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Study protocol for a pivotal randomised study assessing vagus nerve stimulation during rehabilitation for improved upper limb motor function after stroke.

ABSTRACT: Background:Vagus nerve stimulation (VNS) paired with a motor task improves motor outcome in rat stroke models. It is hypothesised that VNS delivered during rehabilitation will improve upper limb function compared to control rehabilitation therapy. Two pilot clinical studies demonstrated acceptable safety and feasibility of VNS paired with rehabilitation for improved upper limb function after stroke. Participants who received rehabilitation paired with VNS demonstrated clinically meaningful improvements in motor function that exceed gains seen among controls who received similar rehabilitation without VNS. These preliminary data support a larger pivotal trial. Methods:VNS-REHAB (VNS-Rehabilitation) is a pivotal, multi-site, double-blinded, randomised trial designed to evaluate safety and efficacy of VNS paired with upper limb rehabilitation after ischaemic stroke. The study will include up to 120 participants with upper limb weakness due to stroke nine months to 10 years prior. All participants will be implanted with a VNS device and randomised to receive either Active (0.8 mA) or Control VNS (0.0 mA) paired with upper limb rehabilitation. All participants receive 18 sessions of in-clinic therapy for six weeks, followed by a home-based therapy for three months. The rehabilitation therapy involves progressive, functionally based and intensive practice of hand and arm tasks. VNS is delivered during each movement repetition. After blinded follow-up is completed, the Active vagus nerve stimulation group continues with home-based Active VNS and the Control group receive six weeks of in-clinic therapy with Active VNS followed by home-based Active VNS. The primary efficacy endpoint will be the difference in Fugl-Meyer assessment-upper extremity scores between the Active VNS and Control VNS groups at the end of six weeks of in-clinic therapy. Additional secondary endpoints will also be measured. Safety will be assessed with analysis of adverse events and device complications during study participation. Discussion:This pivotal trial will determine whether VNS paired with rehabilitation is a safe and effective treatment for improving arm function after stroke.Trial Registration: ClinicalTrials.gov, NCT03131960. Registered on 27 April 2017.

SUBMITTER: Kimberley TJ

PROVIDER: S-EPMC6921938 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Study protocol for a pivotal randomised study assessing vagus nerve stimulation during rehabilitation for improved upper limb motor function after stroke.

Kimberley Teresa J TJ Prudente Cecília N CN Engineer Navzer D ND Pierce David D Tarver Brent B Cramer Steven C SC Dickie David Alexander DA Dawson Jesse J

European stroke journal 20190617 4

<h4>Background</h4>Vagus nerve stimulation (VNS) paired with a motor task improves motor outcome in rat stroke models. It is hypothesised that VNS delivered during rehabilitation will improve upper limb function compared to control rehabilitation therapy. Two pilot clinical studies demonstrated acceptable safety and feasibility of VNS paired with rehabilitation for improved upper limb function after stroke. Participants who received rehabilitation paired with VNS demonstrated clinically meaningf ...[more]

PMID: 31903435

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Project description:BackgroundLong-term loss of arm function after ischaemic stroke is common and might be improved by vagus nerve stimulation paired with rehabilitation. We aimed to determine whether this strategy is a safe and effective treatment for improving arm function after stroke.MethodsIn this pivotal, randomised, triple-blind, sham-controlled trial, done in 19 stroke rehabilitation services in the UK and the USA, participants with moderate-to-severe arm weakness, at least 9 months after ischaemic stroke, were randomly assigned (1:1) to either rehabilitation paired with active vagus nerve stimulation (VNS group) or rehabilitation paired with sham stimulation (control group). Randomisation was done by ResearchPoint Global (Austin, TX, USA) using SAS PROC PLAN (SAS Institute Software, Cary, NC, USA), with stratification by region (USA vs UK), age (≤30 years vs >30 years), and baseline Fugl-Meyer Assessment-Upper Extremity (FMA-UE) score (20-35 vs 36-50). Participants, outcomes assessors, and treating therapists were masked to group assignment. All participants were implanted with a vagus nerve stimulation device. The VNS group received 0·8 mA, 100 μs, 30 Hz stimulation pulses, lasting 0·5 s. The control group received 0 mA pulses. Participants received 6 weeks of in-clinic therapy (three times per week; total of 18 sessions) followed by a home exercise programme. The primary outcome was the change in impairment measured by the FMA-UE score on the first day after completion of in-clinic therapy. FMA-UE response rates were also assessed at 90 days after in-clinic therapy (secondary endpoint). All analyses were by intention to treat. This trial is registered at ClinicalTrials.gov, NCT03131960.FindingsBetween Oct 2, 2017, and Sept 12, 2019, 108 participants were randomly assigned to treatment (53 to the VNS group and 55 to the control group). 106 completed the study (one patient for each group did not complete the study). On the first day after completion of in-clinic therapy, the mean FMA-UE score increased by 5·0 points (SD 4·4) in the VNS group and by 2·4 points (3·8) in the control group (between group difference 2·6, 95% CI 1·0-4·2, p=0·0014). 90 days after in-clinic therapy, a clinically meaningful response on the FMA-UE score was achieved in 23 (47%) of 53 patients in the VNS group versus 13 (24%) of 55 patients in the control group (between group difference 24%, 6-41; p=0·0098). There was one serious adverse event related to surgery (vocal cord paresis) in the control group.InterpretationVagus nerve stimulation paired with rehabilitation is a novel potential treatment option for people with long-term moderate-to-severe arm impairment after ischaemic stroke.FundingMicroTransponder.

Project description:Background: Repetitive peripheral nerve sensory stimulation (RPSS) has emerged as a potential adjuvant strategy to motor training in stroke rehabilitation. The aim of this study is to test the hypothesis that 3 h sessions of active RPSS associated with functional electrical stimulation (FES) and task-specific training (TST) distributed three times a week, over 6 weeks, is more beneficial to improve upper limb motor function than sham RPSS in addition to FES and TST, in subjects with moderate to severe hand motor impairments in the chronic phase (>6 months) after stroke. Methods: In this single-center, randomized, placebo controlled, parallel-group, double-blind study we compare the effects of 18 sessions of active and sham RPSS as add-on interventions to FES and task-specific training of the paretic upper limb, in 40 subjects in the chronic phase after ischemic or hemorrhagic stroke, with Fugl-Meyer upper limb scores ranging from 7 to 50 and able to voluntarily activate any active range of wrist extension. The primary outcome measure is the Wolf Motor Function Test (WMFT) after 6 weeks of treatment. The secondary outcomes are the WMFT at 3, 10, and 18 weeks after beginning of treatment, as well as the following outcomes measured at 3, 6, 10, and 18 weeks: Motor Activity Log; active range of motion of wrist extension and flexion; grasp and pinch strength in the paretic and non-paretic sides (the order of testing is randomized within and across subjects); Modified Ashworth Scale; Fugl-Meyer Assessment-Upper Limb in the paretic arm; Barthel Index; Stroke Impact Scale. Discussion: This project represents a major step in developing a rehabilitation strategy with potential to have impact on the treatment of stroke patients with poor motor recovery in developing countries worldwide. The study preliminarily evaluates a straightforward, non-invasive, inexpensive intervention. If feasibility and preliminary efficacy are demonstrated, further investigations of the proposed intervention (underlying mechanisms/ effects in larger numbers of patients) should be performed. Trial Registration: NCT02658578.

Project description:Implanted vagus nerve stimulation (VNS) delivered concurrently with upper limb rehabilitation has been shown to improve arm function after stroke. Transcutaneous auricular VNS (taVNS) offers a non-invasive alternative to implanted VNS and may provide similar therapeutic benefit. There is much discussion about the optimal approach for combining VNS and physical therapy, as such we sought to determine whether taVNS administered during robotic training, specifically delivered during the premotor planning stage for arm extension movements, would confer additional motor improvement in patients with chronic stroke. Thirty-six patients with chronic, moderate-severe upper limb hemiparesis (>6 months; mean Upper Extremity Fugl-Meyer score = 25 ± 2, range 13-48), were randomized to receive 9 sessions (1 h in length, 3x/week for 3 weeks) of active (N = 18) or sham (N = 18) taVNS (500 ms bursts, frequency 30 Hz, pulse width 0.3 ms, max intensity 5 mA, ∼250 stimulated movements per session) delivered during robotic training. taVNS was triggered by the onset of a visual cue prior to center-out arm extension movements. Clinical assessments and surface electromyography (sEMG) measures of the biceps and triceps brachii were collected during separate test sessions. Significant motor improvements were measured for both the active and sham taVNS groups, and these improvements were robust at 3 month follow-up. Compared to the sham group, the active taVNS group showed a significant reduction in spasticity of the wrist and hand at discharge (Modified Tardieu Scale; taVNS = -8.94% vs. sham = + 2.97%, p < 0.05). The EMG results also demonstrated significantly increased variance for the bicep peak sEMG amplitude during extension for the active taVNS group compared to the sham group at discharge (active = 26.29% MVC ± 3.89, sham = 10.63% MVC ± 3.10, mean absolute change admission to discharge, p < 0.01), and at 3-month follow-up, the bicep peak sEMG amplitude was significantly reduced in the active taVNS group (P < 0.05). Thus, robot training improved the motor capacity of both groups, and taVNS, decreased spasticity. taVNS administered during premotor planning of movement may play a role in improving coordinated activation of the agonist-antagonist upper arm muscle groups by mitigating spasticity and increasing motor control following stroke. Clinical Trial Registration: www.ClinicalTrials.gov, identifier (NCT03592745).

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Study protocol for a pivotal randomised study assessing vagus nerve stimulation during rehabilitation for improved upper limb motor function after stroke.

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Study protocol for a pivotal randomised study assessing vagus nerve stimulation during rehabilitation for improved upper limb motor function after stroke.

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