EVASION-UC
Research type
Research Study
Full title
Electrical VAgal StimulatION in Ulcerative Colitis – EVASION-UC
IRAS ID
230030
Contact name
Tamara Mogilevski
Contact email
Sponsor organisation
Queen Mary University of London
Clinicaltrials.gov Identifier
N/A, N/A
Duration of Study in the UK
1 years, 0 months, 6 days
Research summary
Research Summary
Inflammatory bowel disease (IBD) is common exerting a large personal and societal burden. For individuals, on going symptoms and side effects of treatments combine to reduce quality of life. For society, healthcare costs are considerable and are estimated to be in the order of €5 billion per year across the European Union. Many medications currently used to treat IBD are directed at reducing inflammation within the bowel. However, many of these are associated with significant side effects, can be very expensive and, for some, require admission to hospital for their administration. Therefore the development of new methods and strategies to reduce inflammation in IBD, which are not drug based, are needed.
The autonomic nervous system has two branches known as the sympathetic and parasympathetic nervous systems. The main nerve of the parasympathetic nervous system is the vagus nerve which supplies the majority of the digestive tract including its immune system. Previous studies have shown that lower vagus nerve activity is linked with increased inflammation in the digestive tract. We have recently shown in a pilot study in healthy participants that transcutaneous (applied to the skin) electrical vagal nerve stimulation can increase activity of the vagus nerve and reduce tumour necrosis factor-alpha; a key chemical (cytokine) that causes inflammation in IBD
We aim to assess the effect of transcutaneous electrical vagal nerve stimulation in reducing cytokines causing inflammation in patients with IBD. In patients with ulcerative colitis in remission, we will experimentally induce stress using a protocol that is known to increase cytokines that cause inflammation, such as tumour necrosis factors-alpha; thereby testing the effect of transcutaneous electrical vagal nerve stimulation on its ability to reduce cytokine production in comparison to dummy (placebo) stimulation. The success of this study will be a major advance in non drug treating of ulcerative colitis.
Summary of Results
There are approximately 2.5-3 million patients with inflammatory bowel disease (IBD) across Europe, with associated healthcare costs of €4.6-5.6 billion per annum. IBD is associated with a significant reduction in quality of life. Treatments directed towards modifying the inflammatory response, such as anti-tumour necrosis factor-alpha (TNF-α) agents, are expensive, can necessitate admission to hospital for their administration and can be associated with side effects. Thus, the development of a novel non-pharmacological anti-inflammatory intervention, such as electrical vagal nerve stimulation, is warranted.
This is a proof of concept study which aims to investigate whether transcutaneous vagal nerve stimulation (tVNS) is effective at reducing stress-induced inflammatory cytokine levels in patients with quiescent ulcerative colitis (UC).We conducted a prospective randomized double-blind crossover study evaluating the use of tVNS in a model of acute psychological stress in participants with quiescent UC.
Visit 1
Participants were randomized to receive either active or sham tVNS (a modified tVNS module that vibrates but does not produce an electrical stimulus, applied over the cervical vagus nerve). Participants were instructed in how to use the device. They were then allowed to return home and self-administer stimulations or sham equivalents.Visit 2
The following day they attended the lab again and received the last dose of intervention. Psychological stress test (i.e., 40 minutes IQ test with noisy music) was administered to the participants. The parasympathetic activity was evaluated at different time points by calculating root mean square of the successive differences (RMSSD), an indicator of parasympathetic activity calculated from heart rate. Moreover, venous blood was taken for assay of lipopolysaccharide (LPS) stimulated cytokine productions (TNF-α, IL6, and IL10) at different time points. The RMSSD values and LPS-stimulated cytokine values were compared between tVNS and sham groups.Visits 3 and 4
Visits 3 & 4 – after a period of no less than 4 weeks, to reduce any potential carry-over effect, subjects were crossed over and restudied to an identical protocol, receiving the alternate tVNS intervention.Results
Twelve UC patients were included in the study [male/ female = 4/8, mean age (range): 43.1 (26-72) years old].
The RMSSD was measured prior to stimulation by active or sham tVNS and taken as the patient baseline. The change in RMSSD from the baseline was then calculated at three distinct stages of the protocol. Administration with the tVNS device increased the parasympathetic activity level compared to administration with the sham device, however this difference was not found to be significant (p > 0.05). The parasympathetic activity increased from the baseline following administration of the stress protocol regardless of whether patients were stimulated with both the tVNS and sham device.The concentration of TNF- in the blood of each patient (following stimulation with LPS for 6 hours) was calculated as a percentage difference from their baseline level (before administration of active or sham tVNS) at three-time points. These time points were immediately before the acute psychological stress protocol, immediately after the psychological stress protocol and 45 minutes after the psychological stress protocol. TNF- increased by 5.9 9.4% after administration of active t-VNS. In contrast, TNF- decreased by 11.9 19.8% following sham tVNS. TNF- increased by 14.3 14.8% in the active group and by 2.0 22.6% in the sham group from baseline after administration of the stress protocol. TNF- increased to its highest point in the active group post-rest 29.9 21.2%, whilst decreasing to its lowest point -28.4 12.9% in the sham group. None of these changes were significant (p > 0.05). There is no significant difference between TNF- levels when patients were treated with active tVNS as compared to sham at any stage of the stress protocol.
The concentration of LPS-stimulated IL-6 and IL-10 in serum was calculated as a percentage change from their baseline level as described for TNF- previously. Following active tVNS, IL6 increased by 13.7 8.4% from the baseline and following sham tVNS, it decreased by 18.12 9.7% from the baseline. The concentration of IL6 then stayed close to the baseline level despite the administration of the acute psychological protocol. IL10 increased in patients when active tVNS was administered by 46.2 28.7% from the baseline. In contrast, IL10 decreased by 33.6 11.7% when sham t-VNS was administered. The acute psychological stress protocol increased the production of IL10 in patients treated with active and sham tVNS. No statistical analysis was performed to analyse whether the difference in IL6 and IL10 concentration following treatment with active or sham tVNS is significant as the sample size of five patients is too small.
REC name
London - Surrey Borders Research Ethics Committee
REC reference
18/LO/1693
Date of REC Opinion
25 Sep 2018
REC opinion
Favourable Opinion