A mechanistic multicentre, parallel group, randomised placebo-controlled trial of mesalazine for the treatment of IBS with diarrhoea (IBS-D)

Ching Lam, Wei Tan, Matthew Leighton, Margaret Hastings, Melanie Lingaya, Yirga Falcone, Xiaoying Zhou, Luting Xu, Peter Whorwell, Andrew F Walls, Abed Zaitoun, Alan Montgomery, Robin Spiller, Ching Lam, Wei Tan, Matthew Leighton, Margaret Hastings, Melanie Lingaya, Yirga Falcone, Xiaoying Zhou, Luting Xu, Peter Whorwell, Andrew F Walls, Abed Zaitoun, Alan Montgomery, Robin Spiller

Abstract

Introduction: Immune activation has been reported in the mucosa of IBS patients with diarrhoea (IBS-D), and some small studies have suggested that mesalazine may reduce symptoms. We performed a double-blind, randomised placebo-controlled trial of 2 g mesalazine twice daily versus placebo for 3 months in patients with Rome III criteria IBS-D. Primary outcome was daily average stool frequency during weeks 11-12; secondary outcomes were abdominal pain, stool consistency, urgency and satisfactory relief of IBS symptoms.

Methods: Participants were randomised after a 2-week baseline stool diary. All participants completed a 12-week stool diary and at the end of each week recorded the presence of 'satisfactory relief of IBS symptoms'.

Results: 136 patients with IBS-D (82 women, 54 men) were randomised, 10 patients withdrew from each group. Analysis by intention to treat showed the daily average stool frequency during weeks 11 and 12 were mean (SD), 2.8 (1.2) in mesalazine and 2.7 (1.9) in the placebo group with no significant group difference, (95% CI) 0.1 (-0.33 to 0.53), p=0.66. Mesalazine did not improve abdominal pain, stool consistency nor percentage with satisfactory relief compared with placebo during the last two-weeks follow-up.

Conclusions: This study does not support any clinically meaningful benefit or harm of mesalazine compared with placebo in unselected patients with IBS-D. More precise subtyping based on underlying disease mechanisms is needed to allow more effective targeting of treatment in IBS.

Trial registration number: NCT01316718.

Keywords: 5-AMINOSALICYLIC ACID (5-ASA); DIARRHOEA; IRRITABLE BOWEL SYNDROME.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Figures

Figure 1
Figure 1
Study design. This shows the timeline for the study and the 12-week treatment period during which participants were randomised to receive either mesalazine or placebo. bd, twice daily; EOT, end of trial; , telephone visits.
Figure 2
Figure 2
Participant flow in the study. ITT, intention to treat.
Figure 3
Figure 3
(A) Baseline mast cell percentage area stained in patients with IBS with diarrhoea (IBS-D) and healthy controls (HV); (B) mast cell percentage area stained before and after mesalazine or placebo groups; (C) CD3-positive cells before and after treatment with mesalazine or placebo.
Figure 4
Figure 4
Improvement of abdominal pain severity following treatment of mesalazine in patients with post-infectious IBS.

References

    1. Thompson WG, Heaton KW, Smyth GT, et al. . Irritable bowel syndrome in general practice: prevalence, characteristics, and referral. Gut 2000;46:78–82. 10.1136/gut.46.1.78
    1. Wells NE, Hahn BA, Whorwell PJ. Clinical economics review: irritable bowel syndrome. Aliment Pharmacol Ther 1997;11:1019–30. 10.1046/j.1365-2036.1997.00262.x
    1. Amouretti M, Le Pen C, Gaudin AF, et al. . Impact of irritable bowel syndrome (IBS) on health-related quality of life (HRQOL). Gastroenterol Clin Biol 2006;30:241–6. 10.1016/S0399-8320(06)73160-8
    1. Creed F, Ratcliffe J, Fernandez L, et al. . Health-related quality of life and health care costs in severe, refractory irritable bowel syndrome. Ann Intern Med 2001;134:860–8. 10.7326/0003-4819-134-9_Part_2-200105011-00010
    1. Hungin AP, Whorwell PJ, Tack J, et al. . The prevalence, patterns and impact of irritable bowel syndrome: an international survey of 40,000 subjects. Aliment Pharmacol Ther 2003;17:643–50. 10.1046/j.1365-2036.2003.01456.x
    1. Spiller RC, Humes DJ, Campbell E, et al. . The Patient Health Questionnaire 12 Somatic Symptom scale as a predictor of symptom severity and consulting behaviour in patients with irritable bowel syndrome and symptomatic diverticular disease. Aliment Pharmacol Ther 2010;32:811–20. 10.1111/j.1365-2036.2010.04402.x
    1. Spiller R, Garsed K. Postinfectious irritable bowel syndrome. Gastroenterology 2009;136:1979–88. 10.1053/j.gastro.2009.02.074
    1. Spiller RC, Jenkins D, Thornley JP, et al. . Increased rectal mucosal enteroendocrine cells, T lymphocytes, and increased gut permeability following acute Campylobacter enteritis and in post-dysenteric irritable bowel syndrome. Gut 2000;47:804–11. 10.1136/gut.47.6.804
    1. Barbara G, Wang B, Stanghellini V, et al. . Mast cell-dependent excitation of visceral-nociceptive sensory neurons in irritable bowel syndrome. Gastroenterology 2007;132:26–37. 10.1053/j.gastro.2006.11.039
    1. Buhner S, Li Q, Vignali S, et al. . Activation of human enteric neurons by supernatants of colonic biopsy specimens from patients with irritable bowel syndrome. Gastroenterology 2009;137:1425–34. 10.1053/j.gastro.2009.07.005
    1. Cremon C, Carini G, Wang B, et al. . Intestinal serotonin release, sensory neuron activation, and abdominal pain in irritable bowel syndrome. Am J Gastroenterol 2011;106:1290–8. 10.1038/ajg.2011.86
    1. Klooker TK, Braak B, Koopman KE, et al. . The mast cell stabiliser ketotifen decreases visceral hypersensitivity and improves intestinal symptoms in patients with irritable bowel syndrome. Gut 2010;59:1213–21. 10.1136/gut.2010.213108
    1. Dunlop SP, Jenkins D, Neal KR, et al. . Relative importance of enterochromaffin cell hyperplasia, anxiety, and depression in postinfectious IBS. Gastroenterology 2003;125:1651–9. 10.1053/j.gastro.2003.09.028
    1. Camilleri M, Madsen K, Spiller R, et al. . Intestinal barrier function in health and gastrointestinal disease. Neurogastroenterol Motil 2012;24:503–12. 10.1111/j.1365-2982.2012.01921.x
    1. Martinez C, Lobo B, Pigrau M, et al. . Diarrhoea-predominant irritable bowel syndrome: an organic disorder with structural abnormalities in the jejunal epithelial barrier. Gut 2013;62:1160–8. 10.1136/gutjnl-2012-302093
    1. Bafutto M, Almeida JR, Leite NV, et al. . Treatment of postinfectious irritable bowel syndrome and noninfective irritable bowel syndrome with mesalazine. Arq Gastroenterol 2011;48:36–40. 10.1590/S0004-28032011000100008
    1. Tuteja AK, Fang JC, Al-Suqi M, et al. . Double-blind placebo-controlled study of mesalamine in post-infective irritable bowel syndrome—a pilot study. Scand J Gastroenterol 2012;47:1159–64. 10.3109/00365521.2012.694903
    1. Corinaldesi R, Stanghellini V, Cremon C, et al. . Effect of mesalazine on mucosal immune biomarkers in irritable bowel syndrome: a randomized controlled proof-of-concept study. Aliment Pharmacol Ther 2009;30:245–52. 10.1111/j.1365-2036.2009.04041.x
    1. Palsson OS, Baggish JS, Turner MJ, et al. . IBS Patients Show Frequent Fluctuations Between Loose/Watery and Hard/Lumpy Stools: Implications for Treatment. Am J Gastroenterol 2012;107:286–95. 10.1038/ajg.2011.358
    1. Tuteja A, Hale D, Stoddard G, et al. . Double-blind placebo controlled study of mesalamine in post-infective irritable bowel syndrome. Am J Gastroenterol 2008;103:S480–S480. 10.1111/j.1572-0241.2007.01755.x
    1. Longstreth GF, Thompson WG, Chey WD, et al. . Functional bowel disorders. Gastroenterology 2006;130:1480–91. 10.1053/j.gastro.2005.11.061
    1. Lewis SJ, Heaton KW. Stool form scale as a useful guide to intestinal transit time. Scand J Gastroenterol 1997;32:920–4. 10.3109/00365529709011203
    1. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand 1983;67:361–70. 10.1111/j.1600-0447.1983.tb09716.x
    1. Kroenke K, Spitzer RL, Williams JB. The PHQ-15: validity of a new measure for evaluating the severity of somatic symptoms. Psychosom Med 2002;64:258–66. 10.1097/00006842-200203000-00008
    1. Garsed K, Chernova J, Hastings M, et al. . A randomised trial of ondansetron for the treatment of irritable bowel syndrome with diarrhoea. Gut 2014;63:1617–25. 10.1136/gutjnl-2013-305989
    1. Ban L, Tata LJ, Fiaschi L, et al. . Limited risks of major congenital anomalies in children of mothers with IBD and effects of medications. Gastroenterology 2014;146:76–84. 10.1053/j.gastro.2013.09.061
    1. Aron J. Response to mesalamine and balsalazide in patients with irritable bowel syndrome refractory to alosetron and tegaserod. Gastroenterology 2005;128:A329–30.
    1. Barbara G, Cremon C, Bellacosa L, et al. . 713 Randomized Placebo Controlled Mulicenter Trial of Mesalazine in Patients With Irritable Bowel Syndrome (IBS). Gastroenterology 2014;146:S–124. 10.1053/j.gastro.2013.11.017
    1. Goldstein F, DiMarino AJ Jr. Diarrhea as a side effect of mesalamine treatment for inflammatory bowel disease. J Clin Gastroenterol 2000;31:60–2. 10.1097/00004836-200007000-00014
    1. Shimodate Y, Takanashi K, Waga E, et al. . Exacerbation of bloody diarrhea as a side effect of mesalamine treatment of active ulcerative colitis. Case Rep Gastroenterol 2011;5:159–65. 10.1159/000326931
    1. Spiller R, Lam C. An Update on Post-infectious Irritable Bowel Syndrome: Role of Genetics, Immune Activation, Serotonin and Altered Microbiome. J Neurogastroenterol Motil 2012;18:258–68. 10.5056/jnm.2012.18.3.258
    1. Tooth D, Garsed K, Singh G, et al. . Characterisation of faecal protease activity in irritable bowel syndrome with diarrhoea: origin and effect of gut transit. Gut 2014;63:753–60. 10.1136/gutjnl-2012-304042
    1. Barbara G, Stanghellini V, De Giorgio R, et al. . Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome. Gastroenterology 2004;126:693–702. 10.1053/j.gastro.2003.11.055
    1. Cremon C, Gargano L, Morselli-Labate AM, et al. . Mucosal immune activation in irritable bowel syndrome: gender-dependence and association with digestive symptoms. Am J Gastroenterol 2009;104:392–400. 10.1038/ajg.2008.94
    1. Waugh N, Cummins E, Royle P, et al. . Faecal calprotectin testing for differentiating amongst inflammatory and non-inflammatory bowel diseases: systematic review and economic evaluation. Health Technol Assess 2013;17:xv–xix, 1–211 10.3310/hta17550
    1. Pavlidis P, Chedgy FJ, Tibble JA. Diagnostic accuracy and clinical application of faecal calprotectin in adult patients presenting with gastrointestinal symptoms in primary care. Scand J Gastroenterol 2013;48:1048–54. 10.3109/00365521.2013.816771
    1. Tibble JA, Sigthorsson G, Foster R, et al. . Use of surrogate markers of inflammation and Rome criteria to distinguish organic from nonorganic intestinal disease. Gastroenterology 2002;123:450–60. 10.1053/gast.2002.34755
    1. Andresen V, Lohse AW, Broicher W, et al. . Tu1436 Development and Risk Factors of Post-Infectious Irritable Bowel Syndrome (PI-IBS) After Severe Outbreak of Enterocolitis Due to Enterohemorrhagic Escherichia coli (EHEC) O104:H4 in Germany 2011: A Cohort Study With Prospective Follow-up. Gastroenterology 2012;142:S–832. 10.1016/S0016-5085(12)63230-2

Source: PubMed

Sponsor e collaboratori

Condizioni mediche

Interventi farmacologici

3
Sottoscrivi