Title: TRAnscutaneous vagal Nerve Stimulation to reduce Ileus: A feasibility sTudy (TRANSIT)
Funder: Department of Health and Social Care

Abstract: BackgroundIleus occurs in 10-20% of patients undergoing major colorectal surgery and is distressing. It is characterised by a delayed return of normal bowel function, leading to painful abdominal distension, persistent vomiting, and delayed faecal elimination which may last up to 10 days. Once regarded as an inevitable consequence of surgery, ileus is now recognised as a research priority by several professional organisations in the United Kingdom. Recent evidence has identified intestinal inflammation as the main mechanism in its development and this may be modulated through electrical stimulation of the vagus nerve. This currently requires invasive access to the cervical or abdominal vagus nerve, which is unacceptable in clinical practice. Transcutaneous (non-invasive) vagus nerve stimulation using a patient-administered device called GammaCore may be a more acceptable approach. Aims & ObjectivesThe study aim is to determine the feasibility of performing a definitive randomised-controlled trial (RCT) of patient-administered, transcutaneous vagus nerve stimulation to reduce ileus after colorectal surgery. The study objectives are to conduct and report three inter-related studies to inform its design: A feasibility RCT to define a protocol, estimate critical trial parameters, and determine compliance to the GammaCore intervention schedule and key trial processes. A mechanistic sub-study to determine the role of inflammatory biomarkers and small bowel motility (measured using a novel imaging technique) as indicators of treatment response A qualitative sub-study to explore patients' acceptability of the GammaCore device, the intervention schedule, and study design. MethodsA single-centre, feasibility, randomised, sham-controlled, blinded, trial (IDEAL Stage 2b) randomising patients between four active and sham stimulation schedules. Participants will receive training on GammaCore during a preoperative study visit. They will self-administer the active or sham device five days before surgery (at home) and five days after surgery (in hospital). Recovery of bowel function will be determined through daily clinical enquiry. Blood and peritoneal fluid samples drawn pre- and postoperatively will be submitted for analysis of inflammatory cytokines (TNF-alpha, Interleukin (IL) 1-beta and IL6). Bowel motility will be assessed at baseline and postoperatively using magnetic resonance enterography in a sub-cohort of participants. Participants' acceptability of the GammaCore device, the intervention schedule, and study design will be explored using semi-structured interviews and analysed using a framework approach.Timelines for deliveryA supervisory group and patient advisory group will be established. In the first five months, the trial protocol will be prepared and NHS ethics approval will be sought. Recruitment to the feasibility RCT, mechanistic and qualitative sub-studies will take place between months six and 30. Dissemination, public engagement and write up of the final report will take place in the final six months.Anticipated Impact & DisseminationThe results will be disseminated to the scientific community in peer-reviewed journals and to study participants as visual abstracts. The findings will be disseminated to relevant collaborators and stakeholders via the NIHR Healthcare Technology Cooperative in Colorectal Therapies. A favourable outcome may support the design of a definitive RCT and wider implementation of transcutaneous vagus nerve stimulation for preventing ileus in the subsequent five years.

Lay abstract: Background to the researchIn the United Kingdom, 30,000 bowel operations are done each year. Most patients recover well before leaving hospital, but one-in-five develop a condition called ileus. This is where the bowel 'goes to sleep' after surgery. It causes vomiting, bloating and pain, and increases the length of hospital stay. Some patients need treatment with a tube placed through the nose into the stomach (nasogastric tube), which is distressing. A new device (called GammaCore) aims to prevent ileus before it occurs by stimulating nerves that supply the bowel. It is a simple, hand-held, electrical device that is used by patients at home and in hospital. This could provide a much-needed solution to ileus and improve patients' experience after bowel surgery.Aims of the researchThis research will provide important information about GammaCore, our research methods, and why ileus occurs. These have to be tested in a small study (a 'feasibility' study) before the device can be tested on a larger scale. The feasibility study will not give a final answer, but it will help us to design a larger study capable of improving care for thousands of patients each year.Design and methods usedWe will invite patients who are due to have bowel surgery to take part. Following a period of training, they will use GammaCore before surgery (at home) and after surgery (in hospital) for five days. This is done by applying the device gently on the neck for two minutes in the morning and at night. Some patients will receive an active device and others will receive a 'dummy' device. Both look and feel the same but only the active device stimulates the nerves. The groups are chosen at random and patients will be unaware which device they are using. This is important to make sure the study is reliable.During the study, blood tests will be taken before and after surgery. We will measure markers in the blood that may help us to decide how well GammaCore works. All patients will be asked about their bowel function daily whilst in hospital. In a small group of patients, bowel function will also be measured using a MRI scan before and after surgery. This takes pictures of the bowel without using radiation. At the end of the study we will invite patients to talk to us about their experiences of GammaCore and taking part in the study. This will help us to improve our methods in the future.Patient and public involvementAs GammaCore is a self-administered device, patient and public involvement is important at each stage of the research. Focus groups and discussions with patients who have had bowel surgery in the past have helped to design this research to date.We will set up a patient advisory group, including 4-6 patients who have used GammaCore previously. This group will meet six times over three years. They will help to design and test study materials (such as device training resources) and provide feedback on how the study is run. A member of the public will also join the study's Supervisory Group, which will meet regularly. They will have an equal voice in managing the study, and will lead the patient advisory group meetings.DisseminationThe results will be sent to patients who were involved in the study in the form of visual summaries. The results will also be communicated to scientific audiences through academic journals and conferences. We will approach key stakeholders, such as patient charities, professional organisations and NHS commissioners to discuss how we can use the results in the future.

Research activity codes: 6.3 MEDICAL DEVICES;6.4 SURGERY
Health categories: ORAL AND GASTROINTESTINAL