Abstract 1: Vagus Nerve Stimulation Paired With Rehabilitation For Upper Limb Motor Function After Ischaemic Stroke: Sub-group Analysis Of The Randomised, Blinded, Pivotal, Vns-Rehab Device Trial.

Background: Vagus Nerve Stimulation (VNS) paired with rehabilitation improved upper extremity impairment and function in a recent pivotal, randomised, blinded, sham-controlled trial. Here we report post-hoc sub-group analyses from the VNS Rehab trial. We aimed to determine whether treatment effects were consistent across subgroups. Methods: VNS Rehab included 108 participants with moderate to severe arm /hand weakness, at least nine months after ischaemic stroke. They were randomised to receive rehabilitation paired with active VNS or rehabilitation paired with sham stimulation (Control). The primary outcome was the change in iFugl-Meyer Assessment Upper Extremity (FMA-UE) score on the first day after completion of in-clinic therapy. The trial was registered on ClinicalTrials.gov (NCT03131960). We explored the effect of VNS treatment by sex (n=70 males; n=38 females), age (≤ 65 or >65 years)), time from stroke (median time, 2 years) and baseline FMA-UE score (<=33 severe, >33 moderate). We assessed whether there was any interaction with treatment. No hypotheses were specified prior to this analysis and no formal adjustment was made for multiplicity. Findings: 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). The between group difference was similar across all subgroups (figure). No significant treatment interactions were observed with baseline characteristics. Interpretation: Participants with moderate to severe arm and hand impairment after ischaemic stroke showed clinically meaningful improvements in motor impairment and function with rehabilitation paired with VNS compared to rehabilitation with sham VNS. The response appeared similar across pre-defined subgroups of interest.