William Chey, MD University of Michigan Ann Arbor, MI

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1 Lin Chang, MD David Geffen School of Medicine at UCLA Los Angeles, CA William Chey, MD University of Michigan Ann Arbor, MI Mark Pimentel, MD Cedars-Sinai Medical Center Los Angeles, CA Accredited by Jointly sponsored by Purdue University School of Pharmacy and the Gi Health Foundation. This activity is supported by Salix Pharmaceuticals. 1

2 Special thanks to our supporter for providing an educational grant: 2

3 Mesalamine granules 1500 mg once daily for 12 weeks provides adequate relief of IBS symptoms in IBS with diarrhea: Results from a Phase 2 trial Aron J et al. Program no. 7 3

4 Design Background Mesalamine granules are approved for ulcerative colitis Aminosalicylate therapy may be of benefit in IBS-D Study design Randomized, double-blind, placebo-controlled, multicenter study Patients 148 patients with IBS-D (Rome III criteria) Treatments Placebo (n=50) Mesalamine granules 750 mg once daily (n=47) Mesalamine granules 1500 mg once daily (n=51) End points Monthly responders for both abdominal pain and stool consistency during the 3-month treatment period 4

5 Monthly Responders for 3 Months (%) Results P= P= Placebo MG 750 mg MG 1500 mg 5

6 Conclusions Mesalamine granules 1500 mg once daily provide statistically significant improvements in abdominal pain and stool consistency in patients with IBS-D Aminosalicylates may have a therapeutic role in symptomatic treatment of IBS-D 6

7 Physician and patient perceptions of treatment outcome after 12 weeks on alosetron: Results of a multi-center observational study Lacy B et al. Program no. P452 7

8 Design Background Alosetron is currently the only FDA-approved therapy for women with severe IBS-D with inadequate response to conventional therapy Purpose Evaluate patient characteristics, dose adjustments, symptom improvement, and perception of treatment outcomes in real-world setting Methods 12-week open-label observational study (N=118) Data collected via daily diaries and questionnaires on lower GI symptoms, QOL, and patient/physician perception of disease severity and treatment outcome 8

9 Results: Impact on Lower GI Symptom Scores Symptom Stool consistency (7-point Bristol Stool Scale) Abdominal Pain Intensity (11-point NRS) Proportion of Days with Fecal Urgency (%) Proportion of Days with Fecal Incontinence (%) Baseline Mean (SE) Week 12 Mean (SE) 5.27 (0.11) 3.85 (0.15) < (0.21) 2.67 (0.21) < (2.57) (3.47) < (2.23) 7.71 (1.71).0001 P 9

10 Results Patient satisfaction (scale of 1 [very unsatisfied] to 7 [very satisfied]) Baseline score: 2.2 Study end: % of patients did not consider the drug to be beneficial Safety No serious adverse events Constipation was most frequent adverse event (13%) 10

11 Effects of linaclotide on abdominal and bowel symptoms over the first 7 days of treatment in patients with IBS with constipation Chang L et al. Program no. P

12 Design Purpose Assess changes from baseline in abdominal and bowel symptoms in patients with IBS-C over first 7 days of treatment with linaclotide Methods Patients with IBS-C (Rome II; N=1602) randomized to linaclotide 290 mcg or placebo (<3 CSBM and 5 SBM) Data from first 7 days of treatment analyzed for daily percent change from baseline in abdominal symptoms and stool consistency Percentages of patients having 1 SBM and CSBM on each of the first 7 days of treatment and mean number of SBMs and CSBMs calculated (C)SBM=(complete) spontaneous bowel movement 12

13 Results Day 1 (%) Day 2 (%) Day 3 (%) Day 4 (%) Day 5 (%) Day 6 (%) Day 7 (%) Parameter (N=1602) Pain (n=1602) a Discomfort (n=1586) a Bloating (n=1571) a Cramping (n=1454) a Fullness (n=1580) a PBO LIN PBO LIN PBO LIN PBO LIN PBO LIN PBO LIN PBO LIN b b b b b b b b b b b b b b b b b b b 10.1 c b b b b b b b b b b b b LIN=linaclotide; PBO=placebo a Patients with baseline score 3 for each respective parameter. b P<.05 favoring linaclotide; c P<.05, favoring placebo. 13

14 Conclusions Compared to placebo, linaclotide was associated with rapid improvement in bowel and abdominal symptoms that continued to increase through the first week of treatment 14

15 Confocal laser endoscopy findings of the small intestine in irritable bowel syndrome Kao D et al. Program no

16 Design Background Increased epithelial cell extrusion may result in barrier dysfunction Increased intestinal permeability has been reported in IBS Purpose Examine and quantify epithelial gaps and cells of terminal ileum using probe-based confocal laser endomicroscopy Study design Prospective, controlled cohort study of IBS patients and healthy controls (N=35) Patients underwent fluorescein-aided confocal laser endoscopy of terminal ileum 16

17 Results Median epithelial gap densities for control and IBS patients were 0.6 and 3.2 gaps/100 cells, respectively (P<.001) Using 3% (~90th percentile of the control population) as cut off for an abnormal value, the diagnostic accuracy of gap density in IBS patients was: Sensitivity of 62% Specificity of 89% Positive predictive value of 83% Negative predictive value of 73% 17

18 Conclusions Density of epithelial gaps as determined by confocal laser endoscopy during colonoscopy was significantly higher in IBS patients 18

19 Does probiotic use increase the risk for developing small intestinal bacterial overgrowth? Samuel MT et al. Program no. P

20 Design Purpose Estimate prevalence of SIBO among patients referred for culture Identify clinical risk factors for SIBO Examine whether probiotic use is a risk factor for SIBO Study design Retrospective chart review of random sample of 250 patients who had undergone duodenal aspirate culture SIBO=small intestinal bowel overgrowth 20

21 Results Variable OR (95% CI) for positive aspirate Adjusting for age, gender OR (95% CI) for positive aspirate Adjusting for age, gender, PPI, narcotic use Age, per 10 years 1.36 (1.10,1.68) 1.37 (1.09,1.71) Male gender 1.15 (0.56,2.39) 1.22 (0.56,2.66) PPI use 4.75 (2.22,10.16) 5.03 (2.30,11.01) Narcotic use 4.97 (1.59,15.61) 5.19 (1.59,16.92) Probiotic use 0.97 (0.42,2.28) 1.00 (0.41,2.46) IBS 0.68 (0.18,1.22) 0.57 (0.22,1.47) PPI=proton pump inhibitor 21

22 Conclusions The prevalence of culture-positive SIBO has increased in the last several years Based on this pilot study, the most important clinical features predictive of SIBO were increasing age, PPI use, and narcotic use, but not major GI comorbidity or probiotic use 22

23 Increased risk of osteoporosis related fractures in patients with irritable bowel syndrome Stobaugh DJ et al. Program no. P719 23

24 Design Background Patients with IBS-D have been shown to have elevated cytokines that have been associated with metabolic bone disease Purpose Examine risk for osteoporosis and fracture in IBS-D patients Study design Data extracted from Nationwide Emergency Department Sample (NEDS) database (28.4 million discharges, 950 hospitals) Data used to determine risk for osteoporosis and related fractures in IBS patients 24

25 Results Age-stratified risk for osteoporosis in patients with IBS Age Group Males Females Odds Ratio 95% CI Lower Limit 95% CI Upper Limit Odds Ratio 95% CI Lower Limit 95% CI Upper Limit Odds Ratio & older Overall, patients with IBS had an increased risk of osteoporosis (OR 4.28; 95% CI ) 25

26 Results Differences in risk for fractures in patients with IBS by anatomical region Fracture location Irritable Bowel Syndrome Crohn s disease Ulcerative Colitis Celiac disease Odds Ratio 95% CI OR 95% CI OR 95% CI OR 95% CI OR Vertebrae Hip Wrist

27 Conclusions A history of IBS appears to be associated with an increased risk of osteoporosis and related fractures Further research is necessary to establish definite mechanisms 27

28 Rise in hydrogen production during lactulose breath test does not represent oro-cecal transit due to lag in peak fermentation Winter R et al. Program no. P

29 Design Background A recent study suggested that hydrogen production reflects oro-cecal transit time rather than bacterial overgrowth based on 5% arrival of lactulose/technetium in the cecum in IBS Conclusions of study may be misleading: Time to reach peak H2 production is unknown 5% lactulose may not be sufficient to produce fermentation Purpose Examine hydrogen production after combining lactulose with fresh stool Study design Healthy subjects recruited 2.5 g stool incubated with lactulose to analyze hydrogen and methane production 29

30 Results The amount of hydrogen produced was greatest with 0.5g of added lactulose Represents expected quantity of lactulose arrival to the colon Using 0.5g, peak hydrogen production occurred at 60 minutes in all cases with median peak hydrogen level of 210ppm Although all subjects were breath methane negative, five had increasing methane in their stool In 4 of the 5, the peak methane production (median=15ppm) occurred at 60 minutes Thus, even low methane production did not inhibit the production and detection of hydrogen in this experiment 30

31 Conclusions The arrival of 0.5 g of lactulose to the colon would produce hydrogen After mixing with colon flora, maximum hydrogen production does not occur until 60 minutes later Given this large time lag, the time to rise in H 2 does not indirectly measure orocecal transit Breath H 2 production at a given moment appears to reflect lactulose fermentation by bacteria that started up to 60 minutes earlier (ie, in small intestine) 31

32 Tricyclic Antidepressants in the Management of IBD patients With Functional GI Symptoms Iskandar H et al. Program no. P

33 Design Background In IBD in remission or with mild disease activity, functional symptoms may dominate the clinical presentation Purpose Assess whether TCA therapy provides benefit by reducing these IBS-type symptoms TCA=tricyclic antidepressant 33

34 Design Study design Retrospective study of open-label antidepressant treatment conducted in two cohorts: 81 IBD patients in clinical remission or with mild inflammation with persistent GI symptoms 65 symptomatic IBS patients without IBD Baseline symptom severity assessed on 4-point Likert scale (0=no symptoms; 3=severe, disabling symptoms) Antidepressant treatment responses graded using 4- point scale (0=no improvement, 3=complete satisfaction) 34

35 Results A similar number of IBD and IBS patients achieved at least moderate improvement (Likert =2) on antidepressant treatment (49.4% vs 52.3%, respectively; P=.73) Among IBD patients, UC patients had a significantly better response than CD patients (1.78 ± 0.14 vs 1.17 ± 0.11, respectively; P=.002) A subset of each study group was followed for a second visit with further symptom improvement (1.38 ± 0.13 and 1.57±0.15, respectively, P=.35) 35

36 Conclusions Antidepressants studied are effective in managing moderately-severe functional symptoms among IBD populations without overt disease activity, similar to their IBS counterparts Symptom responses to antidepressants occur at modest doses, significantly lower than those for IBS UC patients respond better than CD patients in this study While prospective validation is needed, this study suggests that antidepressants may be an option in the management of functional symptoms in IBD patients 36

37 Fecal incontinence in US adults from : Epidemiology and Risk Factors Ditah I et al. Program no. P445 37

38 Design Purpose Estimate prevalence of fecal incontinence Identify risk factors for fecal incontinence Study design Data used from NHANES Fecal Incontinence Severity Index ( ) Participants Men and women aged 20 years (N=52,195) 38

39 Results Prevalence of fecal incontinence: 8.27% Incidence increased over time 2005: 6.96% 2007: 8.58% 2010: 9.01% Occurred at least weekly in 1.13% of participants Prevalence similar in women (9.13%) and men (7.36%) FI increased with age from 1.16% in <20 years old through 5.88% in those 50 to 60 years old up to 17.46% in participants aged 70 years and older Correlates: Age Level of education Diabetes 39

40 Conclusions Prevalence of fecal incontinence is increasing (likely due to growing elderly population) Optimal diabetes control may reduce incidence 40

41 Assessment of Abdominal Symptoms Before and After Biofeedback Therapy in Patients With Dyssynergic Defecation Baker J et al. ACG

42 Methods Purpose Assess the impact of biofeedback therapy (BFT) on abdominal and bowel-related symptoms in patients with dyssynergic defecation (DD) Methods All patients with chronic constipation referred for anorectal manometry and balloon expulsion testing prospectively completed the Personal Assessment of Constipation Symptom (PAC-SYM) questionnaire* Patients with DD by ARM/BET were treated by physical therapists with 6-8 weeks of BFT at a single tertiary care center between 2008 and 2012 Patients completed a follow-up PAC-SYM after the completion of BFT *Frank L et al. Scand J Gastroenterol. 1999;34:

43 Results Effect of Biofeedback on Abdominal Symptoms Symptom Pre minus Post PAC-SYM Score Standard Deviation P Abdominal Discomfort <.001 Abdominal Pain <.001 Abdominal Bloating <.001 Abdominal Cramps

44 Results Prevalence of Moderate to Severe Abdominal Symptoms 80% 60% 69% 75% Pre Biofeedback Pac-sym Questionnaire Responses Post Biofeedback Pac-sym Questionnaire Responses 52% 51% 40% 20% 34% * * 20% 29% * 19% * 0% Abdominal Discomfort Abdominal Pain Abdominal Bloating Abdominal Cramping *P=.05 44

45 Conclusions Abdominal symptoms are quite common in patients with dyssynergic defecation For patients with DD, biofeedback therapy improves bowel related complaints For patients with DD, abdominal symptoms such as discomfort, pain, bloating, and cramping also improve following biofeedback therapy 46

Nicholas J. Talley, MD University of Newcastle Callaghan, NSW Australia. Mark Pimentel, MD Cedars-Sinai Medical Center Los Angeles, CA

Lin Chang, MD David Geffen School of Medicine at UCLA Los Angeles, CA Mark Pimentel, MD Cedars-Sinai Medical Center Los Angeles, CA Nicholas J. Talley, MD University of Newcastle Callaghan, NSW Australia