Vagus nerve stimulation paired with rehabilitation for upper limb motor function after ischaemic stroke (VNS-REHAB): a randomised, blinded, pivotal, device trial

Abstract

Background: Long-term loss of arm function after ischaemic stroke is common and may be improved by Vagus Nerve Stimulation (VNS) paired with rehabilitation. Methods: In this pivotal, randomised, triple-blind, sham-controlled trial, we assigned participants with moderate to severe arm weakness, at least nine months after ischaemic stroke, to receive rehabilitation paired with active VNS or rehabilitation paired with sham stimulation (Control). All participants were implanted with a VNS device and received six weeks of in-clinic therapy followed by a home exercise program. The primary outcome was the change in impairment measured by the Fugl-Meyer Assessment Upper Extremity (FMA-UE) score on the first day after completion of in-clinic therapy. All analyses were by intention to treat. The trial was registered on ClinicalTrials.gov (NCT03131960). Findings: We randomised 108 participants between Oct 2, 2017 and Sept 12, 2019 (53 to VNS and 55 to Control). A total of 106 completed the study. On the first day after completion of in-clinic therapy, the mean (±SD) FMA-UE score increased by 5.0 points (SD 4.4) in the VNS group and by 2.4 points (SD 3.8) in the Control group (p=0.001, between group difference 2.6, 95% CI 1.03 to 4.2). Ninety days later, a clinically meaningful response on the FMA-UE score was achieved in 47% with VNS versus 24% in controls (p=0.01; between group difference 24%, 95% CI 6 to 41%). The Wolf Motor Function Test (WMFT) functional score increased by 0.46 (±0.40) points in the VNS group compared to 0.16 (±0.30) points in the Control group (p<0.0001, between group difference 0.30, 95% CI 0.16 to 0.43). The FMA-UE score increased by 5.8 points (±6.0) from baseline with VNS and by 2.8 points (±5.2) in controls (p=0.008, between group difference 2.96, 95% CI 0.83 to 5.08). There was one serious adverse event related to surgery (vocal cord paresis). Interpretation: Participants with moderate to severe arm impairment after ischaemic stroke showed clinically meaningful improvements in motor impairment and function with paired VNS compared to rehabilitation with sham VNS. Funding: The trial was funded by MicroTransponder Inc.