Table 1 Eligibility criteria

Inclusion criteria

1. Aged ≥ 18 years with a diagnosis of IBS (of any subtype of stool pattern [diarrhoea, constipation, mixed bowel habit, or unclassified]) in their primary care record, and fulfilling the Rome IV criteria for IBS

2. Ongoing symptoms, defined as an IBS symptom severity score (IBS-SSS) score of ≥ 75 at screening, despite being offered dietary advice and first-line therapies, as defined by the NICE guideline (antispasmodics [e.g. mebeverine], fibre supplements [e.g. fybogel], laxatives [e.g. bisacodyl], or anti-diarrhoeals [e.g. loperamide]), assessed at screening via patient self-report

3. A normal haemoglobin, total white cell count, and platelets within the last 6 months prior to screening

4. A normal C-reactive protein within the last 6 months prior to screening

5. Exclusion of coeliac disease, via anti-tissue transglutaminase antibodies, as per NICE guidance

6. As amitriptyline is harmful in overdose, patients must have no evidence of active suicidal ideation, as determined by three clinical screening questions, and no recent history of self-harm (within 12 months prior to screening). All patients will be asked (1) whether they have experienced any thoughts of harming themselves, or ending their life in the last 7–10 days; (2) whether they currently have any thoughts of harming themselves or ending their life; and (3) whether they have any active plans or ideas about harming themselves, or taking their life, in the near future. These questions are used in preference to a formal suicidal risk rating scale, as such scales perform poorly in clinical practice. Any positive response on any of the questions will trigger an urgent GP review

7. If female, patients must be post-menopausal, or surgically sterile, or using highly effective contraception (and must agree to continue for 7 days after the last dose of the investigational medicinal product [IMP])

8. Able to complete questionnaires and trial assessments and to provide written informed consent

Exclusion criteria

1. Age > 60 years with no GP review in the 12 months prior to screening (a safety criterion due to the increased risk of gastrointestinal pathology > 60 years to ensure any changes in bowel habit are IBS-related and do not require further investigation)

2. Meeting locally adapted NICE 2-week referral criteria for suspected lower gastrointestinal cancer

3. A known documented diagnosis of inflammatory bowel disease or coeliac disease

4. A previous diagnosis of colorectal cancer

5. Individuals participating currently, or who have within the 3 months prior to screening been involved in, another clinical trial of an investigational medicinal product

6. Pregnancy, breastfeeding, or planning to become pregnant within the next 18 months

7. Current use of a TCA, or use of a TCA within the last 2 weeks prior to randomisation, for another indication

8. Allergy to TCAs or any other known contraindication to the use of TCAs. The latter includes taking monoamine oxidase inhibitors, or receiving them within the last 2 weeks; already receiving a TCA for the treatment of depression; previous myocardial infarction; recorded arrhythmias, particularly heart block of any degree, or prolonged Q-T interval on an ECG; mania; severe liver disease; porphyria; congestive heart failure or coronary artery insufficiency; or receiving concomitant drugs that prolong the QT interval (e.g. amiodarone. fluconazole, or terfenadine)