Recruitment

Participants were recruited between April 2011 and May 2013, with the last patient completed in August 2013. Recruitment was from IBS clinics at the investigators’ hospital, or from lists of patients who had previously taken part in research studies and had indicated that they would like to be contacted about future relevant research projects. In addition, we had, in conjunction with the local Primary Care Research Network (PCRN), approached general practitioners to ask them to search their databases for eligible participants and send out letters of invitation along with participant information sheets (PISs). Either way, the initial approach was from a member of the patient’s usual care team or from appropriately authorised research nurses. We also advertised in the local newspaper. Initial recruitment into this trial was slow, using the Rome III criteria¹ based on daily diary recordings, whereas previous studies had used reported symptoms based on recall. We felt that the eligibility criteria for IBS-D were too demanding. We therefore modified the eligible criteria for IBS-D following registration with ‘ClinicalTrials.gov’ to reflect the fact that, as others have found, the bowel habit of patients with IBS-D is less abnormal than patients’ reported symptoms suggest.⁴⁰

The patients were required to meet the modified Rome III criteria for IBS-D,¹ defined as a stool frequency of ≥ 3 per day for > 2 days per week and ≥ 25% of stools to be of types 5–7 [i.e. unlike standard Rome III criteria,¹ which state Bristol Stool Form Scale (BSFS) 6 and 7, to include stool form 5 as well] and < 25% of types 1 and 2 according to the BSFS.⁴¹ To exclude other causes of diarrhoea, we required normal colonoscopy and colonic biopsies, normal full blood count, serum calcium and albumin, C-reactive protein and negative serological test for coeliac disease. Lactose intolerance was tested by asking patients to consume 568 ml of milk per day and performing a lactose breath hydrogen test if they developed diarrhoeal symptoms within 3 hours. If the stools were watery and frequent then the patient underwent a 7-day retention of selenium-75-labelled homocholic acid taurine test or a trial of cholestyramine to exclude bile acid malabsorption. If any of these tests were positive then the patient was excluded from the study. All patients gave written consent. Another inclusion criterion was age 18–75 years. Exclusion criteria were prior history of major abdominal surgery; liver or kidney impairment; or chronic ingestion of any anti-inflammatory drugs or medications that could affect the gut motility. All childbearing female patients tested negative on the pregnancy test during the randomisation day and had to agree to adequate contraception during the trial. Patients who were on long-term selective serotonin reuptake inhibitors (SSRIs) or tricyclic antidepressants (TCAs) were included if they were on a stable dose for 3 months and undertook to maintain the dose unaltered throughout the trial. During the screening period of 2 weeks, patients were allowed a maximum of only two doses of 4 mg loperamide (Immodium^®, Janssen) per week and discontinued any IBS medication. Once randomised, patients were allowed to take loperamide to control their symptoms, as we hypothesised that mesalazine would take at least 6 weeks to exert its effect on the gut. During the last 2 weeks of the trial when the primary end points were being assessed, patients were not allowed loperamide or any antibiotics. Ethical approval was sought for any adverts or posters displayed in the relevant clinical areas. Patients were seen in the research centres in participating hospitals and enrolled by research nurses or doctors.

Patient visits and contacts are shown in Table 1.

TABLE 1

Patient visits and contacts

Inclusion criteria

1. Male or female patients, aged 18–75 years, able to give informed consent.
2. Patients should all have had a colonoscopy or sigmoidoscopy within the last 12 months to exclude microscopic or any inflammatory colitis (if not, but they have had a negative colonoscopy within 5 years and symptoms are unchanged, then a sigmoidoscopy and mucosal biopsy of the left colon would be sufficient to exclude microscopic or any inflammatory colitis).
3. Patients with IBS-D, meeting Rome III criteria¹ prior to screening phase.
4. Patients with ≥ 25% soft stools (score > 4, i.e. 5–7) and < 25% hard stools (score 1 or 2) during the screening phase, as scored by the daily symptom and stool diary.*
5. Patients with a stool frequency of ≥ 3 per day for ≥ 2 days per week during the screening phase.*
6. Satisfactory completion of the daily stool and symptom diary during the screening phase at the discretion of the investigator.
7. Women of childbearing potential willing and able to use at least one highly effective contraceptive method throughout the study. In the context of this study, an effective method is defined as those that result in low failure rate (i.e. < 1% per year) when used consistently and correctly, such as implants, injectables, combined oral contraceptives, sexual abstinence or vasectomised partner.

*If inclusion criterion 4 and/or 5 is/are not met but the results are considered atypical (as observed from medical history and patient recall) then the patient can be rescreened on one occasion only. There must be sufficient data completed during the screening phase to allow adequate classification.

Exclusion criteria

1. Women who are pregnant or breastfeeding.
2. Prior abdominal surgery that may cause bowel symptoms that are similar to IBS (note appendectomy and cholecystectomy will not be exclusions).
3. Patients unable to stop antimuscarinic drugs, antispasmodic drugs, high-dose TCAs (i.e. > 50 mg/day), opiates/antidiarrhoeal drugs,* non-steroidal anti-inflammatory drugs (occasional over-the-counter use and topical formulations are allowed), long-term antibiotic drugs, other anti-inflammatory drugs or 5-ASA-containing drugs.
4. Patients on SSRIs and low-dose TCAs (i.e. ≤ 50 mg/day) for at least 3 months, previously unwilling to remain on a stable dose for the duration of the trial.
5. Patients with other gastrointestinal diseases, including colitis and Crohn’s disease.
6. Patients with the following conditions: renal impairment, severe hepatic impairment or salicylate hypersensitivity.
7. Patients currently participating in another trial or who have been involved in a trial within the previous 3 months.
8. Patients who in the opinion of the investigator are considered unsuitable owing to an inability to comply with instructions.
9. Patients with serious concomitant diseases, for example cardiovascular, respiratory, neurological, etc.

(A full list of excluded or dose-controlled medications can be found in Appendix 1.)

*Loperamide is allowed as rescue medication throughout the trial; however, if > 2 doses per week are taken during the screening phase then they are not eligible, although they can be rescreened on one occasion only.

Expected duration of participant participation

Study participants participated in the study for 14 weeks.

Removal of participants from therapy or assessments

The following subject withdrawal criteria applied:

1. Non-compliance – if < 75% of the investigational medicinal product (IMP) doses are taken between visits, at the investigator’s discretion. (Dose as advised by the study doctor, taking into account that not all participants will be advised to take the full study dose owing to intolerance.)
2. If the participant has remained on the initial lower dose of 2 g once a day for 3 weeks and the medication is still not tolerated, at the investigator’s discretion.
3. Adverse reaction (serious and non-serious) with clear contraindications.
4. Participant withdraws consent.
5. Safety reasons, for example pregnancy.*
6. Lost to follow-up.
7. Participant develops an excluded/contraindicated condition.
8. Investigator discretion (e.g. protocol violations).
9. Unblinding, at the discretion of the principal investigator in conjunction with the chief investigator.

*In the event of a pregnancy occurring in a trial participant or the partner of a trial participant, monitoring will occur during the pregnancy and after delivery to ascertain any trial-related adverse events (AEs) in the mother or the offspring. When pregnancy occurs in the partner of a trial participant, consent will be obtained for this observation from both the partner and her medical practitioner.

Participants withdrawn from the study were replaced. The participants were told that withdrawal would not affect their future care. Participants were also made aware (via the information sheet and consent form) that, should they withdraw, the data collected up to their withdrawal could not be erased and may still be used in the final analysis.