Percutaneous Auricular Nerve Stimulation for Treating Post-COVID Fatigue (PAuSing-pCF): a single-site, single-blind, sham-controlled, randomized, interventional, crossover study protocol

BackgroundAccording to the Office for National Statistics, an estimated 2.3% of people in the UK suffer from post-COVID Fatigue (pCF) following acute COVID-19 infection. Feedback from those with pCF has highlighted the devastating impact it has on their lives and the need for novel therapeutic options. Fatigue encompasses not only the perception of increased physical effort and extreme tiredness but also cognitive/mental fatigue. As part of a previous study (Baker et al., 2023), we recently showed that fatigue in pCF correlates with dysregulation in specific components of the central, peripheral and autonomic nervous systems. The vagus nerve is a major component of the autonomic nervous system and plays an important role both in metabolic homeostasis and in inflammatory modulation. Transcutaneous auricular vagus nerve stimulation (taVNS) offers an easy and reliable approach to activating the vagus nerve non-invasively and can be self-administered safely at home. This study will probe the mechanisms of pCF in adults by testing whether taVNS self-administered using a transcutaneous electrical nerve stimulation (TENS) device can reduce symptoms of fatigue and normalise changes in the peripheral and central nervous system that are hypothesized to mediate fatigue. DesignThis will be a single-site, single-blind, sham-controlled, randomized, interventional trial in 96 people with pCF. Participants will be randomized to one of three groups, one active and two control interventions, which they will self-administer for 8 weeks. After 8 weeks everyone will crossover to the active intervention for another 8 weeks of taVNS. Ongoing levels of fatigue will be assessed using visual analogue scales and a battery of relevant questionnaires. All participants will undergo extensive electrophysiological testing at week 0, week 8 and week 16. Ambulatory data (heart rate variability, activity levels) will be collected using wearable technology. DiscussionThis study will establish whether vagus nerve dysfunction is important mechanistically in pCF and whether boosting vagus nerve activity by taVNS can not only improve symptoms of fatigue in pCF but normalise biological and behavioural correlates of fatigue in otherwise healthy members of the public with pCF. Trial registrationThis trial is prospectively registered at www.isrctn.com/ISRCTN18015802. Registered May 12, 2022.