Amitriptyline at low-dose and titrated for irritable bowel syndrome as second-line treatment (The ATLANTIS study): A double-blind placebo-controlled trial
A GP will prescribe a low dose of the antidepressant amitriptyline to 518 adults with irritable bowel syndrome (IBS) whose symptoms persist after first-line treatments, to see if it provides relief where standard care has failed. IBS affects roughly one in ten people in the UK, but current second-line options are limited. Many patients continue to experience pain, bloating, and disrupted daily life despite dietary changes and first-line therapies. Low-dose tricyclic antidepressants are sometimes used off-label for IBS, but robust evidence from primary care is lacking. This trial directly tests whether amitriptyline—titrated from 10mg to 30mg nightly over six months—outperforms an identical placebo in reducing symptom severity, measured by the IBS Symptom Severity Score. If amitriptyline proves effective, GPs would have a cheap, widely available, and evidence-backed second-line treatment to offer before referring patients to specialist care. The trial also includes a cost-effectiveness analysis from both NHS and societal perspectives, so funders could assess whether the drug reduces healthcare use and improves quality of life. For patients, a positive result would mean a practical option to manage symptoms without leaving primary care.
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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.
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