Title: 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
Funder: Medical Research Council

Abstract: AIMS_x000D_ We will find out whether the effects of physiotherapy for arm recovery after stroke can be improved with a treatment called “transcutaneous Vagus nerve stimulation (TVNS)”._x000D_ _x000D_ BACKGROUND_x000D_ Over 15 million people suffer a stroke worldwide annually. One third are left with permanent weakness of their arm causing difficulties with daily activities. Whilst physiotherapy does help post stroke, the benefits are modest._x000D_ In a recent ground-breaking clinical trial, electrically stimulating a nerve called the Vagus nerve (VN) at the same time as the participants moved their weak arm (in physiotherapy) resulted in better arm recovery compared with physiotherapy alone. However, the electrical stimulator was surgically implanted under a general anaesthetic and the VNS was triggered by a therapist, and treatment was delivered in hospital. Consequently, the uptake of this therapy may be limited._x000D_ _x000D_ DESIGN AND METHODS_x000D_ In this trial, we will use a non-invasive way of stimulating the VN which does not involve surgery or anaesthesia. The VN has a branch that goes to the ear which can be stimulated through the skin, using a small earpiece (TVNS). In a study of 12 participants, we found that TVNS done at the same time as exercises of the stroke-affected arm led to significant improvement in arm function. Although improvements were extremely promising, larger trials with control groups (no treatment) are needed. The treatment had little or no side effects._x000D_ In this trial, we will be able to see whether TVNS combined with physiotherapy is beneficial after stroke. An new feature is a smart motion-sensor worn on the arm. This removes the need for someone else to trigger VNS on arm movement and will allow treatment at home._x000D_ We aim to include up to 243 participants, but will stop early if it appears unlikely that TVNS will work, saving money and time. We will start with 3 groups: The control group will receive self-delivered physiotherapy (1 hr/week, 5X a week) with sham TVNS (the earpiece will produce no stimulation). Of the two treatment groups, one will receive TVNS and self-delivered physiotherapy, while the other will receive TVNS during self-delivered physiotherapy and will also receive TVNS (8 hrs a day, 5X a week) while doing daily living activities. Treatment period is 12 weeks and the main outcome, improvement in arm function, will be assessed at 3 months. We will reassess participants at 6 months, to check if improvement observed at 3 months is sustained. We will also explore how the TVNS works using special brain scanning called fMRI._x000D_ _x000D_ OUTCOMES_x000D_ At the end, we will know whether TVNS combined with physiotherapy results in better arm improvement than physiotherapy. We will also know whether receiving TVNS during daily living activities is even more effective._x000D_ _x000D_ PATIENT AND PUBLIC INVOLVMENT_x000D_ Stroke survivors identified arm rehabilitation as a research priority. Our panel of stroke survivors contributed to this trial design and will be involved throughout the project.

Lay abstract: RESEARCH QUESTION: Does transcutaneous Vagus nerve stimulation (TVNS) combined with self-delivered home physiotherapy improve after stroke?_x000D_ _x000D_ 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._x000D_ _x000D_ 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._x000D_ _x000D_ 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._x000D_ 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._x000D_ _x000D_ AIMS AND OBJECTIVES: The overall aim is to determine whether TVNS paired with physiotherapy of the affected arm post-stroke improves motor function._x000D_ _x000D_ 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._x000D_ _x000D_ 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._x000D_ 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._x000D_ _x000D_ 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._x000D_ _x000D_ 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.

Research activity codes: 6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES;6.7 PHYSICAL
Health categories: STROKE