Title: Amitriptyline at low-dose and titrated for irritable bowel syndrome as second-line treatment (The ATLANTIS study): A double-blind placebo-controlled trial
Funder: Department of Health and Social Care

Abstract: Design: Pragmatic, multi-centre, randomised, double-blind, placebo-controlled trial with internal pilot. Setting: 75 GP practices in 3 hubs. Target population: Adults with IBS symptoms despite dietary changes and first-line therapies, not currently receiving secondary care management. Inclusion criteria: >/=18 years, Rome IV IBS (any subtype), with active symptoms (IBS-SSS score >/=75) (1). Exclusion of organic diseases via GP investigation, as per NICE guidance (7, 8), with normal FBC and CRP, and negative coeliac serology. Exclusion criteria: Age >60 with no GP review, meeting NICE 2-week referral criteria (8), inflammatory bowel disease (IBD), coeliac disease, previous colorectal cancer, allergy to tricyclic antidepressants (TCAs), pregnancy/breastfeeding, suicidal thoughts, current TCA use, or contraindications to TCAs. Health technology being assessed: Amitriptyline 10mg once at night for 6 months from randomisation. Dose titration to 20-30mg, as response and side effects allow. Inert identical placebo prescribed and titrated similarly. Participants individually-randomised (1:1) using minimisation with a random component, stratified by subtype, mood scores, and hub. Measurement of costs and outcomes: From self-completed postal or web questionnaires at baseline, 12 weeks, 6, and 12 months; self-reported pill counts and central reconciliation; costs via self-report. Primary: Effect on IBS symptoms via IBS-SSS at 6 months. Secondary: IBS-SSS (at 12 weeks and 12 months), global symptom relief (at 12 weeks, 6 and 12 months), mood, acceptability of treatment, adherence to therapy, adverse events, self-reported health care use, use of other medication, secondary care referrals, quality of life, and ability to work and participate in other activities. Sample size: 518 patients provide 90% power to detect the minimal clinically important difference of 35 points on the IBS-SSS (9) between amitriptyline and placebo at 6 months (a small to moderate effect size of 0.32). This assumes a maximum IBS-SSS SD of 110 points (10, 11), 5% significance, and 20% loss to follow-up. The sample size gives at least 85% power to detect a 15% absolute difference in the key secondary outcome (global symptom relief), considered by industry and regulators as the threshold at which uptake of a drug is more likely. Analysis: Primary ITT analysis will compare 6-month IBS-SSS scores via a linear regression model adjusted for stratification variables and IBS-SSS at baseline, reported according to CONSORT. Outcomes from internal pilot participants will be included in final analysis. Qualitative work will explore patients’ and GPs’ experiences of treatments and trial participation. A within trial cost-effectiveness analysis, from both a UK NHS and Personal Social Services and a societal perspective, with QALYs as the outcome measure. Difference between current and planned care pathways: Addition of amitriptyline or placebo to GP’s usual treatment. Project timetable: 47 months duration 10 months set-up (screen from month 8) 19 months recruitment (includes 6-month internal pilot) 12 months follow-up 6 months analysis, write-up, dissemination. Expertise in team: Gastroenterology, primary care, psychiatry, statistics, health economics, trial design and delivery, qualitative research, PPI. Feedback from previous applications has consistently pointed out this is a very strong team of applicants.

Lay abstract: Aims: We want to find out whether a tablet called amitriptyline helps people with irritable bowel syndrome (IBS). Amitriptyline will be prescribed by a GP, at a low dose, when other treatments (e.g. changes to diet) have not worked. We are interested in its effect on both the symptoms of IBS, costs of managing it, and whether use of amitriptyline in people with IBS is likely to offer value for money to the NHS. Background: About 1 in 10 people report on-going tummy pain or bloating and changes in bowel habit. These are typical symptoms of IBS. IBS is a long-term condition. It causes discomfort and distress, reducing people’s quality of life. There is no cure and it can be difficult to treat. IBS is also expensive, because people often visit their GP, take time off work, or need to see specialists. Amitriptyline can be used to treat IBS at a low dose. Amitriptyline is also used in higher doses to treat depression. We believe it helps with IBS because it relieves pain and changes bowel activity, rather than because it affects mood. Small studies of amitriptyline have shown promising results and guidelines suggest trying it when people with IBS have ongoing symptoms. We are unsure whether the drug benefits people with IBS who are looked after by their GP, as there has been no large study. The research: GPs will invite people who have tried other treatments (such as fibre supplements or anti-spasm tablets), but still have IBS symptoms, to take part. We will check that people are suitable by doing a telephone questionnaire and blood tests at their GP practice. People will be given either amitriptyline or dummy (placebo) tablets. A computer will randomly decide who gets which tablets. People will be asked to take the tablets for 6 months, in addition to their GP’s usual treatment for IBS. They will also get an advice sheet about the role of diet in IBS. People will not be aware which treatment they get. After 6 months participants will be able to continue the treatment, if they wish. We will follow people up at 12 weeks, and 6 and 12 months. We will ask people to fill out questionnaires about their IBS symptoms, mood, and, quality of life. We will look at how many prescriptions for other drugs have been given to people, and how many tests or referrals have been asked for by their GP. We will also record any side effects and problems during treatment. As we will need over 500 people, the study will take place across 75 UK general practices. We will also interview participants and GPs about their experience of being in the trial. Patient and public involvement: We have involved patients in the development of this grant application. Specifically, we have a co-applicant with experience of IBS, and have worked with an IBS support group. We will continue to collaborate closely with both if the study is funded. The team: We are a team of doctors, researchers, and patients. Together we have expertise in IBS, long-term conditions, and carrying out similar research studies. The research will be run by a clinical trials research unit with experience in carrying out large scale studies. Dissemination: We will publish the results in academic journals and present them at conferences. We will also feedback to all GPs involved in the study. We plan to hold a public involvement workshop towards the end of the study to discuss how to share findings with our study participants and the general public in an accessible way.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: ORAL AND GASTROINTESTINAL