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.

Keywords: Vagus nerve; neuromodulation; plasticity; rehabilitation; stroke; upper limb.

© European Stroke Organisation 2019.

Figures

Figure 1.

Study flow for all stages of the VNS-REHAB trial. During the blinded phase (Stage I), after initial screening and baseline measures, all participants will be implanted with the VNS device and randomised to receive either Active or Control VNS paired with upper limb rehabilitation. Both groups will receive in-clinic therapy for six weeks, followed by home-based therapy of three months. During Stage II (unblinded), the Active VNS group will continue with home-based Active VNS until the end of the year, while the Control group will cross-over to receive the Active VNS therapy. During Stage III, participants will continue to receive home-based active VNS therapy. Assessment timepoints for the Active VNS and Control VNS groups are shown on the left and right, respectively. VNS: vagus nerve stimulation; wks: weeks; green: in-clinic active VNS; grey: in-clinic and home-based control VNS; blue: home-based Active VNS.

Figure 2.

Stage I: Enrolment, assessments, and interventions. *Optional. BDI: beck depression inventory; FMA-UE: Fugl-Meyer assessment-upper extremity; mo: months; MAL: motor activity log; MRI: magnetic resonance imaging; SIS: stroke impact scale; SS-QOL: stroke specific quality of life; VNS: vagus nerve stimulation; wks: weeks; WMFT: Wolf motor function test.

Figure 3.

Assessments and interventions. BDI: beck depression inventory; FMA-UE: Fugl-Meyer assessment-upper extremity; mo: months; MAL: motor activity log; SIS: stroke impact scale; SS-QOL: stroke specific quality of life; VNS: vagus nerve stimulation; wks: weeks; WMFT: Wolf motor function test. Note: Stages II and III: Stage II starts with a quarterly assessment for the Active VNS group three months after the end of Stage I (or 30 weeks after the start of the blinded in-clinic therapy). In contrast, the Control group starts the crossover therapy in Stage II and the therapy period will end 24 weeks after the blinded in-clinic therapy.

Figure 4.

Vagus nerve stimulation (VNS) paired with rehabilitation. (a) In-clinic rehabilitation session set-up. The therapist is shown holding the VNS trigger button which delivers a VNS pulse when the participant performs the task-specific movements (e.g. lifting a bottle). Also depicted in the figure is the wireless transmitter on the table connected to the notebook via a USB cable. When the therapist presses the VNS trigger button, the wireless transmitter sends a signal to the implanted device which in turn stimulates the left vagus nerve via a cuff electrode in the participant’s neck. Note: The therapist typically stands near the participant to help adjust tasks and difficulty level. (b) Possible mechanism for VNS paired with movement. Stimulation of the vagus nerve stimulates the deep brain cholinergic nucleus basalis and noradrenergic locus coeruleus neurons (base of green arrow). Stimulation of the vagus nerve during task-specific movements (insert) modulates activity of the motor cortex (blue and red area) in a task-specific manner.