ROME Update DDW Rome Faculty Douglas Drossman, MD University of - PowerPoint PPT Presentation

ROME Update DDW

Rome Faculty Douglas Drossman, MD University of North Carolina Drossman Gastroenterology PLLC Chapel Hill, NC Lin Chang, MD David Geffen School of Medicine at UCLA Los Angeles, CA William Chey, MD University of Michigan Ann Arbor, MI

Rome Faculty Disclosures Douglas Drossman, MD Nothing to disclose Lin Chang, MD Advisory Board Membership: Salix, QOL Medical, Takeda, Ironwood, Allergan, Commonwealth Labs, Astra Zeneca, Ardelyx William Chey, MD Grants/Research Support: Ironwood, Perrigo, Prometheus, Nestle Consultant/Speaker Bureau: Ardelyx, Astra-Zeneca, Albivro, Actoris, Ironwood Honorarium Recipient: Ardelyx, Astra-Zeneca, Albivro, Actoris, Ironwood

Planning Committee Julie Messick Nothing to disclose

This Program is Supported by Educational Grants from: Prometheus Laboratories Inc., Ferring Pharmaceuticals Inc., Salix, a division of Valeant Pharmaceuticals North America LLC., Ironwood Pharmaceuticals, Inc. 5

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A Double-blind Crossover Study Using Magnetic Resonance Imaging Shows That Fructose and Inulin Mediate Symptoms in IBS Patients Through Different Mechanisms: Early Increase in Small Bowel Water versus Late Increase in Colonic Gas Giles A. Major , Susan E. Pritchard , Kathryn Murray , Jan A. Paul , Caroline L. Hoad , Luca Marciani , Penny A. Gowland , Robin C. Spiller

Aims and Methods Aims • To test whether fructose or inulin ingestion would cause more symptoms than glucose in IBS patients and to determine which biomarkers could explain the origin of their symptoms Methods • A 3-period, 3-treatment randomized, double-blind crossover study of adults (18-65) meeting Rome III criteria for IBS and reporting bloating – On each day an identically appearing drink was consumed: 500ml water flavoured with lime juice containing 40 glucose (control), fructose or inulin • Primary endpoint was a clinically important change in a composite symptom score – Symptoms included gas/ flatulence, bloating, pain/ discomfort and diarrhoea, each scored 0-3 (total max 12) – Increase ≥3 from baseline was defined as an important change • Secondary endpoints included composite symptom intensity, breath hydrogen (H 2 ), SBWC, colonic volume and colonic gas – Measures were taken at baseline (fasted) and 0, 60, 120, 180, 240 and 300 min postprandially – Symptoms and H 2 were also measured at 30 and 90 min. Major GA et al. DDW 2015. May 15-19, 2015; Washington, DC: Abstract 246.

Results Patients with Increase in CSS ≥3 • 29 patients completed 3 study days After Ingestion • Symptom intensity was higher after * both interventions than controls 50 44.8 • In those with symptoms after inulin 37.9 40 there was a correlation between the Patients, % peak rises in symptom intensity and 30 colonic gas ( P <0.05, r 2 = 0.33) 20.7 • H 2 was a poor predictor (r 2 = 0.08). 20 After fructose the best correlate of 10 symptoms was SBWC ( P =0.05, r 2 = 0.26) n=6/29 n=13/29 n=11/29 0 Glucose Inulin Fructose *P <0.04 CSS, composite symptom score. Major GA et al. DDW 2015. May 15-19, 2015; Washington, DC: Abstract 246.

Results Peak Rise from Baseline in Symptoms and Physiological Variable with Different Carbohydrate Drinks Glucose Fructose Inulin Symptom intensity on VAS 21.8 (39.1) 49.3* (55.3) 45.5* (54.8) (mm) SBWC/mL 80 (37-122) 182** (117-258) 73 (38.5-111) Colonic volume/mL 56 (59) 142* (140) 265** (191) Colonic gas/units 13.1 (3.3-21.5) 21.9* (10.1-62.0) 45.4** (17.2-88.7) Breath hydrogen/ppm 1 (-0.5-3) 18** (5-50) 66** (31.5-125.5) Mean (SD) or median (Q25-Q75). * P <0.05; ** P <0.005 vs glucose (paired t-tests). Major GA et al. DDW 2015. May 15-19, 2015; Washington, DC: Abstract 246.

Results Peak Rise from Baseline in Colonic Gas in Inulin in Those With and Without a Symptom Response * • While fructose increased Peak colonic gas volume/units 300 SBWC, inulin increased 250 colonic gas more than either fructose or glucose, in addition * 200 to increasing total colonic 150 volume • No significant differences 100 between patients who reported 50 a rise in symptoms and those 0 who did not No Yes Change in composite symptom score ≥3 with inulin Major GA et al. DDW 2015. May 15-19, 2015; Washington, DC: Abstract 246.

Conclusions • Inulin induced symptoms in more IBS patients than glucose • Peak symptoms and colonic gas correlated with a similar time to peak • Any effect of fructose on symptoms may be by a different mechanism, perhaps increased luminal water • The similarity of findings between patients with and without a symptom increase suggests that the mechanism of effect may not be abnormal luminal content, but an abnormal sensory response Major GA et al. DDW 2015. May 15-19, 2015; Washington, DC: Abstract 246.

Candidate Genes, Mucosal mRNA and Protein Expression, Colon Transit and Large Scale Validation of a Biomarker for Diarrhea-Predominant Irritable Bowel Syndrome Mark Pimentel , Walter Morales , Ali Rezaie , Emily Marsh , Anthony Lembo , James Mirocha , Daniel Leffler , Zachary Marsh , Stacy Weitsman , Kathleen Shari Chua , Gillian M. Barlow , Enoch Bortey , William P. Forbes , Allen Yu , Christopher Chang

Aim/Methods Aim • To assess blood anti-CdtB and anti-vinculin antibodies as a bimarker for D-IBS in humans for the work up of chronic diarrhea Methods • IBS subjects were recruited from a large multicenter clinical trial for D-IBS (TARGET 3) – Healthy controls, inflammatory bowel disease (IBD) subjects and celiac disease subjects were obtained for comparison • Plasma levels of anti-CdtB and anti-vinculin antibodies were determined by ELISA and compared between groups to determine an optimal threshold that was predictive of D-IBS • Since there is a biomarker for celiac, the primary outcome measure was to assess the effectiveness of these antibodies to differentiate IBS from Crohn’s and ulcerative colitis Pimentel M et al. DDW 2015. May 15-19, 2015; Washington, DC: Abstract 31.

Results Diagnostic Accuracy for Differentiating • Demographic characteristics IBS Over IBD At Ideal Cut-Points similar among IBS subjects Anti-CdtB Anti-vinculin (n=2375) compared to IBD (OD≥2.80) (OD≥1.68 ) (n=142), healthy controls Sensitivity 91.6% 83.8% (n=43) and celiac disease (n=121) Specificity 43.7% 32.6% – Fewer female IBD subjects Positive 5.2 2.0 ( P <0.001) likelihood ratio • Anti-CdtB and anti-vinculin Area under the 0.81 0.62 antibodies were highest in IBS receiver operating curve compared to all other groups individually or non-IBS, collectively ( P <0.00001) • Both tests were significant, but less specific for, differentiating D-IBS from celiac disease OD, optical density. Pimentel M et al. DDW 2015. May 15-19, 2015; Washington, DC: Abstract 31.

Conclusions • This is the first large scale validation of anti-CdtB and anti-vinculin antibodies as a mechanism-based biomarker for D-IBS • Both tests appear most important in differentiating D-IBS from IBD in subjects presenting with chronic diarrhea Pimentel M et al. DDW 2015. May 15-19, 2015; Washington, DC: Abstract 31.

Effects of Rifaximin on Urgency, Bloating, and Abdominal Pain in Patients with IBS-D: A Randomized, Controlled, Repeat Treatment Study William D. Chey , Lin Chang , Anthony Lembo , Kavita Aggarwal , Enoch Bortey , Craig Paterson , William P. Forbes

Aim/Methods Aim • To examine the effect of subsequent courses of rifaximin (RFX) on core symptoms in IBS-D subjects who responded to an initial course of RFX Methods • Subjects with IBS- D (Rome III criteria) who presented with mean severity scores of ≥ 3 for abdominal pain (AP, scale 0-10) and bloating (scale 0- 6), and ≥ 2 stools with Bristol Stool Scale (BSS) Type 6 (loose) or 7 (watery) during the 7-day baseline were enrolled • Subjects who responded to an open-label, 2-week course of RFX 550 mg TID, and subsequently experienced a recurrence of symptoms within 18 weeks, were randomized to receive two, 2-week, double-blind (DB), repeat treatments (RFX 550 mg TID or placebo) separated by 10 weeks • Primary endpoint, assessed after the first repeat treatment during the 4-week follow-up period, was the proportion of patients who were responders during ≥2 of 4 weeks for both AP (≥30% decrease from baseline in mean weekly pain score) and stool consistency (SC, ≥50% decrease from baseline in number of days/week with BSS Type 6 or 7) • Secondary endpoints included proportion responders for individual symptoms: AP, SC, urgency (≥30% improvement from baseline in percentage of days with urgency), and bloating (≥1 -point decrease from baseline in weekly average bloating score) Chey WD et al. DDW 2015. May 15-19, 2015; Washington, DC: Abstract 313.