Efficacy and mechanism evaluation of transcutaneous vagal nerve stimulation for upper limb recovery post-stroke – a randomised, controlled, multi-arm, multi-stage, adaptive design trial

RESEARCH QUESTION: Does transcutaneous Vagus nerve stimulation (TVNS) combined with self-delivered home physiotherapy improve after stroke? BACKGROUND: A third of stroke survivors are left with permanent arm weakness causing difficulties with activities of daily living (ADLs). Whilst physiotherapy post-stroke is helpful, the benefits are modest. In a recent ground-breaking clinical trial, electrically stimulating the Vagus nerve (VN) while participants moved their weak arm (in physiotherapy) resulted in better arm recovery compared with physiotherapy alone. However, the electrical stimulator was surgically implanted under general anaesthetic, the VNS was triggered by a therapist, and treatment was delivered in hospital. Consequently, the uptake of this may be limited. In this trial, we will stimulate the VN non-invasively. The VN has a branch that goes to the ear which can be stimulated transcutaneously, using an earpiece (TVNS). In a preliminary study of 12 participants, we found that TVNS combined with simultaneous exercise of the stroke-affected arm led to significant improvement in arm function. Importantly, there were little or no side effects. Although these data are extremely promising, larger trials with control groups are needed. An innovative feature of this study is that we will trigger VNS during physiotherapy by a smart motion-sensor worn on the affected arm. This will remove the need for someone else to trigger the VNS and will allow self-delivered physiotherapy and TVNS treatment at home. AIMS AND OBJECTIVES: The overall aim is to determine whether TVNS paired with physiotherapy of the affected arm post-stroke improves motor function. METHODS: We propose an innovative 3-arm 2-stage adaptive multistage adaptive design study (involving up to 243 participants) that will stop early if it appears unlikely that the TVNS approach will work. If, on the other hand, there is an indication that TVNS combined with physiotherapy could be beneficial, we will proceed to the next stage and add further participants to reach a definitive answer. We will start with 3 groups: The control group will receive self-delivered physiotherapy (1 hr/week, 5X a week) with sham TVNS. Of the two treatment groups, one will receive TVNS and self-delivered physiotherapy, while the other will receive TVNS, self-delivered physiotherapy and additionally will receive TVNS (8 hrs/day, 5X a week) while doing ADLs. Treatment period is 12 weeks and the main outcome, improvement in arm function, will be assessed at 90 days. We will reassess participants at 6 months, to see whether any improvement observed at 90 days is sustained. fMRI imaging will be used to study mechanisms of action. At the end, we will know whether TVNS combined with physiotherapy results in better arm improvement than physiotherapy alone and whether the effect is sustained at 6 months. We will also know whether receiving TVNS during ADLs is even more efficacious. TIMELINES FOR DELIVERY: The full study is 54 months. However, interim analysis will occur at 24 months. The study will stop then if it appears unlikely that TVNS is efficacious. IMPACT AND DISSEMINATION: Stroke survivors identified arm rehabilitation as a research priority. Our panel of stroke survivors contributed to this trial design. We will publish our results in peer-reviewed journals and present at conferences and to patient groups.