ROME FOUNDATION - FGIDs: YEAR IN REVIEW

ROME FOUNDATION - FGIDs: YEAR IN REVIEW Program Description/Statement of Need: Functional gastrointestinal disorders (FGIDs) are a large heterogeneous group of digestive disorders linked only by the fact that the underlying pathophysiology of disease is unknown. The diagnosis and management of these disorders in real world clinical practice is often challenging. In this program, we have selected the top abstracts to analyze and interpret for the broader clinician audience Target Audience: This activity has been designed to meet the educational needs of gastroenterologists, physician assistants and nurse practitioners involved in the management of FGIDs. Learning Objectives: Upon completion of this activity, the participant will be better prepared to: Identify key advances in the management of functional gastrointestinal disorders Incorporate into daily practice, as applicable, new data on functional gastrointestinal disorders from the major international meetings and literature of 2014 Accreditation Statement: This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education through the joint providership of Purdue University College of Pharmacy and the GI Health Foundation. Purdue University College of Pharmacy, an equal access/equal opportunity institution, is accredited by the ACCME to provide continuing medical education for physicians. Credit Designation: Purdue University College of Pharmacy designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credit(s) Release Date: April 1, 2015 Expiration Date: April 1, 2016 Faculty Disclosure Statement: All faculty and staff involved in the planning, review or presentation of the continuing education activities provided by Purdue University, College of Pharmacy are required to disclose to the audience all relevant financial relationships with any commercial interest that may pose a conflict with the principles of balance and independence of the activity content. Full disclosure of all commercial relationships must be made in writing to the audience prior to the activity. Additional planning committee, reviewer and Focus Medical Communications and Purdue University staff have no relationships to disclose. Introduction The management of functional gastrointestinal disorders (FGIDs) which encompass a broad range of conditions that are characterized by persistent, recurrent symptoms in the absence of clear structural abnormalities 1 has undergone a major shift in the past decade, from poorly recognized, often misunderstood symptom complexes to conditions with clear diagnoses and better delineated treatment pathways. Nowhere is this better illustrated than in the increasing pace of publications and the increasingly overwhelming quantity of presentations and abstracts at major international meetings focusing on FGIDs. This monograph serves as a summary of highlights from 2014 meetings and literature focusing on these common and clinically consequential disorders. To develop this Year in Review summary, several sources were searched for key data on FGIDs, fecal incontinence, and opioid-induced constipation, including abstracts and presentations from major international meetings particularly Digestive Disease Week (DDW) 2014 and the American College of Gastroenterology (ACG) 2014 Annual Meeting. A review panel of experts from the Rome Foundation then selected those abstracts and presentations thought to be most impactful for clinical practice and research in 2014. Functional Dyspepsia Diagnosis Adult Rome III criteria for functional dyspepsia (FD) subtypes patients into those with epigastric pain syndrome (EPS), characterized by pain unrelated to eating, and those with postprandial distress syndrome (PDS), which is mealrelated fullness, discomfort, or early satiety. 1 However, the pediatric criteria for FD does not distinguish EPS from PDS and, instead, relies on a general description of upper abdominal pain/discomfort not relieved by defecation, and meal-related symptoms are not required. Van Tilburg, et al. examined a community and clinical sample to determine whether adult FD subtypes of EPS and PDS can be distinguished in children. 2 Epigastric abdominal discomfort at least 2-3 days a week, meeting criteria for FD in children, was observed in 23 children [N=1437 (1.6%)] in a large community sample and 62 children (45.9%) in a clinically-based FGID sample. Understandably, epigastric pain was the most common FD 1

symptom reported, but also feeling full, early satiety, bloating, and nausea (symptoms associated with adult PDS), were reported by about 60% of subjects. Criteria for EPS was not as common as PDS and about half of the sample could not be subtyped into either of these categories. Also, a large proportion of unsubtyped patients had epigastric pain relieved by defecation (60.7% 83.3%), and the majority of these met Rome III criteria for irritable bowel syndrome (IBS) (51.7% 91.7%). These data suggest that meal-related symptoms of PDS are common in children with epigastric pain and should be included in pediatric criteria in addition to EPS. Furthermore, for many of these children, epigastric pain is relieved by defecation, suggesting that IBS needs to be excluded before diagnosis of FD. Management of FD in Patients with Chronic Idiopathic Constipation (CIC) Patients with CIC often report overlapping gastrointestinal (GI) conditions, including FD, which Rome III characterizes as the presence of 1 of 4 key symptoms: postprandial fullness, early satiation, epigastric pain, or epigastric burning. 1 In a study conducted by Talley et al., CIC patients with abdominal bloating at baseline ( 5 on a 0-10 numerical rating scale) were randomized to daily oral linaclotide (145 or 290 mcg) or placebo. Using a functional dyspepsia-specific symptom index, the Nepean Dyspepsia Index (NDI), patients were asked to rate 3 aspects of 15 dyspepsia symptoms (i.e., frequency, intensity, bothersomeness) at baseline and weeks 2, 4, 8, and 12 of treatment. 3 Notably, patients with CIC experiencing bloating also have functional dyspeptic symptoms, including upper abdominal pain or ache, burning, fullness after a meal, and inability to finish a meal. Overall, reductions in these symptoms were greater among linaclotide patients than in placebo patients; reductions were significant (P<.05) for pain/aches in the upper abdomen, pain/ache in the chest (290 mcg only), fullness after eating or slow digestion, and bloating in the upper abdomen. Further studies are needed to determine if the effect of linaclotide is symptom reduction due to relief of constipation or if the therapy independently affects the upper GI symptoms of FD. Advances in IBS Pathophysiology Many patients find fatigue among the most distressing symptoms of IBS, and it clearly has a negative impact on daily life. 4 However, few studies have evaluated how fatigue interacts with the other signs and symptoms of IBS. In a cross-sectional study conducted by Jakobssen and colleagues presented at DDW 2014, the relationship between fatigue, symptoms and coping resources was evaluated. 4 A total of 162 patients were enrolled; all completed self-reported questionnaires to assess the impact of fatigue on daily life, as well as questionnaires to measure psychological distress, GI-specific anxiety, GI symptom severity, and coping resources. In addition, patients underwent colonic transit time assessments and a rectal sensitivity test. With increasing severity of IBS, there was a progressive increase in the impact of fatigue on daily life. Women reported significantly more severe physical fatigue than men (P=.01). The strongest associations with fatigue were seen modestly for abdominal pain (r = 0.35; P<.0001) and for all psychosocial parameters, including the greatest for depression (r=0.65; P<.0001) and general anxiety (r=0.48; P<.0001), and less so for GI-specific anxiety (r=0.24; P<.01) and sense of coherence, a coping measure (r=-0.47; P<0.001). In the multivariate analysis, depression (P<.0001), anxiety (P=.004), and abdominal pain (P<.0001) were found to be the strongest independent predictors of pain. Notably, no correlations were found between fatigue and colonic transit time or rectal sensitivity. The authors concluded that fatigue is more common in severe IBS and relates to pain and psychosocial effects rather than to motility. Fears of GI symptoms among patients with IBS are thought to increase the frequency and intensity of anxiety and heighten hypervigilance toward potentially aversive visceral stimuli or their cues. This fear can cause excessive avoidance of activities or situations in which GI symptoms are expected to occur; however, the extent to which fear impacts IBS-specific quality of life (QOL) had not previously been studied. In a study conducted by Lackner and colleagues, 5,234 patients with IBS by Rome III criteria completed a testing battery that included IBS-specific QOL, a generic QOL instrument (SF-12), and the UCLA GI Symptom Severity Score. Data supported an overall model that included sociodemographic, clinical (eg, current severity of GI symptoms), and psychosocial (eg, fear of GI symptoms, distress, neuroticism) variables, accounting for 48.7% of the variance in IBS-QOL (P<.01). GI symptom fear was the most robust predictor of IBS-QOL (P<.01), accounting for 14.4% of the total variance. These data indicate that patients fears that GI symptoms have aversive consequences is a powerful predictor of IBS-specific QOL that cannot be explained by the severity of GI symptoms, overall emotional well-being, neurotic personality style, or other clinical features of IBS. An understanding of the unique impact that GI symptom fears have on IBS-specific QOL can inform treatment planning and help gastroenterologists better manage more severe IBS patients. Role of the Microbiota in Disease Pathogenesis Over the past decade, there has been an accumulation of data suggesting that gut flora has a role in IBS. 6-8 This growing area of literature has led to new IBS treatment concepts involving the use of antibiotics, including nonabsorbable agents such as rifaximin. Postinfectious IBS (PI-IBS) is now well accepted as an etiology of IBS. 9-11 A broad range of pathogenic GI bacteria and some parasites have been shown to trigger PI-IBS; in patients infected with Clostridium difficile, the incidence of PI-IBS is relatively low approximately 4.3% after the first episode. 12 A study 2

conducted by Garg and colleagues reported at DDW 2014, evaluated the incidence and clinical features of PI-IBS in patients undergoing fecal microbiota transplantation (FMT) for recurrent C. difficile colitis. 13 The study included 27 patients who met ROME III criteria for IBS after undergoing fecal transplant. Of these 27 patients, 18.5% developed PI-IBS symptoms within 0.5 6 weeks of FMT and continued to have symptoms for the entire time of follow-up (16 35 months). There was no statistical difference in the age, gender, race, or duration of symptoms of C. difficile colitis before FMT between patients who developed PI-IBS after FMT and those who did not develop PI-IBS. A 16S ribosomal RNA microbiota analysis did not show significant differences in the diversity or abundance of major microbiota members between patients with and without PI-IBS after FMT. Although the incidence of developing C. difficile colitis after FMT is high (18.5%), it should be recognized that the population treated were selected because they had recurrent C. difficile colitis, which may predetermine the presence of the colitis after transplant. Rifaximin, a nonabsorbable antibiotic, was evaluated in 2 trials TARGET 1 14 and TARGET 2 14 in patients with IBS without constipation. In these studies, significantly more patients in the rifaximin group than in the placebo group had adequate relief of global IBS symptoms during the first 4 weeks after treatment (40.8% vs 31.2%, P=.01, in TARGET 1; 40.6% vs 32.2%, P=.03, in TARGET 2; 40.7% vs 31.7%, P<.001, in the 2 studies combined). Similarly, more patients in the rifaximin group than in the placebo group had adequate relief of bloating (39.5% vs 28.7%, P=.005, in TARGET 1; 41.0% vs 31.9%, P=.02, in TARGET 2; 40.2% vs 30.3%, P<.001, in the 2 studies combined). In addition, significantly more patients in the rifaximin group had a response to treatment as assessed by daily ratings of IBS symptoms, bloating, abdominal pain, and stool consistency. The question remained, however, whether repeated treatment with rifaximin would be effective and safe. The TARGET 3 study, presented at ACG 2014, evaluated the efficacy and safety of repeat treatment with rifaximin for IBS with diarrhea (IBS-D). 15 In this study, patients with IBS-D who presented with severity scores of 3 for IBS-related abdominal pain and bloating and experienced 2 loose or watery stools during a 7-day baseline were entered into the open-label phase of the trial, in which all patients were treated with rifaximin 550 mg 3 times daily orally for 2 weeks, followed by a 4-week treatment-free follow-up period to assess response to treatment. Adequate relief was defined as the proportion of patients who responded during 2 of 4 weeks for both abdominal pain ( 30% decrease from baseline in mean weekly pain score) and stool consistency ( 50% decrease from baseline in number of days/week with bowel symptom scale [BSS] Type 6 or 7). Subjects responding with adequate relief to open-label therapy were subsequently followed for up to 18 additional weeks until they experienced symptom recurrence. Those with recurrence were randomized to receive 2 double-blind, placebo-controlled, repeat treatments separated by 10 weeks. Patients were retreated with rifaximin 550 mg 3 times daily or placebo for 2 weeks followed by a 4-week treatment-free follow-up evaluation period. The 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 abdominal pain and stool consistency. A total of 2579 IBS-D patients entered the trial, of whom 42% were responders during the open-label phase. Of the 1074 patients who responded to open-label rifaximin, 36% (n=382) did not experience recurrent IBS-D symptoms. Of 692 patients with recurrent symptoms, 636 (mean age 46.8 years, 69% female) were randomized to receive rifaximin 550 mg TID (n=328) or placebo (n=308). During both the first and second retreatment, significantly more rifaximin patients than placebo patients responded to therapy (Figure 1). Notably, an exploratory analysis using deep gene sequencing, as well as culturing with antibiotic susceptibility, revealed that up to 3 courses of therapy did not adversely affect bacterial sensitivity to other antibiotic classes, promote pathogenic bacterial growth, alter the overall microbiota of the intestine, or increase the risk for opportunistic infections as compared with a single course of rifaximin. The findings indicate that retreatment with rifaximin is associated with a modest improvement in IBS symptoms but does not appear to promote pathogenic bacterial growth. In addition, about 30% of patients treated with rifaximin experience a sustained benefit for up to 18 weeks. Responders (%) 100 80 60 P=.02 40 33 25 20 0 Retreatment 1 Rifaximin 550 mg TID Placebo P=.04 37 29 Retreatment 2 Figure 1. Responders to 2 Rounds of Retreatment in the TARGET 3 Study of Rifaximin in IBS-D14 Meditation for IBS It was previously reported that mindfulness training a group intervention focused on training patients to meditate improved overall IBS symptoms to a 13 3

significantly greater extent than a support group 16 ; in this study, bowel symptoms, QOL, and psychological symptoms were all significantly more improved in the mindfulness training group than in the support group 3 months after intervention. 16-18 In a study presented at DDW 2014, Faurot and colleagues evaluated the continued impact of mindfulness meditation at 6 and 12 months following the initial intervention. 19 A total of 75 women with IBS were initially randomized to an initial mindfulness meditation course or to a support group. The intervention consisted of 8 weekly group sessions and a half-day retreat. Participants completed the IBS Severity Scale (IBS-SS), the IBS-QOL, the Brief Symptom Inventory-18 (BSI-18), the Visceral Sensitivity Index (VSI), and the Five-Facet Mindfulness Questionnaire (FFMQ) pre-treatment and at 1, 3, 6, and 12 months posttreatment. At baseline, IBS symptom severity and QOL were equivalent; for the primary outcome of overall IBS severity on the IBS-SS, significantly greater improvement was seen in the mindfulness meditation group as compared with the support group (at 6 months, -151 vs -108, P=<.001; at 12 months, -115 vs -26, P=.004). Greater improvements were also seen in the meditation group than in the support group in IBS-QOL scores, visceral anxiety, and psychological distress at both 6 and 12 months. Thus 8 weeks of Mindfulness Treatment is seen to have lasting benefits with regard to reduction in overall IBS severity and psychological distress with improvement in health-related QOL for up to one year of follow-up. Novel Therapies for IBS Plecanatide, an investigative compound currently pending FDA approval, is a minimally absorbed peptide analog of uroguanylin. Plecanatide is a naturally occurring ligand for the human intestinal guanylate cyclase-c receptor. The results of a 12-week, randomized, double-blind, placebo-controlled, dose-ranging trial in patients with IBS with constipation (IBS-C) were reported at ACG in 2014. 20 In this study, patients with IBS-C (N=424) were randomly assigned to groups given 0.3, 1.0, 3.0, or 9.0 mg oral tablets of plecanatide or placebo once daily for 12 weeks; the primary efficacy parameter was change from baseline in complete spontaneous bowel movements (CSBMs). The plecanatide 1.0, 3.0, and 9.0 mg dose groups had significantly improved weekly rates of CSBM frequency compared with placebo; the increases were 2.12, 2.74, and 2.44 for plecanatide doses 1.0, 3.0, and 9.0 mg, respectively (Figure 2; P.05 for each pair-wise comparison). The 3.0 mg dose also significantly improved all important secondary endpoints: change from baseline in worst abdominal pain intensity, FDA overall responder endpoint, stool consistency, and straining. The 9.0 mg dose demonstrated statistical improvement on the FDA overall responder endpoint, stool consistency, and straining and numerical improvement on worst abdominal pain intensity. The most common adverse event was diarrhea (9.4% at 1.0 mg, 9.3% at 3.0 mg, and 11.8% at the highest 9.0 mg dose). This study demonstrated the efficacy of the 2 higher doses of a guanylate cyclase C-agonist in relieving abdominal symptoms and bowel habits in patients with IBS-C. CSBM Frequency Over Placebo 5 4 3 2 1 0 2.12 Plecanatide 1.0 mg 2.75 Plecanatide 3.0 mg 2.44 Plecanatide 9.0 mg 18 Figure 2. Increases in CSBM Frequency vs Placebo in IBS-C Patients Treated with Plecanatide 19 In a study presented at DDW 2014, Lembo and colleagues reported the results of a study of eluxadoline in IBS-D. 21 Eluxadoline, currently in late-phase development, is a locally active, mixed mu-opioid receptor agonist and delta-opioid receptor antagonist. These double-blind, placebo-controlled, phase 3 clinical trials 21 randomized patients meeting Rome III criteria for IBS-D to eluxadoline 75 or 100 mg, administered twice daily, or to placebo for 26 weeks of treatment. One of the studies included an additional 26 weeks of double-blind treatment for long-term safety evaluations, while the other included a 4-week placebo withdrawal period. In both, the primary endpoint was composite response, based on simultaneous daily improvement in abdominal pain and stool consistency evaluated over study weeks 1 to 12 (FDA responder) or study weeks 1 26 (European Medicines Agency [EMA] responder). A total of 2428 patients with IBS-D were enrolled across the 2 clinical trials; in both, significantly (P<.005) more patients receiving 100 mg eluxadoline were FDA and EMA composite responders than patients receiving placebo (Figure 3). Comparable results for both endpoints were seen for the 75 mg eluxadoline group though the difference over placebo was not significant for the EMA response although in one of the studies. Patients receiving eluxadoline were also significantly more likely than placebo patients to have adequate relief of IBS symptoms. Responder rates for individual components of the FDA and EMA responder endpoints for both eluxadoline groups were significantly higher than placebo for the stool consistency component, and numerically higher for the pain component. Patients receiving eluxadoline at both doses also had greater improvements in numbers of daily bowel movements and urgent episodes, daily IBS-D global symptom scores, and IBS-QOL scores (P<.05). The most commonly reported adverse events in the 2 clinical trials were constipation (7.4% and 8.3% for eluxadoline 75 mg and 100 mg; 2.4% for placebo) and nausea (7.8% and 7.3% for eluxadoline 75 mg and 100 mg; 4.8% for placebo). Of note, although not reported at the meeting, 4

a press release reported that there were infrequent adjudicated events of mild pancreatitis among patients who received eluxadoline (0.3% of those treated with the compound); however, 3 of these cases involved patients who reported heavy alcohol consumption and 1 had biliary sludge (a known risk factor for pancreatitis). 21 These results demonstrate that eluxadoline, which has a novel mechanism of action, is efficacious in relieving overall symptoms and individual symptoms in IBS-D, although the beneficial effect appears to be more apparent for bowel symptoms than abdominal pain. 0.4 0.3 0.2 0.1 0 p<0.001 p=0.004 p=0.014 0.251 0.239 0.171 0.162 p<0.001 0.289 0.295 Study 3001 Study 3002 Placebo Eluxadoline 75 mg Eluxadoline 100 mg period and during the study period (3 patients). During the treatment period, 2 patients had minor abdominal pain during the study period that resolved spontaneously, 2 had diarrhea, 1 had flatulence, and 1 had a sensation of abdominal wall twitches. This unique nonpharmacologic treatment modality may potentially have benefit for chronic constipation. However, this is a proof of concept study that was not specifically designed for efficacy as much as for safety, and better designed studies are currently underway. Is Mesalazine Effective for IBS? Recent reports have suggested that mesalazine, compared with placebo, improves general wellbeing in IBS. 23-25 At ACG 2014, 2 studies evaluated the efficacy of this agent in patients with IBS. 26,27 The first study 26 was a phase 3, randomized, double-blind, placebo-controlled trial in which 185 patients with IBS (regardless of bowel habit) were randomly allocated to either oral mesalazine [5-aminosalicylic acid (800 mg 3 times daily)] or placebo for 12 weeks; patients were followed for an additional 12 weeks after the treatment period for the primary endpoint of proportion of patients with satisfactory relief of abdominal discomfort/pain. For the primary endpoint, the prevalence of responders was 68.6% in the mesalazine group vs 67.4% in the placebo group (P=NS). Figure 3. Rates of the FDA responder endpoint in two phase 3, doubleblind, randomized controlled trials of eluxadoline 75 and 100 mg twice daily. 21 The FDA responder endpoint was composite response based on simultaneous daily improvement in abdominal pain and stool consistency, evaluated over Weeks 1 to 12. While pharmacologic treatment is the mainstay of constipation management in CIC and IBS-C, nearly half of patients are unsatisfied with treatment, leaving the door open to new nonpharmacologic modalities. The vibrating capsule, which is similar in size and shape to video capsules but vibrates in the colon, is a unique nonpharmacologic approach to constipation. In a study presented at ACG 2014, Ron and colleagues presented a small pilot study of the vibrating capsule that was conducted in 22 consecutive constipated patients with Rome III CIC or IBS-C. All patients underwent a 2-week run-in period in which all laxatives were stopped. The capsule was activated and started vibrating 6 hours after administration; each patient received 2 capsules per week and filled a daily bowel movement and laxative use questionnaire. On each follow-up visit, expelled capsules were collected and side effects were recorded. In the 20 patients who completed the study, there was a significant increase in the number of spontaneous bowel movements from 2.21 to 3.99 per week (P<.001), and the total number of constipation parameters was reduced from 5.25 to 3.2 (P=.0009). The number of patients requiring rescue laxatives more than once was identical during the run-in However, compared with placebo, mesalazine improved overall satisfaction with treatment, abdominal pain/discomfort and bloating score, and IBS-related QOL and reduced the use of rescue medications, although these differences did not reach statistical significance. The safety profile of mesalazine was similar to placebo. In the second study, 27 114 patients with IBS-D were randomized to mesalazine 2 grams/day or placebo for 1 week, followed by 2 grams twice daily if the initial dose was tolerated. Consistent with the results of the first study, treatment has no impact on IBS symptoms, including bowel frequency, abdominal pain, or stool consistency. Together, these results suggest that mesalazine, while safe, is not effective in an unselected population of patients with IBS. Whether disease characteristics can be identified for which mesalazine is effective remains to be determined. Conclusions This monograph summarizes a number of recent, principal advances in the diagnosis and management of gastrointestinal disorders, highlighting both nonpharmacologic techniques as well as novel pharmacotherapies. Recent reports have stressed the clinical advantages of distinguishing epigastric pain syndrome (EPS) from postprandial distress syndrome (PDS) in the pediatric population and how data suggest that meal-related symptoms of PDS not only occur commonly in children who present with epigastric pain 5

but also that a majority of these young patients with unsubtyped epigastric pain meet the Rome III criteria for IBS. Further, patients who experience chronic idiopathic constipation (CIC) often report GI symptoms that overlap with functional dyspepsia, marked by upper abdominal pain, burning, post-prandial fullness and early satiety. Such patients appear to respond to linaclotide, a guanylate cyclase-c (GC-C) receptor agonist and an intestinal secretagogue, which has been shown to reduce upper as well as lower GI symptoms. By evaluating the interactions of fatigue with other manifestations of IBS, we continue to expand and deepen our understanding of the association of symptom severity with abdominal pain and the psychosocial parameters of depression and generalized anxiety. We also have learned that GI symptom fear serves as a powerful predictor of IBS-specific QoL, not otherwise explained by symptom severity, overall emotional well-being, neurotic personality, or other clinical features of IBS. New data on mindfulness training reinforces previous reports of improvement in overall symptom severity, IBS-QoL scores, visceral anxiety and psychological distress at both 6 and 12-month time intervals among patients with IBS. The accumulation of data, accompanied by a growing body of literature supports the potential contribution of the gut microbiota to the genesis and progression of IBS. Additionally, antibiotics, in particular nonabsorbable agents such as rifaximin, have joined the therapeutic armamentarium for both IBS without constipation and IBS-D. As induction therapy and in re-treatment, rifaximin achieves a statistically significant therapeutic responsiveness while maintaining bacterial sensitivity to other antibiotic classes and without promoting pathogenic bacterial growth. Other novel therapies for IBS include plecanatide, a naturally occurring ligand of human intestinal guanylate cycle-c receptor for IBS-C, which demonstrated statistical improvement on the FDA overall responder endpoint, stool consistency, and straining at doses of 3 mg and 9 mg. In two, double-blind, placebo-controlled, phase 3 clinical trials of 26 weeks duration, eluxadoline, a mixed mu-opioid receptor agonist and delta-opioid receptor antagonist attained statistically significant responder rates. Dosed twice daily, eluxadoline 75 mg and 100 mg, exhibited statistically significant differences in stool consistency, daily bowel movements, urgent episodes, global symptom scores, and IBS-specific QoL compared with placebo. Through its novel mechanism of action, eluxadoline appears to be comparatively more efficacious in relieving overall and individual bowel symptoms than the abdominal pain associated with IBS. Lastly, while mesalazine, a 5-aminosalicylic acid anti-inflammatory, improved overall treatment satisfaction and IBS-related QoL, it failed to elicit a treatment impact versus placebo on the IBS symptoms of bowel frequency, abdominal pain, and stool consistency. Taken together, the data generated from two studies affirmed the safety but not the efficacy of mesalazine in unselected, IBS patient populations. These findings may warrant future clinical trials of IBS subgroups in which mesalazine may prove clinically beneficial. 6

References 1. Drossman DA. The functional gastrointestinal disorders and the Rome III process. Gastroenterology. 2006;130:1377-1390. 2. Van Tilburg MA, Hyams JS, Leiby A, et al. Functional Dyspepsia in Children: Can We Distinguish Epigastric Pain and Postprandrial Distress? Digestive Disease Week 2014. Abstract no. 818. 3. Talley NJ, Shiff SJ, Lavins BJ, et al. Linaclotide Efficacy on Dyspepsia Symptoms Using Nepean Dyspepsia Index (NDI) in a Phase 3B Trial of CIC Patients With Bloating. American College of Gastroenterology Annual Meeting 2014. Program no. 11. 4. Jakobsson S, Bjorkman I, Ung EJ, Tornblom H, Simren M. Interplay Between Fatigue, Gastrointestinal Symptoms, Psychological Distress and Coping in Patients With Irritable Bowel Syndrome (IBS). Digestive Disease Week 2014. Abstract no. Su2069. 5. Lackner JM, Gudleski GD, Ma CX, Dewanwala A, Naliboff B, Representing the IOSRG. Fear of GI Symptoms has an Important Impact on Quality of Life in Patients With Moderate-to-Severe IBS. Am J Gastroenterol. 2014. 6. Posserud I, Stotzer PO, Bjornsson ES, Abrahamsson H, Simren M. Small intestinal bacterial overgrowth in patients with irritable bowel syndrome. Gut. 2007;56:802-808. 7. Ford AC, Spiegel BM, Talley NJ, Moayyedi P. Small intestinal bacterial overgrowth in irritable bowel syndrome: systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2009;7:1279-1286. 8. Shah ED, Basseri RJ, Chong K, Pimentel M. Abnormal breath testing in IBS: a meta-analysis. Dig Dis Sci. 2010;55:2441-2449. 9. Hanevik K, Wensaas KA, Rortveit G, Eide GE, Morch K, Langeland N. Irritable bowel syndrome and chronic fatigue 6 years after giardia infection: a controlled prospective cohort study. Clin Infect Dis. 2014;59:1394-1400. 10. Jalanka-Tuovinen J, Salojarvi J, Salonen A, et al. Faecal microbiota composition and host-microbe cross-talk following gastroenteritis and in postinfectious irritable bowel syndrome. Gut. 2014;63:1737-1745. 11. Grover M, Camilleri M, Smith K, Linden DR, Farrugia G. On the fiftieth anniversary. Postinfectious irritable bowel syndrome: mechanisms related to pathogens. Neurogastroenterol Motil. 2014;26:156-167. 12. Piche T, Vanbiervliet G, Pipau FG, et al. Low risk of irritable bowel syndrome after Clostridium difficile infection. Can J Gastroenterol. 2007;21:727-731. 13. Garg S, Song Y, Ai Thanda Han M, Girotra M, Dutta S. Post-Infectious Irritable Bowel Syndrome in Patients Undergoing Fecal Microbiota Transplantation for Recurrent Clostridium difficile Colitis. Digestive Disease Week 2014. Abstract no. 392. 14. Pimentel, Mark, et al. N Engl J Med 2011; 364:22-32 January 6, 2011 15. Lembo A, Pimentel M, Rao SS, et al. Efficacy and Safety of Repeat Treatment With Rifaximin for Diarrhea-Predominant Irritable Bowel Syndrome (IBS-D): Results of the TARGET 3 Study. Program no. 45. American College of Gastroenterology Annual Meeting 2014. Program no. 45. 16. Garland EL, Gaylord SA, Palsson O, Faurot K, Douglas Mann J, Whitehead WE. Therapeutic mechanisms of a mindfulness-based treatment for IBS: effects on visceral sensitivity, catastrophizing, and affective processing of pain sensations. J Behav Med. 2012;35:591-602. 17. Gaylord SA, Palsson OS, Garland EL, et al. Mindfulness training reduces the severity of irritable bowel syndrome in women: results of a randomized controlled trial. Am J Gastroenterol. 2011;106:1678-1688. 18. Gaylord SA, Whitehead WE, Coble RS, et al. Mindfulness for irritable bowel syndrome: protocol development for a controlled clinical trial. BMC Complement Altern Med. 2009;9:24. 7

References 19. Faurot KR, Gaylord SA, Palsson OS, Garland EL, Mann JD, Whitehead WE. Mindfulness Meditation Has Long-Term Therapeutic Benefits in Women With Irritable Bowel Syndrome (IBS): Follow-Up Results From a Randomized Controlled Trial. Digestive Disease Week 2014. Abstract no. 75. 20. Miner PB, DeLuca R, La Portilla MD, et al. Plecanatide, a Novel Uroguanylin Analog: A 12-Week, Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Trial to Evaluate Efficacy and Safety in Patients With Irritable Bowel Syndrome With Constipation (IBS-C). American College of Gastroenterology Annual Meeting 2014. Program no. 14. 21. Lembo A, Dove S, Andrae D, et al. Eluxadoline for the Treatment of Diarrhea-Predominant Irritable Bowel Syndrome: Results of 2 Randomized, Double-blind, Placebo-Controlled Phase 3 Clinical Trials of Efficacy and Safety. American College of Gastroenterology Annual Meeting 2014. Abstract no. 929d. 22. Furiex Pharmaceuticals. Furiex Pharmaceuticals Announces Positive Top-Line Results of Two Pivotal Phase III Clinical Trials of Eluxadoline in Patients with IBS-D. http://investor.furiex.com/releasedetail.cfm?releaseid=822849. Accessed November 1, 2014. 23. Bafutto M, Almeida JR, Leite NV, Costa MB, Oliveira EC, Resende-Filho J. Treatment of diarrhea-predominant irritable bowel syndrome with mesalazine and/or Saccharomyces boulardii. Arq Gastroenterol. 2013;50:304-309. 24. Xue L, Huang Z, Zhou X, Chen W. The possible effects of mesalazine on the intestinal microbiota. Aliment Pharmacol Ther. 2012;36:813-814. 25. 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;30:245-252. 26. Giovanni B, Cremon C, Annese V, et al. Randomised controlled trial of mesalazine in IBS. Gut. 2014;0:1-9. 27. Lam C, Tan WJ, Leighton MP, et al. A Multi-Centre, Parallel Group, Randomised Placebo Controlled Trial of Mesalazine for Treatment of Diarrhoea-Predominant Irritable Bowel Syndrome (IBS-D). American College of Gastroenterology Annual Meeting 2014. Abstract no. 712. 8

Assessment 1. What was the increase in CSBM frequency in patients treated with plecanatide 3 mg compared to placebo? a. 2.11 b. 2.75 c. 5.62 d. 7.75 2. What was the most common adverse event associated with plecanatide? a. Diarrhea b. Constipation c. Pancreatitis d. Respiratory distress (mild) 3. Which correctly characterizes the mechanism of eluxadoline? a. CIC-2 antagonist b. Mixed mu-opioid receptor agonist and delta-opioid receptor antagonist c. Mixed mu opioid receptor antagonist and delta opioid receptor agonist d. Mu opioid receptor agonist only 4. What was the most common adverse event reported in patients receiving eluxadoline 75 mg? a. Nausea b. Constipation c. Diarrhea d. Pancreatitis 5. What conclusions can be drawn from 2 large randomized clinical trials evaluating the use of mesalazine in patients with IBS? a. Mesalazine is effective for patients with IBS, regardless of subtype b. Mesalazine is ineffective for patients with IBS, regardless of subtype c. Mesalazine is effective for IBS-D, but not IBS-C d. Mesalazine is effective for IBS-C, but not IBS-D 6. The TARGET 3 study showed that rifaximin retained efficacy for at least round(s) of treatment. a. 1 b. 2 c. 3 d. 4 7. What percentage of patients with C. difficile colitis develop PI-IBS following fecal transplant? a. 3.5% b. 9.7% c. 12.9% d. 18.5% 8. True or false: In a large proportion of children with epigastric pain, pain is relieved with defecation, suggesting they may qualify for a diagnosis of IBS. a. True b. False 9

2194249191 ROME FOUNDATION - FGIDs: YEAR IN REVIEW Evaluation Form We respect and appreciate your opinions. To assist us in evaluating the effectiveness of this activity and to make recommendations for future educational offerings, please take a few minutes to complete this evaluation form. To receive acknowledgement of participation for this activity, the completed form must be faxed to 866-615-1527. Please answer the following questions by filling in the circle for the appropriate rating: 5 = Outstanding 4 = Good 3 = Satisfactory 2 = Fair 1 = Poor How well did this activity meet the following learning objectives? This learning objective did or will impact my: Identify key advances in the management of functional gastrointestinal disorders 5 4 3 2 1 Knowledge Competence Performance Patient Outcomes Incorporate into daily practice, as applicable, new data on functional gastrointestinal disorders from the major international meetings and literature of 2014 5 4 3 2 1 Knowledge Competence Performance Patient Outcomes Please comment if the above objectives were not met: What percentage of information presented in this activity will be of use to you? 0% 20% 40% 60% 80% 100% Impact of the Activity Please indicate which of the following American Board of Medical Specialties/Institute of Medicine core competencies were addressed by this educational activity (select all that apply): Patient care or patient-centered care Practice-based learning and improvement Interpersonal and communication skills Employ evidence-based practice Interdisciplinary teams Professionalism Quality improvement Medical knowledge The content of this activity matched my current (or potential) scope of practice. Yes No, please explain System-based practice Utilize informatics None of the above Was this activity scientifically sound and free of commercial bias* or influence? Yes No, please explain * Commercial bias is defined as a personal judgment in favor of a specific product or service of a commercial interest.. 10

1715249199 ROME FOUNDATION - FGIDs: YEAR IN REVIEW The educational activity has enhanced my professional effectiveness in treating patients.................................... The educational activity will result in a change in my practice behavior...... Strongly Agree Agree Disagree Evaluation Form Strongly Disagree Not Applicable How will you change your practice as a result of participating in this activity (select all that apply)? Create/revise protocols, policies, and/or procedures I will not make any changes to my practice Change the management and/or treatment of my patients Other, please specify: This activity validated my current practice What new information did you learn during this activity? Please indicate any barriers you perceive in implementing these changes. Lack of experience Lack of resources (equipment) Lack of time to assess/counsel patients Lack of consensus of professional guidelines Lack of opportunity (patients) Lack of administrative support If you indicated any barriers, how will you address these barriers in order to implement changes in your knowledge, competency, performance, and/or patients outcomes? Reimbursement/insurance issues Patient compliance issues No barriers Cost Other Comments to help improve this activity? Recommendations for future educational topics. To assist with future planning, please attest to time spent on activity: I spent hours on this program. 11

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