Literature Review

1. Literature Review Peter R. McNally, DO, FACP, FACG University Colorado Denver School of Medicine Center for Human Simulation Aurora, Colorado 80045

2. Abbreviations Used • IBS Irritable Bowel Syndrome • SIBO Small Intestinal Bacterial Overgrowth • BM Bowel movement • DTO Deodorized Tincture of Opium • TCA’s Tricyclic Anti-Depressants • SSRI’s Selective Serotonin Inhibitors • SNRI’s Selective Norepinephrine Inhibitors • CAM Complimentary and Alternative Medicine • 1º & 2º  Primary & Secondary • 5-HT4 5-hydroxytryptophan -4 inhibitor • PG E1 Prostaglandin E-1 • DBPC Double Blind Placebo Controlled

3. P R McNally, DO, FACP, FACG Introduction • IBS is a chronic, recurrent, functional bowel disorder characterized by recurrent abdominal pain and disturbed bowel movements. • IBS affects 10–20% of the adult population worldwide and causes significant morbidity, quality-of-life impairment, and burden on the healthcare system. Hungin Ap, et al. APT. 2005;21:1365-75; Sandler RS, et al. Gastroenterol. 2002;122:1500-11; Lacy BE, et al. Ther Adv Gastroenterol. 2009;2:221-38.

4. P R McNally, DO, FACP, FACG IBS Pathophysiology • Despite the high prevalence of IBS, its underlying mechanism(s) are not fully understood. • Mounting evidence suggests that IBS is caused by interactions of numerous biological and psychosocial factors. Brandt, LJ, et al. Am J Gastroenterol. 2002;97: S7–S26; Al-Khatib K et al. Gut Liver. 2009;3:14-9. Thabane M et al. W J Gastro. 2009;15:3591-6. Manabe N et al. Sm Mus Res. 2009;45:15-23. Spiller R, et al. Gut. 2007;56:1770-98. Farhadi A et al. W J Gastro. 2007;13:3027-30. Frissora CL & Cash BD. APT. 2007;25:1271-81.

5. P R McNally, DO, FACP, FACG IBS is a Complex SyndromeCaused by Many System Interactions Brain-Gut Interactions Motility Abnormalities Gut Eco- System Micro- biotica Visceral Hyper-sensitivity IBS Gut-Immune Interactions Genetic Factors Psycho-logical Distress Brandt, LJ, et al. Am J Gastroenterol. 2002;97: S7–S26; Al-Khatib K et al. Gut Liver. 2009;3:14-9. Thabane M et al. W J Gastro. 2009;15:3591-6. Manabe N et al. Sm Mus Res. 2009;45:15-23. Spiller R, et al. Gut. 2007;56:1770-98. Farhadi A et al. W J Gastro. 2007;13:3027-30. Frissora CL & Cash BD. APT. 2007;25:1271-81.

6. P R McNally, DO, FACP, FACG IBS is a Disorder Diagnosed by Symptom Based Criteria • Manning Criteria • Rome I Criteria • Rome II Criteria • Rome III Criteria • (-) H&P, labs, & no • Recurrent abd pain > 3 days/mo in last 3 mo assoc w/ > 2 following: • Improvement w/ BM • Onset w/ ∆ freq BM • Onset w/ ∆ form of stool Longstreth GF, et al. Gastroenterol. 2006;130:1480-91

7. Treatment of IBS • IBS Treatment has focused on individual Sx: • Abdominal Pain • Bloating • Constipation • Diarrhea

8. Treatment of IBS • Abdominal Pain: Smooth MM relaxants, TCA’s, SSRI’s, SSRI/SNRI’s, CAM (peppermint, germander, lavender oils) • Bloating: Probiotics, Diet Modification, Antibiotics • Diarrhea: Anticholenergic, Probiotics, Antibiotics, Loperamide, Diphenoxylate-atropine, Alosetron, Cilansetron, Cholestyramine, DTO, TCA’s • Constipation: Dietary, emollients, laxatives, osmotic, 5-HT4, PG E1, Antibiotics

9. Treatment of IBS • Perhaps no treatment for IBS has generated more interest and criticism, then antibiotic therapy directed toward presumed mechanisms of IBS: SIBO &/or Gut Dysbiosis. • Pimentel1,2, DiStefano3 and many other have shown that a limited course of broad spectrum antibiotics can improve both IBS Symptom scores and Breath test results. 1 Pimentel, M et al. Ann Intern Med. 2006;145: 557–63. 2 Pimentel, M et al. Am J Gastroenterol 2003;98:412–419.   3 Di Stefano, M. Aliment Pharmacol Ther 2000;14:1001–08.

10. Mark Pimentel, M.D., Anthony Lembo, M.D., William D. Chey, M.D.,Salam Zakko, M.D., Yehuda Ringel, M.D., Jing Yu, Ph.D.,Shadreck M. Mareya, Ph.D., Audrey L. Shaw, Ph.D., Enoch Bortey, Ph.D.,and William P. Forbes, Pharm.D., for the TARGET Study Group* *Members of the TARGET Study Group Rifaximin Therapy for Patients with Irritable Bowel Syndrome without Constipation. N Engl J Med 2011;364:22-32.

11. Pimentel M, et al. NEJM. 2011;364:22. Introduction • IBS is a functional gastrointestinal disorder characterized by recurrent symptoms of abdominal pain, bloating, altered bowel function in the absence of structural, inflammatory or biochemical abnormalities. • Patients with IBS have alterations in gut microbiotica leading some investigators to treat IBS with antibiotics. • Rifaximin (Xifaxan, Salix Pharmaceutical) is an oral, non-systemic, broad spectrum antibiotic that has been shown to have promising results in the treatment of IBS.

12. Pimentel M, et al. NEJM. 2011;364:22. Study Aim • Determine if Rifaximin (Xifaxan, Salix, Pharmaceutical) treatment (550 mg tid for 14 days) for IBS patients without constipation would improve symptoms: • 1º End point Improvement in global IBS symptoms • 2º End point: Improvement in IBS-related bloating.

13. Pimentel M, et al. NEJM. 2011;364:22. Methods • Study Design: randomized, double-blind trial, efficacy evaluation of Rifaximin vs. Placebo in 1260 adults with IBS without constipation. • All IBS pts met the following enrollment criteria: • > 18 yrs of age, Negative colonoscopy examination within 2 years of enrollment • Rome II Criteria for IBS, but without constipation • IBS Symptom Scores • Daily abdominal pain : all 2-4.5 on Likert score (1-7) • Ave Daily consistency of stool > 3.5 on score (1-5, very hard to watery) • Exclusion Criteria: • IBD, DM, unstable thyroid disease, previous abdominal surgery (except appendectomy of cholecystectomy). HIV infection renal or hepatic disease. • Concurrent medication: alosetron, tegaserod, lubiprostone, warfarin, antipsychotic, antispasmotic, antidiarrheal, probiotic, narcotic, antibiotics within previous 14 days, or rifaximin within 60 days. • Patients were allowed to continue SSRI and TCA medications if on a chronic and stable dose > 6 wk

14. Pimentel M, et al. NEJM. 2011;364:22. Methods • Study Design: randomized, double-blind trial, efficacy evaluation of Rifaximin vs. Placebo in 1260 adults with IBS without constipation. • All IBS pts met Rome II Criteria. • Patients were randomly assigned to 2 Tx Groups: • Rifaximin 550 mg po tid for 14 days • Placebo po tid for 14 days • The Study was conducted in two Parallel Study Groups: • Target 1 (n=623) • Target 2 (n=637)

15. Pimentel M, et al. NEJM. 2011;364:22. Methods • Study Design see Study Design Figure – next • Efficacy & Safety End Points • Statistical Analysis: • Five analysis centers: Binary data, ordinal data, continuous data • P value of < 0.05 considered significant Efficacy: Wk global IBS sx Wk IBS-bloating Daily IBS QOL score Safety: AE’s & Other Rx Vital Signs Lab Tests Phys Exam

16. Pimentel M, et al. NEJM. 2011;364:22. Study Design: Enrollment, Randomization & Follow-Up 1260 Pts were enrolled Target 1, n=623 Target 2, n=637 Rifaximin, n=316 Placebo, n=321 Rifaximin, n=309 Placebo, n=314 Drop Outs N=26 Drop Outs N=22 Drop Outs N=15 Drop Outs N=19 309 included in the ITT Analysis 314 included in the ITT Analysis 315 included in the ITT Analysis 320 included in the ITT Analysis

17. Pimentel M, et al. NEJM. 2011;364:22. Study Design Screening 14-D blind Rx 10 wk Follow-up (no study Rx) • 7 14 21 28 35 42 49 56 63 70 77 84 • Days • Phone F/U • * * * * * * * * * * * * * • * * * * * * * * * * * * * • * * * * • * * * * * * * * • * * * * * • * * * • * * * Efficacy Wk global IBS sx Wk IBS-bloating Daily IBS QOL score Safety AE’s & Other Rx Vital Signs Lab Tests Phys Exam

18. Pimentel M, et al. NEJM. 2011;364:22. Demographics

19. Pimentel M, et al. NEJM. 2011;364:22. DemographicsBaseline Characteristics

20. Pimentel M, et al. NEJM. 2011;364:22. % of Pts with Adequate Relief of Global IBS Sx 10 wk Follow-Up (no Study Rx) T-0 4wk 6wk 8wk 10wk 12wk 14-Day Double-Blind Treatment Phase

21. Pimentel M, et al. NEJM. 2011;364:22. Efficacy Outcomes (Combined data from Target 1 & Target 2)

22. Pimentel M, et al. NEJM. 2011;364:22. Adverse Events During 12 wk Study

23. Pimentel M, et al. NEJM. 2011;364:22. Adverse Events During 12 wk Study

24. Pimentel M, et al. NEJM. 2011;364:22. Study Conclusions • Results of 2 (Target 1 & Target 2) large DBPC Trials Evaluating Rifaximin in the treatment of IBS without constipation show the following: • Rifaximin is effective in improving Global & Bloating symptoms among IBS patients without constipation • Safety profile for Rifaximin appears to be similar to Placebo • Durability of IBS symptom relief is evident for 10 wk after Rifaximin treatment. • No cases of C. difficle colitis were identified

25. Pimentel M, et al. NEJM. 2011;364:22. Reviewer Comments Pimentel, and the other members of the TARGET Study Group are praised for conducting a much needed study on the efficacy of Rifaximin vs. Placebo in IBS patients without constipation. The investigators’ research shows that Rifaximin is effective with durable IBS symptom relief for 10 weeks. Equally important, Rifaximin is safe, with a profile similar to placebo in these IBS patients. P R McNally, DO, FACP, FACG

26. P R McNally, DO, FACP, FACG Reviewer Comments However, Pimentel, et al, fail to answer the following questions? • Will these Rifaximin responsive IBS patients relapse overtime? Are the short term “10 wk ” improvements in IBS global & bloating symptoms durable? • Will re-treatment with Rifaximin be as effective or associated with resistance or toxicities that were not evident in a single course of 14 days of treatment?

27. P R McNally, DO, FACP, FACG Reviewer Comments • Today, IBS patients have few FDA approved treatment options. It is encouraging to see medical investigators and the Pharmaceutical Industry expend extensive resources to evaluate and develop effective and safe treatments for this complex disorder. • The results of this study are very encouraging that IBS patients without constipation have a new and effective treatment for relief of global symptoms and IBS related bloating.

28. P R McNally, DO, FACP, FACG Reviewer Comments • Is there an “Re-Treatment Strategy” for IBS patients with relapse? Will repeated courses of Rifaximin prove to be just as safe and effective? • Are there other counter-measures that can be instituted after Rifaximin treatment that will prevent or delay the relapse period, i.e., prokinetics, probiotics, dietary modifications?

29. P R McNally, DO, FACP, FACG Reviewer Conclusions • IBS is a very common disorder in need to better diagnostic and treatment options. • Rifaximin is a unique intra-luminal, non-systemic antibiotic THAT is safe and has little to no apparent associated development of bacterial drug resistance. Making Rifaximin an ideal agent to treat IBS related Dysbiosis. • The study by Pimentel reviewed in this edition of www.VHJOE.org is just one of MANY that have repeatedly shown that Rifaximin is an effective treatment of SIBO & IBS without constipation.

30. P R McNally, DO, FACP, FACG Reviewer Conclusions • It is a great surprise that the FDA recently ruled against the approval of this agent for treatment for IBS pts without constipation, since both the TARGET 1 & 2 clinical trials have clearly shown that Rifaximin is both SAFE & EFFECTIVE in the treatment of IBS without constipation. • Hopefully, the sponsor (Salix) for this drug (Rifaximin) development will not abandon further research required to achieve FDA approval marking Rifaximin for the treatment of IBS patients without constipation.