Digesting the Facts in IBS: From Early Diagnosis to Effective Treatment Options

Digesting the Facts in IBS: From Early Diagnosis to Effective Treatment Options September 19, 213 Boston, Massachusetts Educational Partner:

Session 3: Digesting the Facts in IBS: From Early Diagnosis to Effective Treatment Options Learning Objectives 1. Evaluate the necessity of diagnostic testing in individual patients prior to diagnosis of IBS. 2. Choose appropriate nonpharmacologic or pharmacologic therapies to aid patients with IBS. 3. Manage the symptoms of IBS over the long term through effective treatment strategies. Faculty Lawrence R. Schiller, MD, FACS Professor of Internal Medicine Texas A&M Health Science Center, Dallas Campus Program Director Gastroenterology Fellowship Baylor University Medical Center Dallas, Texas Lawrence R. Schiller, MD, FACS, was born in Philadelphia, Pennsylvania, and attended Pennsylvania State University and Jefferson Medical College of Philadelphia. He completed his internal medicine training at Temple University Hospital in Philadelphia and then served in the US Army Medical Corps for 2 years. Dr Schiller moved to Texas in 1978 for training in gastroenterology at the University of Texas Southwestern Medical Center in Dallas and then stayed on the faculty at the medical school and was an attending physician at the Dallas VA hospital for 5 years. He moved to Baylor University Medical Center in Dallas in 1985 to continue research activities with John Fordtran, MD, and has been there ever since, most recently serving as program director for the gastroenterology fellowship. Dr Schiller has been involved with patient care as a founding partner of Digestive Health Associates of Texas, one of the largest singlespecialty gastroenterology practices in the United States, and has continued with research and education activities at Baylor University and University of Texas Southwestern. He is currently attending physician and chairman of the Institutional Review Board for Human Subject Protection at Baylor University as well as clinical professor of internal medicine at the University of Texas Southwestern, where he has won 2 fellow teaching awards. He has been elected to fellowships in the American College of Physicians and the American College of Gastroenterology (ACG) and has been governor for North Texas for the ACG. Dr Schiller currently is serving the ACG as president and has also served as president of the Texas Society for Gastroenterology and Endoscopy. Dr Schiller has published more than 8 papers and 45 book chapters dealing with gastric physiology, intestinal transport, diarrheal diseases, and motility disorders. Brian E. Lacy, MD, PhD Professor of Medicine Dartmouth Medical School Hanover, New Hampshire Director of the GI Motility Laboratory Dartmouth-Hitchcock Medical Center Lebanon, New Hampshire Brian E. Lacy, MD, PhD, is currently professor of medicine at the Geisel School of Medicine at Dartmouth, section chief of the division of gastroenterology & hepatology, and director of the GI Motility Laboratory at the Dartmouth-Hitchcock Medical Center in Lebanon, New Hampshire. Dr Lacy s clinical and basic science research interests focus on disorders of gastrointestinal motility, with an emphasis on irritable bowel syndrome, dyspepsia, gastroparesis, acid reflux disease, constipation, intestinal pseudo-obstruction, achalasia, and visceral pain. He is the author or coauthor of more than 85 peer-reviewed articles and the author or coauthor of numerous textbook chapters on gastrointestinal motility disorders and functional bowel disorders. Dr Lacy is a reviewer for a number of scientific journals and is a member of the American College of Gastroenterology, the American Gastroenterology Association, the American Motility Society, and the Rome Committee. Dr Lacy is the coauthor of a book for the general public on acid reflux disease, Healing Heartburn; is the author of Session 3

Making Sense of IBS, a book for the general public on irritable bowel syndrome; and is the editor and author of Curbside Consultations in IBS: 49 Clinical Questions. Dr Lacy earned his doctorate in cell biology from Georgetown University in Washington, DC, and his medical degree from the University of Maryland in Baltimore. Dr Lacy was a resident in internal medicine at the Dartmouth-Hitchcock Medical Center, where he continued his training as chief resident and then as a fellow in gastroenterology. He is board certified in gastroenterology. Faculty Financial Disclosure Statements The presenting faculty reports the following: Lawrence R. Schiller, MD, FACS, is a speaker for Ironwood Pharmaceuticals, Forest Laboratories, and Takeda Pharmaceuticals. He is a consultant for Synergy Pharmaceuticals. Brian E. Lacy, MD, PhD, serves on the scientific advisory board for Ironwood Pharmaceuticals, Forest Laboratories, and Takeda. Education Partner Financial Disclosure Statement The content collaborators at CME Incite report the following: Rose O Connor, PhD, and Monique Pond, PhD, have no financial relationships to disclose. Suggested Reading List Brandt LJ, Chey WD, Foxx-Orenstein AE, et al; for the American College of Gastroenterology Task Force on Irritable Bowel Syndrome. An evidence-based position statement on the management of irritable bowel syndrome. Am J Gastroenterol. 29;14(suppl 1):S1-S35. Cash BD, Rubenstein JH, Young PE, et al. The prevalence of celiac disease among patients with nonconstipated irritable bowel syndrome is similar to controls. Gastroenterology. 211;141(4):1187-1193. Cash BD, Chang E, Talley NJ, et al. Fresh perspectives in chronic constipation and other functional bowel disorders. Rev Gastroenterol Disord. 27;7(3):116-133. Chey WD, Drossman DA, Johanson JF, et al. Safety and patient outcomes with lubiprostone for up to 52 weeks in patients with irritable bowel syndrome with constipation. Aliment Pharmacol Ther. 212;35(5):587-599. Chey WD, Nojkov B, Rubenstein JH, et al. The yield of colonoscopy in patients with non-constipated irritable bowel syndrome: results from a prospective, controlled US trial. Am J Gastroenterol. 21;15(4):859-865. Chey WD, Lembo AJ, Lavins BJ, et al. Am J Gastroenterol. 212;17(11):172-1712. Ford AC, Talley NJ, Spiegel BMR, et al. Effect of fibre, antispasmodics, and peppermint oil in the treatment of irritable bowel syndrome: systematic review and meta-analysis. BMJ. 28;337:a2313. Guyonnet D, Chassany O, Ducrotte P, et al. Effect of a fermented milk containing Bifidobacterium animalis DN-173 1 on the healthrelated quality of life and symptoms in irritable bowel syndrome in adults in primary care: a multicentre, randomized, double-blind, controlled trial. Aliment Pharmacol Ther. 27;26(3):475-486. Kaptchuk TJ, Kelley JM, Conboy LA, et al. Components of placebo effect: randomised controlled trial in patients with irritable bowel syndrome. BMJ. 28;336(7651):999-13. Lembo A, Camilleri M. Chronic constipation. N Engl J Med. 23;349(14):136-1368. Longstreth GF, Thompson WG, Chey WD, et al. Functional bowel disorders. Gastroenterology. 26;13(5):148-1491. Rao S, Lembo AJ, Shiff SJ, et al. A 12-week, randomized, controlled trial with a 4-week randomized withdrawal period to evaluate the efficacy and safety of linaclotide in irritable bowel syndrome with constipation. Am J Gastroenterol. 212;17(11):1714-1724. Session 3

SESSION 3 11am 12:15pm Digesting the Facts in IBS: From Early Diagnosis to Effective Treatment Options SPEAKERS Lawrence R. Schiller, MD, FACS Brian E. Lacy, MD, PhD Presenter Disclosure Information The following relationships exist related to this presentation: Lawrence R. Schiller, MD, FACS, is a speaker for Ironwood Pharmaceuticals, Forest Laboratories, and Takeda Pharmaceuticals. He is a consultant for Synergy Pharmaceuticals. Brian E. Lacy, MD, PhD, serves on the scientific advisory board for Ironwood Pharmaceuticals, Forest Laboratories, and Takeda. Off-Label/Investigational Discussion In accordance with pmicme policy, faculty have been asked to disclose discussion of unlabeled or unapproved use(s) of drugs or devices during the course of their presentations. Drug List Digesting the Facts in IBS: From Early Diagnosis to Effective Treatment Options Brian Lacy, MD, PhD Lawrence Schiller, MD Boston, Massachusetts September 19, 213 Lotronex Elavil, Tryptizol, Laroxyl, etc Celexa Norpramin, Pertofane Adapin, Silenor, Sinequan, etc Prozac, Sarafem, Fontex, etc Antideprin, Deprimin, Deprinol, etc Linzess Amitiza Colofac Paxil, Aropax, Seroxat, Pexeva, etc Xifaxan Alosetron Amitriptyline Citalopram Desipramine Doxepin Fluoxetine Imipramine Linaclotide Lubiprostone Mebeverine Paroxetine Rifaximin Learning Objectives Today s Agenda Evaluate the necessity of diagnostic testing in individual patients prior to diagnosis of irritable bowel syndrome (IBS) Choose appropriate nonpharmacologic or pharmacologic therapies to aid patients with IBS Manage the symptoms of IBS over the long term through effective treatment strategies Fact or Fiction? Select 1 for Fact Select 2 for Fiction Discussion of Case Study 1: Diane Discussion of Case Study 2: Mary Audience participation will enhance this program. 1

Rome III Criteria for IBS Positive IBS Diagnosis May Reduce Diagnostic Testing and Resource Utilization Recurrent abdominal pain or discomfort at least 3 days/month in the last 3 months associated with 2 of the following: Improvement with defecation Onset associated with a change in frequency of stool Onset associated with a change in form of stool Criteria fulfilled for the last 3 months with symptom onset at least 6 months prior to diagnosis Consider IBS a Diagnosis of Exclusion, % 8 IBS Experts (n=27) 72 Community Clinicians (n=281) Clinicians who believed IBS was a diagnosis of exclusion ordered 1.6 times more tests and spent $364 more on diagnostic tests per patient (P<.1) Longstreth GF, et al. Gastroenterology. 26;13:148-1491; erratum in: Gastroenterology. 26;131:688. Spiegel BMR, et al. Am J Gastroenterol. 21;15:848-858. Alarm Features for IBS Yield of Colonoscopy in IBS Refractory or worsening abdominal symptoms Older patient ( 5 years; 45 years if African-American) Blood in stools Anemia Weight loss (unintentional) Anorexia Family history of organic gastrointestinal disease Lembo A, et al. N Engl J Med. 23;349:136-1368. Brandt LJ, et al. Am J Gastroenterol. 25;1(suppl 1):S5-S21. Cash BD, et al. Rev Gastroenterol Disord. 27;7:116-133. If present, investigate and treat appropriately; colonoscopy may be indicated Histologic Findings in IBS Patients and Controls; Populations Not Matched for Age or Gender Lesion IBS Patients n=466 (%) Controls n=451 (%) P Value Adenomas 36 (7.7) 118 (26.1) <.1 Hyperplastic polyps 39 (8.4) 52 (11.5) NS Colorectal adenocarcinoma (.) 1 (.2) NS IBD 2 (.4) (.) NS Microscopic colitis 7 (1.5) N/A N/A Microscopic colitis was more common in a subset of patients with IBS-D who were 45 years (2.3%). IBD, inflammatory bowel disease; IBS-D, irritable bowel syndrome diarrhea-predominant; N/A, not applicable; NS, not significant. Chey WD, et al. Am J Gastroenterol. 21;15:859-865. Pretest Probability of Organic Disease 1 Organic Disease IBS Patients (%) Control/Population (%) Colitis/IBD.51-.98.3-1.2 Colorectal cancer -.51-6 (varies with age) Lactose malabsorption 38 26 Thyroid dysfunction 4.2 5-9 Celiac disease 3.6.7 Celiac disease: antibodies 2 7.3 4.8 Celiac disease: confirmed 2.41.44 Bulking Agents for IBS-C: Systematic Review and Metaanalysis RCTs N Response* RR of Unimproved Symptoms NNT (95%CI) Fiber Placebo (95% CI) Overall 12 591 48% 43%.87 (.76-1.) 11 (5-1) Ispaghula 6 321 48% 36%.78 (.63-.96) 6 (3-5) Bran 5 221 46% 46% 1.2 (.82-1.27) *Improved or resolved symptoms. Heterogeneity with ispaghula No evidence of publication bias 4 out of 5 bran studies of poor quality 1. American College of Gastroenterology Task Force on Irritable Bowel Syndrome, et al. Am J Gastroenterol. 29;14(suppl 1):S1-S35. 2. Cash BD, et al. Gastroenterology. 211;141:1187-1193. CI, confidence interval; NNT, number needed to treat; RCTs, randomized, controlled trials; RR, relative risk. Ford AC, et al. BMJ. 28;337:a2213. 2

Responders Abdominal Discomfort (FDDQL), % Bifidobacterium animalis DN-173 1 for IBS-C 1 9 8 7 6 5 4 3 2 1 65 63 48* 57 Week 3 Week 6 Probiotic (n=135) Placebo (n=132) Stool frequency increased in patients with <3 bowel movements/week *P=.3 Probiotic: fermented milk product (Activia ) containing B. animalis 1.25 x 1 1 CFU per serving, Streptococcus thermophilus, and Lactobacillus bulgaricus Patients With Improved Symptom Response, % Improvements in IBS Symptom Scores: Low FODMAP vs Control Diet 1 9 8 7 6 5 4 3 2 1 * * Standard Diet Low FODMAP Diet *P.1 P<.5 CFU, colony forming unit; FDDQL, Functional Digestive Disorders QoL Questionnaire. Guyonnet D, et al. Aliment Pharmacol Ther. 27;26:475-486. Staudacher HM, et al. J Hum Nutr Diet. 211;24:487-495. What Are FODMAPs? Fermentable Oligo-, Di-, Monosaccharides And Polyols Antispasmodics for IBS Excess Fructose Fructans Sorbitol Raffinose Honey, apples, pears, peaches, mangos, fruit juice, dried fruit Wheat (large amounts), rye (large amounts), onions, leeks, zucchini Apricots, peaches, artificial sweeteners, artificially sweetened gums Lentils, cabbage, Brussels sprouts, asparagus, green beans, legumes 22 randomized controlled trials comparing 12 different antispasmodics vs placebo (N=1778 patients) Significant heterogeneity among studies Many agents not available in US Appear most useful for abdominal pain In meta-analysis, symptoms persist in 39% of patients receiving antispasmodics vs 56% of placebo-treated patients (RR:.68; 95% CI:.57-.81) Shepherd SJ, et al. J Am Diet Assoc. 26;16:1631-1639. Shepherd SJ, et al. Clin Gastroenterol Hepatol. 28;6:765-771. Gibson PR, et al. J Gastroenterol Hepatol. 21;25:252-258. Ford AC, et al. BMJ. 28;337:a2313. Global Relief of IBS Symptoms With TCAs/SSRIs TCAs: 9 studies (N=319 drug vs 256 control) Imipramine, desipramine, amitriptyline, doxepin*; doses 1-15 mg Meta-analysis favors treatment SSRIs: 5 studies (N=113 drug vs 117 control) Fluoxetine, paroxetine, citalopram*; dose 1-4 mg Meta-analysis favors treatment *These agents are not currently FDA approved for IBS. SSRIs, selective serotonin reuptake inhibitors; TCAs, tricyclic antidepressants. Ford AC, et al. Gut. 29;58:367-378. Psychological Therapies for IBS RR NNT Trials N 95% CI 95% CI Cognitive behavior 7 491.6 3 therapy.42-.87 2-7 Relaxation 5 234.82 training.63-1.8 Dynamic 2 273.6 3.5 psychotherapy.39-.93 2-25 Hypnotherapy 2 4.48 2.26-.87 1.5-7 Ford AC, et al. Gut. 29;58:367-378. 3

Alosetron: Therapeutic Gain for IBS-D Alosetron for IBS-D Study N Female, % Response: Alosetron, % Response: Placebo, % 1. Camilleri M, et al. Aliment Pharmacol Ther. 1999;13:1149-1159. 2. Camilleri M, et al. Lancet. 2;355:135-14. 3. Camilleri M, et al. Arch Intern Med. 21;161:1733-174. 4. Lembo T, et al. Am J Gastroenterol. 21;96:2662-267. 5. Jones R, et al. Aliment Pharmacol Ther. 1999;13:1419-1427. Therapeutic Gain, % Camilleri 1 37 53 6 33 27 Camilleri 2 647 1 41 29 12 Camilleri 3 626 1 43 26 17 Lembo 4 81 1 73 57 16 Jones 5 * 623 1 58 48 1 *Comparison mebeverine instead of placebo. Mebeverine not available in the US. Female patients with chronic, severe IBS-D who failed other treatments Dose:.5-1. mg QD to BID Patient education regarding possible serious adverse effects of severe constipation or ischemic colitis.95 cases of ischemic colitis/1 patient-years.36 cases of severe constipation/1 patient-years If ischemic colitis occurs, it is usually within the first month of therapy Prescribing program mandated by FDA Requires patient to sign attestation form BID, twice a day; QD, once a day. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=search.drugdetails. Accessed May 15, 212. Rifaximin* Trials: Global Relief of IBS Without Constipation 45 4 35 3 25 Rifaximin 2 Placebo 15 1 5 T-I T-II Comb *Rifaximin is not currently FDA approved for IBS. Comb, Combination of both trials; T-I, TARGET 1 trial; T-II, TARGET 2 trial; TID, 3 times a day. Pimentel M, et al. N Engl J Med. 211;364:22-32. Adequate Symptom Relief, % 2 Phase 3 randomized controlled trials; N=126 patients Rifaximin 55 mg TID x 2 weeks; patients followed additional 1 weeks 4.7% vs 31.7% with adequate relief of global symptoms (P<.1) Rifaximin*: Most Extensively Studied Antibiotic for IBS Not systemically absorbed Doses studied for IBS: 4 mg BID to 55 mg TID Primary adverse effects include headache, abdominal pain, and upper respiratory tract infection *This agent is not currently FDA approved for IBS. Ford AC, et al. Clin Gastroenterol Hepatol. 29;7:1279-1286. Pimentel M, et al. N Engl J Med. 211;364:22-32. 8 7 6 5 4 3 2 1 PEG for IBS-C # BMs Pain Level BMs, bowel movements; PEG, polyethylene glycol. Pretreatment Posttreatment 1. Brandt L, et al. Am J Gastroenterol. 29;14(suppl):S1-S35. 2. Khoshoo V, et al. Aliment Pharmacol Ther. 26;23:191-196. No adult studies of laxatives in IBS-C 1 27 adolescents: PEG improved number of BMs (P<.5) but not pain in IBS-C patients 2 Mean SBM Frequency per Month Effect of Lubiprostone on IBS-C: Patients With Follow-up Over 52 Weeks Abdominal Pain/Discomfort 8 -.25 Phase 3 Randomized Studies Withdrawal/Extension Studies 7 -.5 6 5 -.75 4 3-1. 2-1.25 1-1.5 Baseline 1 2 3 4 5 6 7 8 9 11112 13 1 2 3 4 5 6 7 8 9 1 11 12 13 Month of Treatment Month of Treatment P/L Group L/P/L Group L/L Group (n=179) (n=8) (n=261) N=52 IBS-C patients who completed 12 or 16 weeks of a placebo-controlled Phase 3 trial; patients enrolled in the extension study all received lubiprostone 8 µg BID SBM, spontaneous bowel movement. Chey WD, et al. Aliment Pharmacol Ther. 212;35:587-599. Change From Baseline 4

Mean Change From Baseline +/- SEM Efficacy of Linaclotide in Patients With IBS-C 3 2 1 Treatment Period * N=8 BL 1 2 3 4 5 6 7 8 9 1 11 12 13 14 15 16 Weeks Weeks Treatment Period Placebo Linaclotide 29 µg ANCOVA, analysis of covariance; RW, randomized withdrawal. Rao S, et al. Am J Gastroenterol. 212;17:1714-1724. RW Period z RW Treatment Sequence Placebo/linaclotide 29 µg Linaclotide 29 µg/linaclotide 29 µg Linaclotide 29 µg/placebo *P<.1 for linaclotide patients vs placebo patients (ANCOVA). P<.1 for linaclotide/linaclotide patients vs linaclotide/placebo patients (ANCOVA). Change in Worst Abdominal Pain, % -1-2 -3-4 -5-6 Linaclotide Phase 3 IBS-C Trial: Abdominal Pain Over 26 Weeks BL 2 4 6 8 1 12 14 16 18 2 22 24 26 ITT population, observed cases, LS-mean presented: P-values based on ANCOVA at each week. Bars represent 95% CI. ITT, intention to treat; LS, least squares. Chey WD, et al. Am J Gastroenterol. 212;17:172-1712. Trial Week Linaclotide 29 µg P=.7 for week 1 P<.1 for weeks 2-26 Placebo N=84 Importance of Patient-Provider Relationship IBS patients who received placebo, augmented with empathetic HCP care reported significantly better outcomes than patients receiving placebo with limited HCP interactions Improvements in Global Adequate relief Symptom severity QoL 59% of IBS patients receiving only placebo and warm, empathetic care reported a decrease in symptom severity score at 6 weeks. Kaptchuk TJ, et al. BMJ. 28;336:999-13. QoL, quality of life. Partnering With Patients to Improve Treatment Adherence and Overall Outcomes Identify patients likely to have poor adherence 1 Provide clear instruction to simplify medication regimen 1 Listen and partner with patient to customize regimen 1 Reinforce desirable behaviors at follow-up visits 1 A good patient-physician relationship can improve adherence to treatment and patient satisfaction. 2,3 1. D Inca R, et al. Aliment Pharmacol Ther. 28;27:166-172. 2. Osterberg L, et al. N Engl J Med. 25:353:487-497. 3. Roter DL, et al. Doctors Talking With Patients/Patients Talking With Doctors: Improving Communication in Medical Visits. 26. INTRODUCING DIANE What should be our first course of action? 5

Which treatment would you recommend for Diane? How should we manage Diane s case over the long term? INTRODUCING MARY Was it necessary to perform these tests before diagnosing Mary with IBS? If Mary s diagnosis was IBS-C, which treatment would you offer her first? If Mary s diagnosis was IBS-D, which treatment would you offer her first? 6

Key Takeaways How should we manage Mary s case over the long term? Diagnose IBS in the absence of diagnostic test results in patients without alarm features Low-FODMAP diet, probiotics, psychological therapy all have clinical efficacy data in IBS Linaclotide and lubiprostone are FDA approved for IBS-C Alosetron is FDA approved for women with IBS-D Strategies to successfully manage symptoms of IBS over the long term include Regular assessment of IBS symptom response Adjustment of treatment strategy, if necessary Development of patient-physician partnership Aim to improve treatment adherence and patient satisfaction Question & Answer 7