Efficacy and mode of action of mesalazine in the treatment of diarrhoea-predominant irritable bowel syndrome(IBS-D)

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Scientific Abstract|RESEARCH DESIGN: A randomised, placebo-controlled, parallel group design evaluating the effect of Mesalazine on IBS symptoms, mast cell numbers and secretion, and small bowel tone in IBS-D patients. STUDY POPULATION: 108 IBS-D patients aged 18-75 years meeting Rome III criteria. |PLANNED INTERVENTION: 12 weeks Mesalazine 800 mgs tds compared with placebo. Patients will complete a daily symptom diary for two weeks prior to randomisation and then during the 12 weeks of treatment. At randomisation and at 12 weeks, they will undergo 1) flexible sigmoidoscopy and biopsy to allow quantification of numbers of mucosal inflammatory and mast cells per high powered field. Biopsies will also be incubated and release of inflammatory mediators measured 2) MRI scanning both fasting and for 4 hours postprandially to assess small bowel water content and indirectly intestinal tone. Patients will also complete validated anxiety, depression and somatisation questionnaires at entry. |PRIMARY OUTCOME MEASURES: |CLINICAL: Reduction in stool frequency, averaged over weeks 11 and 12 compared with average of 2 weeks prior to randomisation. |MECHANISTIC: Reduction in mucosal mast cell counts |SECONDARY OUTCOME MEASURES: |CLINICAL: 1.Decrease in IBS symptom severity score, 2.% patients achieving satisfactory relief of IBS symptoms MECHANISTIC: 1.Change in mast cell tryptase release from mucosal biopsy 2.Reduction in stool mast cell tryptase concentrations 3.Change in small bowel tone a) fasting b) average 0-4 hrs post prandially |ASSESSEMENT AND FOLLOW-UP: Since Mesalazine is expected to have 1-2 months to have its full effect the assessment will be by means of daily stool diary analysed in the last 2 weeks. Visits are planned at 2, 4, 8 and 12 weeks for safety monitoring. |PROPOSED SAMPLE SIZE: 96 patients based on the primary end point of stool frequency. Our previous study on IBS-D patients gives a mean stool frequency of 3.1 (SD 2.0). Tuteja et al 2008 reported Mesalazine decreasing stool frequency by 1.4 bowel movements per day. Our study will have an 80% power to detect such an effect at the 1% significance level (90% at 5% significance). Allowing for a 10% dropout we will recruit 108. |STATISTICAL ANALYSIS: Analysis of the Primary outcome measure will be performed using an Analysis of Covariance in the form of a General Linear Model incorporating terms for baseline frequency, treatment arm, centre, age, diet and gender. All analyses will be performed using the current version of Stata. PROJECT TIME TABLE 0-6 Months: Set up and regulatory approval. 6-24 Months: Recruitment: 70 in Nottingham and 40 in Manchester. We have recruited 25 IBS patients in the first 6 months of this year and see 450 new IBS patients /year with 700 IBS-D/ year at the Manchester centre. 27 Months: Last patient out, lock database and undertake final analysis 27 - 33 Months: Complete analysis 33 - 36 Months: Write up and publish. |