sichuan University
  • Yunnan
    • Kunming, Yunnan, China, 650032
      • Recruiting
      • The First Affiliated Hospital of Kunming Medical University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age ≥22 years and <80 years, all gender is acceptable.
2. History of unilateral supratentorial ischemic stroke ≥ 9 months but < 10 years.
3. Upper Extremity motor section of the Fugl-Meyer Assessment score ≥20 and ≤50.
4. Right- or left-sided weakness of upper extremity.
5. Ability to communicate, understand, and give appropriate consent. Subjects can follow trial commands.
6. Subjects have good compliance and can complete the visits after surgery.

Exclusion Criteria:

1. History of hemorrhagic stroke.
2. Presence of ongoing dysphagia or aspiration difficulties.
3. Prior injury to vagus nerve, either bilateral or unilateral.
4. Subject receiving medication that may significantly interfere with actions of VNS on neurotransmitter systems at study entry, clinic rehabilitation follow-up timepoint, or home rehabilitation follow-up timepoint, such as centrally acting cholinoceptor blockers, centrally acting adrenoceptor blockers, norepinephrine re-uptake inhibitors, etc.
5. Botox injections within 4 weeks prior to enrollment through the unmasking follow-up timepoint (Visit 6).
6. Severe spasticity of the upper extremity (Modified Ashworth ≥ 3).
7. Significant sensory loss of the upper extremity (Upper Extremity sensory section of the Fugl-Meyer Assessment score < 6).
8. Severe depression (Beck Depression Scale > 29).
9. Current requirement, or likely future requirement, of diathermy.
10. Current use of any other stimulation device, such as a pacemaker or other neurostimulator.
11. Pregnancy or plans to become pregnant or to breastfeed during the study period.
12. Participated in any other clinical trials within the preceding 3 months.
13. Not considered to be applicable by the investigator.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: VNS group; Active VNS paired with rehabilitation	Device: VNS; An neuromodulation treatment that delivers electrical impulses to the brain via the vagus nerve.; Other: Rehabilitation; Rehabilitation movements to improve upper limb function after stroke.
Active Comparator: Control group; Sham VNS paired with rehabilitation	Other: Rehabilitation; Rehabilitation movements to improve upper limb function after stroke.; Device: Sham VNS; An neuromodulation treatment that delivers electrical impulses to the brain via the vagus nerve, the actual intensity is 0 mA.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Upper Extremity Motor Section of the Fugl-Meyer Assessment (FMA-UE) Average Change	The FMA-UE is a common scale used to measure motor impairment after a stroke. The range is 0 (more impairment) to 66 (no impairment). The FMA-UE will be analyzed for difference in average change at Clinic rehabilitation follow-up timepoint compared to Baseline follow-up timepoint (Difference in average change in FMA-UE from V3 to V4).	V4, 6 weeks after Baseline follow-up timepoint

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Upper Extremity Motor Section of the Fugl-Meyer Assessment (FMA-UE) Response	The Upper Extremity Motor Section of the Fugl-Meyer Assessment (FMA-UE) Response is the percent of patients with a 6 point or greater improvement on the FMA-UE.	V4, 6 weeks after Baseline follow-up timepoint; V5, 6 weeks after Clinic rehabilitation follow-up timepoint
Upper Extremity Motor Section of the Fugl-Meyer Assessment (FMA-UE) Average Change	The FMA-UE is a common scale used to measure motor impairment after a stroke. The range is 0 (more impairment) to 66 (no impairment).	V5, 6 weeks after Clinic rehabilitation follow-up timepoint; V6, 6 weeks after Home exercise follow-up timepoint
Wolf Motor Function Test (WMFT) Average Change	The Wolf Motor Function Test (WMFT) is an assessment scale of upper extremity functional level after stroke. The functional assessment range is an average of 15 sub-items with a range from 0 to 5, with 0 (meaning did not attempt) to 5 (meaning normal).	V4, 6 weeks after Baseline follow-up timepoint; V5, 6 weeks after Clinic rehabilitation follow-up timepoint; V6, 6 weeks after Home exercise follow-up timepoint
Wolf Motor Function Test (WMFT) Response	Wolf Motor Function Test (WMFT) Response is the percent of patients with a 0.4 point or greater improvement on the WMFT.	V4, 6 weeks after Baseline follow-up timepoint; V5, 6 weeks after Clinic rehabilitation follow-up timepoint
Beck Depression Inventory (BDI) Average Change	The Beck Depression Inventory (BDI) is a self-report questionnaire used to identify overt behavioral characteristics of depression. Items are scored on a 4-point scale that ranges from 0 to 3. Ratings are summed to provide a total score ranging from 0 to 63.	V6, 6 weeks after Home exercise follow-up timepoint
Montreal Cognitive Assessment (MoCA) Average Change	MoCA is designed to assess cognitive function in patients. It assesses a number of different cognitive domains, including visuospatial and executive function, naming, memory, attention, language, abstraction, delayed recall, and orientation. The total score is 30, with higher scores indicating better cognitive function.	V4, 6 weeks after Baseline follow-up timepoint; V5, 6 weeks after Clinic rehabilitation follow-up timepoint; V6, 6 weeks after Home exercise follow-up timepoint
Motor Activity Log (MAL) Average Change	The Motor Activity Log (MAL) consists of 30 activities of daily living such as using a towel, brushing teeth, and picking up a glass. The individual is asked to rate how often and how well each activity was performed with the more impaired arm. The response scale ranges from zero (never used) to 5 (same as pre-stroke)	V4, 6 weeks after Baseline follow-up timepoint; V5, 6 weeks after Clinic rehabilitation follow-up timepoint; V6, 6 weeks after Home exercise follow-up timepoint
Stroke impact scale (SIS) Average Change	The Stroke Impact Scale (SIS) is a self-reported measure of stroke outcomes. Each item is selfrated on a 5-point Likert scale in terms of the difficulty the person has experienced in completing them after the score.	V4, 6 weeks after Baseline follow-up timepoint; V5, 6 weeks after Clinic rehabilitation follow-up timepoint; V6, 6 weeks after Home exercise follow-up timepoint
EQ-5D-3L Average Change	The EQ-5D-3L is a general measure of health outcomes in any population. It is a self-report questionnaire which provides a simple descriptive profile and a single index value for health status.	V4, 6 weeks after Baseline follow-up timepoint; V5, 6 weeks after Clinic rehabilitation follow-up timepoint; V6, 6 weeks after Home exercise follow-up timepoint
Incidence of Adverse Events	The incidence of adverse events occurred during the clinical trial, whether or not related to the device.	V4, 6 weeks after Baseline follow-up timepoint; V5, 6 weeks after Clinic rehabilitation follow-up timepoint; V6, 6 weeks after Home exercise follow-up timepoint

Collaborators and Investigators

• Sponsor: Beijing Pins Medical Co., Ltd

Publications and helpful links

General Publications

• Walker-Batson D, Curtis S, Natarajan R, Ford J, Dronkers N, Salmeron E, Lai J, Unwin DH. A double-blind, placebo-controlled study of the use of amphetamine in the treatment of aphasia. Stroke. 2001 Sep;32(9):2093-8. doi: 10.1161/hs0901.095720.
• 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.
• 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.
• 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.
• 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.
• Dawson J, Liu CY, Francisco GE, Cramer SC, Wolf SL, Dixit A, Alexander J, Ali R, Brown BL, Feng W, DeMark L, Hochberg LR, Kautz SA, Majid A, O'Dell MW, Pierce D, Prudente CN, Redgrave J, Turner DL, Engineer ND, Kimberley TJ. Vagus nerve stimulation paired with rehabilitation for upper limb motor function after ischaemic stroke (VNS-REHAB): a randomised, blinded, pivotal, device trial. Lancet. 2021 Apr 24;397(10284):1545-1553. doi: 10.1016/S0140-6736(21)00475-X.
• Dawson J, Engineer ND, Prudente CN, Pierce D, Francisco G, Yozbatiran N, Tarver WB, Casavant R, Kline DK, Cramer SC, Van de Winckel A, Kimberley TJ. Vagus Nerve Stimulation Paired With Upper-Limb Rehabilitation After Stroke: One-Year Follow-up. Neurorehabil Neural Repair. 2020 Jul;34(7):609-615. doi: 10.1177/1545968320924361. Epub 2020 Jun 1.
• Bolognini N, Pascual-Leone A, Fregni F. Using non-invasive brain stimulation to augment motor training-induced plasticity. J Neuroeng Rehabil. 2009 Mar 17;6:8. doi: 10.1186/1743-0003-6-8.
• Dawson J, Engineer ND, Cramer SC, Wolf SL, Ali R, O'Dell MW, Pierce D, Prudente CN, Redgrave J, Feng W, Liu CY, Francisco GE, Brown BL, Dixit A, Alexander J, DeMark L, Krishna V, Kautz SA, Majid A, Tarver B, Turner DL, Kimberley TJ. Vagus Nerve Stimulation Paired With Rehabilitation for Upper Limb Motor Impairment and Function After Chronic Ischemic Stroke: Subgroup Analysis of the Randomized, Blinded, Pivotal, VNS-REHAB Device Trial. Neurorehabil Neural Repair. 2023 Jun;37(6):367-373. doi: 10.1177/15459683221129274. Epub 2022 Oct 13.
• Kimberley TJ, Prudente CN, Engineer ND, Pierce D, Tarver B, Cramer SC, Dickie DA, Dawson J. Study protocol for a pivotal randomised study assessing vagus nerve stimulation during rehabilitation for improved upper limb motor function after stroke. Eur Stroke J. 2019 Dec;4(4):363-377. doi: 10.1177/2396987319855306. Epub 2019 Jun 17.
• Dickie DA, Kimberley TJ, Pierce D, Engineer N, Tarver WB, Dawson J. An Exploratory Study of Predictors of Response to Vagus Nerve Stimulation Paired with Upper-Limb Rehabilitation After Ischemic Stroke. Sci Rep. 2019 Nov 4;9(1):15902. doi: 10.1038/s41598-019-52092-x.
• Hays SA, Khodaparast N, Sloan AM, Fayyaz T, Hulsey DR, Ruiz AD, Pantoja M, Kilgard MP, Rennaker RL 2nd. The bradykinesia assessment task: an automated method to measure forelimb speed in rodents. J Neurosci Methods. 2013 Mar 30;214(1):52-61. doi: 10.1016/j.jneumeth.2012.12.022. Epub 2013 Jan 23.
• Elsner B, Kugler J, Pohl M, Mehrholz J. Transcranial direct current stimulation (tDCS) for improving function and activities of daily living in patients after stroke. Cochrane Database Syst Rev. 2013 Nov 15;(11):CD009645. doi: 10.1002/14651858.CD009645.pub2.
• Plow EB, Carey JR, Nudo RJ, Pascual-Leone A. Invasive cortical stimulation to promote recovery of function after stroke: a critical appraisal. Stroke. 2009 May;40(5):1926-31. doi: 10.1161/STROKEAHA.108.540823. Epub 2009 Apr 9.
• Adkins DL, Hsu JE, Jones TA. Motor cortical stimulation promotes synaptic plasticity and behavioral improvements following sensorimotor cortex lesions. Exp Neurol. 2008 Jul;212(1):14-28. doi: 10.1016/j.expneurol.2008.01.031. Epub 2008 Feb 20.
• Barbay S, Nudo RJ. The effects of amphetamine on recovery of function in animal models of cerebral injury: a critical appraisal. NeuroRehabilitation. 2009;25(1):5-17. doi: 10.3233/NRE-2009-0495.
• Sawaki L, Butler AJ, Leng X, Wassenaar PA, Mohammad YM, Blanton S, Sathian K, Nichols-Larsen DS, Wolf SL, Good DC, Wittenberg GF. Constraint-induced movement therapy results in increased motor map area in subjects 3 to 9 months after stroke. Neurorehabil Neural Repair. 2008 Sep-Oct;22(5):505-13. doi: 10.1177/1545968308317531.
• Takahashi CD, Der-Yeghiaian L, Le V, Motiwala RR, Cramer SC. Robot-based hand motor therapy after stroke. Brain. 2008 Feb;131(Pt 2):425-37. doi: 10.1093/brain/awm311. Epub 2007 Dec 20.
• Zhang T, Zhao J, Li X, Bai Y, Wang B, Qu Y, Li B, Zhao S; Chinese Stroke Association Stroke Council Guideline Writing Committee. Chinese Stroke Association guidelines for clinical management of cerebrovascular disorders: executive summary and 2019 update of clinical management of stroke rehabilitation. Stroke Vasc Neurol. 2020 Sep;5(3):250-259. doi: 10.1136/svn-2019-000321. Epub 2020 Jun 28.

Study record dates

Study Major Dates

• Study Start (Actual): November 19, 2024
• Primary Completion (Estimated): August 1, 2025
• Study Completion (Estimated): November 1, 2025

Study Registration Dates

• First Submitted: November 10, 2024
• First Submitted That Met QC Criteria: December 4, 2024
• First Posted (Actual): December 9, 2024

Study Record Updates

• Last Update Posted (Estimated): December 10, 2024
• Last Update Submitted That Met QC Criteria: December 9, 2024
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Keywords: Rehabilitation; Stroke; Neuromodulation; Randomized Controlled Trial; Ischemic Stroke; Vagus Nerve Stimulation; Paresis; Upper Extremity Paresis
• Additional Relevant MeSH Terms: Neurologic Manifestations; Musculoskeletal Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Muscular Diseases; Neuromuscular Manifestations; Pathologic Processes; Ischemic Stroke; Stroke; Ischemia; Muscle Weakness; Paresis
• Other Study ID Numbers: G115R&PINS-C2-01-53

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No