Protocol. This trial protocol has been provided by the authors to give readers additional information about their work.

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1 Protocol This trial protocol has been provided by the authors to give readers additional information about their work. Protocol for: Pimentel M, Lembo A, Chey WD, et al. Rifaximin therapy for patients with irritable bowel syndrome without constipation. N Engl J Med 2011;364:22-32.

2 Protocol RFIB3007 CRP TITLE PAGE CLINICAL RESEARCH PROTOCOL A PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, MULTICENTER STUDY TO ASSESS THE EFFICACY AND SAFETY OF RIFAXIMIN 550 mg TID IN THE TREATMENT OF SUBJECTS WITH NON-CONSTIPATION IRRITABLE BOWEL SYNDROME Protocol Number: RFIB3007 Clinical Phase: 3 Treatment Regimen: Indication: Sponsor: Rifaximin 550 mg Tablets (3 times daily [TID] dosing) for 14 days Treatment of non-constipation Irritable Bowel Syndrome (Non-constipation IBS) Salix Pharmaceuticals, Inc 1700 Perimeter Park Drive Morrisville, North Carolina, USA Sponsor Signatory: Audrey L. Shaw, Ph.D. Director, Clinical Development Medical Monitor: Scott Sykes, M.D. Safety Consultant Principal Investigator: Multicenter Protocol Date: 07 March 2008 Date: 15 August 2008 This protocol contains confidential information about a product provided by Salix Pharmaceuticals, Inc. This information is provided for the exclusive use of the Investigators participating in this study. Any and all confidential information contained herein may not be disclosed to any other person or party without the prior written consent of Page 1

3 Protocol RFIB3007 CRP I agree: RFIB3007 Investigator Protocol Agreement To assume responsibility for the proper conduct of the study at this site. To conduct the study in compliance with this protocol, any future amendments, and with any other study conduct procedures provided by the Sponsor, Salix Pharmaceuticals, Inc (Salix). Not to implement any deviations from or changes to the protocol without agreement from the Sponsor and prior review and written approval from the Institutional Review Board/Independent Ethics Committee (IRB/IEC), except where necessary to eliminate an immediate hazard to the subjects, or for administrative aspects of the study (where permitted by all applicable regulatory requirements). That I am thoroughly familiar with the appropriate use of the investigational drug(s), as described in this protocol and any other information provided by the Sponsor including, but not limited to the following: the current Investigator s Brochure or equivalent document provided by Salix and approved product label, if applicable. That I am aware of, and will comply with, good clinical practices (GCP) and all applicable regulatory requirements. To ensure that all persons assisting me with the study are adequately informed about the investigational drug(s) and of their study-related duties and functions as described in the protocol. To periodic on-site monitoring of the case report forms (CRFs) and source documents by Salix or designee and to on-site inspection of CRFs and source documents by appropriate regulatory authorities, including but not limited to the United States Food and Drug Administration (FDA), local governing regulatory bodies, and IRB/EC inspectors. That I have been informed that certain regulatory authorities require the Sponsor to obtain and supply details about the investigator s ownership interest in the Sponsor or study drug, and more generally about his/her financial ties with the Sponsor. Salix will use and disclose the information solely for the purpose of complying with regulatory requirements. Hence I: Agree to supply Salix with any information regarding ownership interest and financial ties (including those of my spouse and dependent children); Agree to promptly update this information if any relevant changes occur during the course of the study and for 1 year following completion of the study; and Agree that Salix may disclose this information about such ownership interests and financial ties to regulatory authorities. Investigator Name (Print) Investigator Signature Date Page 3

4 Protocol RFIB3007 CRP STUDY SYNOPSIS PROTOCOL TITLE: PROTOCOL NUMBER: SPONSOR: TREATMENT: PRIMARY OBJECTIVE: STUDY DESIGN: STUDY DURATION: NUMBER OF SUBJECTS: NUMBER OF CENTERS: LOCATION: SUBJECT POPULATION: A PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO- CONTROLLED, MULTICENTER STUDY TO ASSESS THE EFFICACY AND SAFETY OF RIFAXIMIN 550 mg TID IN THE TREATMENT OF SUBJECTS WITH NON-CONSTIPATION IRRITABLE BOWEL SYNDROME RFIB3007 Rifaximin 550 mg tablets TID (1650 mg/day) or matching placebo for 14 days. The primary objective of this trial is to evaluate the efficacy of a 14-day course of rifaximin at 550 mg TID (1650 mg/day) versus placebo in providing adequate relief from IBS symptoms over a 12-week study duration in subjects with nonconstipation IBS. This is a phase 3, multi-center, randomized, double-blind, placebo-controlled study of rifaximin in patients with nonconstipation IBS. Eligible subjects will be randomized (1:1) to receive either rifaximin 550 mg TID or placebo TID. The study will consist of the following phases: Screening Phase; Treatment Phase (Days 1 to 14) which includes the Randomization Visit (Day 1) and visits at Week 1 (Day 7 ± 1) and Week 2 (Day )/End of Treatment; and a Follow-up Phase including an End of Study visit at Week 12 (Day 84 ± 3). Subjects will receive study drug (rifaximin or placebo) for 14 days and will be followed for 10 weeks. The total study duration (including the Screening Phase) is approximately 14 weeks. Approximately 600 subjects will be randomized (300 per treatment group). Multicenter, outpatient study, to be conducted at approximately 90 sites. United States, Canada Adult subjects with non-constipation IBS. Page 4

5 Protocol RFIB3007 CRP STUDY SYNOPSIS KEY ELIGIBILITY CRITERIA Subjects are eligible if they meet the following criteria (additional details of eligibility criteria are described in the protocol sections on inclusion and exclusion criteria): Male or non-pregnant, non-lactating female subjects 18 years of age Diagnosed with IBS confirmed by the Rome II criteria Do not have adequate relief of IBS symptoms and IBS symptom of bloating Have daily IBS symptom scores during screening as below: o Average score of 2 to 4.5 (inclusive) for abdominal pain and discomfort; o Average score of 2 to 4.5 (inclusive) for bloating; and o At least 3.5 for stool consistency. Subjects are ineligible if any of the following apply: Present with the following symptoms of constipation IBS: o Less than 3 bowel movements a week, o Hard or lumpy stools, and o Straining during a bowel movement. History of inflammatory bowel disease, GI surgery, abnormal thyroid function Evidence of duodenal ulcer, gastric ulcer, diverticulitis, gastroesophageal reflux disease, or infectious gastroenteritis Has a history of human immunodeficiency virus (HIV) or hepatitis (B or C) Diabetes (Type 1 or Type 2) A significant medical condition including but not limited to hepatic, renal, cardiovascular, pulmonary or psychiatric disease, which in the opinion of investigator precludes study participation Page 5

6 Protocol RFIB3007 CRP STUDY SYNOPSIS EFFICACY: Primary Endpoint: The proportion of subjects who achieve adequate relief of IBS symptoms for at least 2 of the first 4 weeks during the Followup Phase (ie, Weeks 3 through 6). Adequate relief of IBS symptoms is defined as a response of yes to the following weekly (every 7 days) subject global assessment (SGA) question: In regards to your IBS symptoms, compared to the way you felt before you started study medication, have you, in the past 7 days, had adequate relief of your IBS symptoms? [Yes/No] Key Secondary Endpoint: The proportion of subjects who achieve adequate relief of the IBS symptom of bloating for at least 2 of the first 4 weeks of the Follow-up Phase (ie, Weeks 3 through 6) Adequate relief of IBS symptom of bloating is defined as a response of yes to the following weekly (every 7 days) SGA question: In regards to your IBS symptom of bloating, compared to the way you felt before you started study medication, have you, in the past 7 days, had adequate relief of your IBS symptom of bloating? [Yes/No] Additional Secondary Efficacy Endpoints: The proportion of subjects who achieve adequate relief of IBS symptoms each week for the duration of the study The proportion of subjects who achieve adequate relief of the IBS symptom of bloating each week for the duration of the study Page 6

7 Protocol RFIB3007 CRP STUDY SYNOPSIS EFFICACY: (continued) The proportion of subjects who are IBS symptom-free monthly responders during the 12 week study duration Subject s relief of IBS symptoms will be rated daily using a 7-point scoring system based on subject response to the following question: In regards to all your symptoms of IBS; on a scale of 0-6, how bothersome were your symptoms of IBS today? 0 = not at all; 1 = hardly; 2 = somewhat; 3 = moderately; 4= a good deal; 5 = a great deal; 6 = a very great deal. IBS symptom-free monthly responders are defined as subjects who rate their relief of IBS symptom as either: 0 (not at all) or 1(hardly) at least 50% of the days in a given month (ie, 14 of 28 days); OR 0 (not at all), 1 (hardly), or 2 (somewhat) 100% of the days in a given month (ie 28 of 28 days). Change from baseline to each week during the 12 week study duration for the following IBS symptoms (assessed daily by the Interactive Voice Response System): Number of stools Stool consistency: 1=very hard; 2=hard; 3=formed; 4=loose; or 5=watery Sense of urgency: Asked as: Have you felt or experienced a sense of urgency today? Yes/No Abdominal pain and discomfort: 7-point scoring system based on subject response to the following question: In regards to your specific IBS symptom of abdominal pain and discomfort; on a scale of 0-6, how bothersome was your IBS-related abdominal pain and discomfort today? 0 = not at all; 1 = hardly; 2 = somewhat; 3 = moderately; 4 = a good deal; 5 = a great deal; 6 = a very great deal. Page 7

8 Protocol RFIB3007 CRP STUDY SYNOPSIS EFFICACY: (continued) Bloating: 7-point scoring system based on subject response to the following question: In regards to your specific IBS symptom of bloating; on a scale of 0-6, how bothersome was your IBSrelated bloating today? 0 = not at all; 1 = hardly; 2 = somewhat; 3 = moderately; 4 = a good deal; 5 = a great deal; 6 = a very great deal. SAFETY: SAMPLE SIZE: STATISTICAL METHODOLOGY: Durability of adequate relief of IBS symptoms Durability of adequate relief of IBS symptom of bloating Change from baseline in quality of life based on the IBS quality of life (IBS-QoL) questionnaire The safety endpoints are as follows: Adverse events (AEs) grouped by body system Changes in clinical laboratory parameters (hematology, clinical chemistries, urinalysis) Changes in vital signs Changes from baseline in physical examination For this study it is assumed that 40% of the subjects on placebo for 14 days and 55% of the subjects on rifaximin 550 mg TID for 14 days would achieve the primary endpoint. Based on a significance level of 0.05, 300 subjects in each treatment group will provide approximately 95% power for the two-sided hypothesis that rifaximin 550 mg TID for 14 days is superior to placebo in 2 out of the first 4 weeks of the Followup Phase (ie, Weeks 3 through 6). Two analysis populations, the Intent-to-Treat (ITT) population, and the safety population, will be defined for this study for efficacy and safety analyses, respectively. The ITT population will include all subjects who ingested at least one dose of the blinded study drug. The safety population will include subjects from the ITT population with at least one postbaseline safety observation. All statistical analyses will be stratified according to study site (study site may refer to individual sites as well as pooled or clustered sites) to account for the fact that the trial was Page 8

9 Protocol RFIB3007 CRP STUDY SYNOPSIS conducted using stratified blocked randomization by site. For the primary endpoint, the number and proportion of subjects with and without adequate relief of IBS symptoms will be summarized by treatment group for the ITT population. Statistical testing of the secondary endpoints will be done in a hierarchical fashion. Significance testing will be reported until a nonsignificant p-value is found (p > 0.05). Once a nonsignificant p-value occurs, all subsequent significance tests will be considered exploratory in nature. Order of statistical testing will be defined prior to unblinding the data. The analyses for binary data will utilize PROC LOGISTIC in SAS/STAT. Fixed effect covariates will be study arm and analysis center. Change from baseline in continuous outcomes will be tested using analysis of covariance techniques model with fixed effects for study arm, analysis center, and baseline value as covariates. The safety population will be used for all safety analyses. Safety evaluations will be based on the incidence, intensity, and type of AEs, and clinically significant changes in vital signs and clinical laboratory results. Exposure to study medication and reasons for discontinuation of study treatment will be tabulated. Page 9

10 Protocol RFIB3007 CRP TABLE OF CONTENTS Page TITLE PAGE... 1 SIGNATURE PAGE... 2 RFIB3007 INVESTIGATOR PROTOCOL AGREEMENT... 3 STUDY SYNOPSIS... 4 TABLE OF CONTENTS LIST OF TABLES ABBREVIATIONS INTRODUCTION Disease Background and Scientific Rationale Current Standard Therapy Rifaximin Background and Rationale for the Study OBJECTIVES AND ENDPOINTS Objectives Primary Objective Secondary Objectives Endpoints Efficacy Endpoints Safety Endpoints INVESTIGATIONAL PLAN Overview of Study Design Treatment Assignment/Randomization Procedures for Breaking the Blind SELECTION AND WITHDRAWAL OF SUBJECTS Inclusion Criteria Exclusion Criteria Prohibited Medications Females of Reproductive Potential Premature Subject Discontinuation Study Contact Information TREATMENT OF SUBJECTS Formulation and Supply Packaging Labeling Storage and Handling Dosing and Dosing Schedule Rationale for Dose Selection Study Drug Accountability Assessment of Compliance Prior and Concomitant Therapy Prior Therapy Page 10

11 Protocol RFIB3007 CRP Concomitant Therapy STUDY PROCEDURES AND ASSESSMENTS Study Schedule by Treatment Visit Screening Baseline/Randomization (Day 1) Visit Week 1 (Day 7 ± 1 day) Week 2 (Day days)/end of Treatment Visit Week 4 (Day 28 ± 3 days) Visit Follow-Up Telephone Contacts at Week 6 (Day 42± 3), Week 8 (Day 56± 3) and Week 10 (Day 70 ± 3) Week 12 (Day 84 ± 3 days)/end of Study Visit Premature Discontinuation Visit Unscheduled Visits Assessment of Efficacy Diary Data Quality of Life Assessment of Safety Adverse Events Clinical Laboratory Tests Urine or Serum Pregnancy Test Physical Examination STATISTICAL CONSIDERATIONS Randomization Determination of Sample Size Analysis Populations Subject Disposition Baseline Characteristics Efficacy Analyses Primary Efficacy Analysis Secondary Efficacy Analyses IBS-QoL Scores Safety Analyses Extent of Exposure and Treatment Compliance Adverse Events Clinical Laboratory Assessments Vital Signs Concomitant Medications Statistical and Analytical Issues Adjustment for Covariates Handling of Dropouts or Missing Data Interim Analyses and Data Monitoring Multicenter Studies Multiple Comparisons/Multiplicity Exploration of the Effects of Various Prognostic Factors on Efficacy Criteria for Unblinding the Results Page 11

12 Protocol RFIB3007 CRP Criteria for Stopping the Study Statistical Analysis Plan STUDY ADMINISTRATION Investigator Information and Training Monitoring Audits ETHICAL AND LEGAL ASPECTS Institutional Review Board/ Independent Ethics Committee Approval Subject Information and Informed Consent Study and Site Closure or Discontinuation Study Discontinuation Study Site Discontinuation Handling and Record Keeping Case Report Forms Source Documents Subject Tracking Study Files Data Management Database Processing Confidentiality Record Retention Financing and Insurance Finance Insurance and Indemnification Publication Policy Ownership REFERENCES APPENDIX 1. OVERALL TIME AND EVENTS SCHEDULE APPENDIX 2. IBS QUESTIONNAIRE APPENDIX 3. IBS-QOL APPENDIX 4. LIST OF CHANGES WITH AMENDMENT 01 (DATED 15 AUGUST 2008) Page 12

13 Protocol RFIB3007 CRP LIST OF TABLES Page Table 1. Potentially Clinically Significant Laboratory Values Page 13

14 Protocol RFIB3007 CRP ABBREVIATIONS Abbreviation AE ANCOVA BID CRF FDA GCP GI HIV IBS IBS-D IBS QoL ICH IEC IND IRB ITT IVR LMP MedDRA PCS PHI RNA SAE Salix SGA SIBO TID ULN Definition Adverse Event Analysis of covariance Twice a day Case Report Form Food and Drug Administration Good Clinical Practice Gastrointestinal Human Immunodeficiency Virus Irritable Bowel Syndrome Diarrhea-predominant Irritable Bowel Syndrome Irritable Bowel Syndrome Quality of Life International Conference on Harmonisation Independent Ethics Committee Investigational New Drug Application Institutional Review Board Intent-to-treat Interactive voice response Last menstrual period Medical Dictionary for Regulatory Affairs Potentially clinically significant Protected health information Ribonucleic acid Serious Adverse Event Subject s Global Assessment Small intestinal bowel overgrowth Three times daily Upper limit of normal Page 14

15 Protocol RFIB3007 CRP INTRODUCTION 1.1. Disease Background and Scientific Rationale Irritable bowel syndrome (IBS) is the most common functional gastrointestinal (GI) disorder in clinical practice. Primary symptoms of IBS are recurrent abdominal pain, bloating, and altered bowel function. Patients with IBS often suffer from diarrhea, constipation, or alternating diarrhea and constipation. The prevalence of IBS is greater in women, but appears to be common for all age groups. While there is variation from country to country, IBS appears to affect up to 20% of a given population. Although most people experience GI disturbances at some time during their lives, subjects with IBS have more frequent and severe symptoms, and are more likely to have symptoms that disrupt their work or social life. 1 Living with IBS symptoms can also result in increased social anxiety, stress, and a lower quality of life. 2 Despite the pervasiveness, incapacitating symptoms and medical costs associated with IBS, treatment options remain limited. Given that there is no recognized physical abnormality or biological marker to define IBS, diagnosis is based on the presence of several characteristic symptoms, known as the Manning criteria. The Manning criteria include abdominal pain or discomfort that is relieved by defecation or is associated with a change in stool frequency or consistency, abdominal distension, sensation of incomplete evacuation, and passage of mucus. The Manning criteria have been modified by an international team to establish restrictive diagnostic criteria for IBS, referred to as the Rome I criteria and, more recently, the Rome II and Rome III criteria. Patients with IBS are often divided into subtypes for diagnosis based on the predominance of either diarrhea or constipation. The Rome II criteria, for example, divide IBS patients into 3 subtypes: diarrhea-predominant IBS, constipation-predominant IBS, or alternating IBS (IBS symptoms alternate between diarrhea and constipation). Though IBS etiology is unknown, alteration in gut flora has been considered among the contributors of symptoms associated with IBS. This is supported by results of a recent study suggesting abnormal lactulose hydrogen breath test is an indicator for the presence of small intestinal bacterial overgrowth (SIBO) Current Standard Therapy While IBS is one of the most common chronic medical conditions, 4,5,6,7,8,9 the etiology of IBS is not completely understood. Early investigations for treatment of IBS focused on a relationship between psychological factors and IBS symptoms. This theory led many investigators to consider antidepressants for IBS treatment with some initial success. Further study of antidepressants in IBS treatment however yielded mostly negative results: antidepressants improved psychological disorders in some IBS patients, but had limited efficacy in improving actual IBS symptoms. 10 Additionally, many antidepressants have been associated with serious side effects and can also prove to be addictive over time. 2 Page 15

16 Protocol RFIB3007 CRP In the 1980s, studies demonstrated that abnormal gut motility was commonly found in patients diagnosed with IBS. In particular, in cases of diarrhea-predominant IBS the gut appeared to be moving too fast and in cases of constipation-predominant IBS the gut appeared to be moving too slowly. The connection to peristalsis caused many researchers to focus on drugs that mediate serotonin levels in the GI tract with initial success in improving IBS symptoms. Currently however, only 1 serotonin agent, LOTRONEX (alosetron hydrochloride), is marketed in the United States for the treatment of IBS. Lotronex is a 5-HT 3 antagonist, which works by inhibiting serotonin production in the gut. It is approved only for the treatment of female patients with severe diarrhea-predominant IBS in whom conventional treatments have failed. The restrictive label is a result of serious GI adverse events (AEs), some fatal, that have been reported with the use of the drug. These events have included ischemic colitis as well as serious complications of constipation that have resulted in hospitalization, blood transfusion, surgery, and even death. ZELNORM (tegaserod maleate), a 5-HT 4 agonist with visceral antinociceptive effects, was another serotonin agent originally approved by the FDA for short-term treatment of women with IBS whose primary bowel symptom was constipation. Due to safety concerns involving an increased risk of serious cardiovascular AEs, the FDA requested that the manufacturer (Novartis Pharmaceuticals Corporation of East Hanover, New Jersey) voluntarily discontinue marketing Zelnorm. Novartis agreed to voluntarily suspend marketing of the drug in the United States. The absence of a serotonin-based class of drugs that is safe for IBS management and the lack of other effective IBS treatments has driven many researchers to look more closely at bacterial involvement in IBS rather than the role of bowel function. Alterations in gut flora have been identified as potentially important in the pathophysiology of IBS. This hypothesis is supported by studies reporting that up to 84% of IBS subjects have an abnormal lactulose hydrogen breath test, suggesting the presence of SIBO. 3 Moreover, symptoms associated with IBS (bloating, abdominal pain, and altered bowel habits) are generally similar to those associated with small intestinal bacterial 3, 11 overgrowth. Early clinical experience with several antibiotics (metronidazole, neomycin, ciprofloxacin, and doxycycline) indicated that antibiotic therapy may be an effective 3, 11, 12 treatment for symptoms associated with IBS. Research suggesting that antibiotics can improve IBS symptoms has been correlated with elimination of bacterial overgrowth as indicated by normalization of the lactulose hydrogen breath test results. 3 In one study, neomycin therapy was associated with a 75% global improvement in IBS when it reduced bacterial overgrowth based on breath test data. 3 While neomycin reduces bacterial overgrowth, it has suboptimal efficacy in the elimination of bacterial overgrowth. Furthermore, side effects limit the use of neomycin. Similar low efficacy results are observed with other antibiotics (eg, doxycycline and amoxicillin/clavulanate) that have been investigated for treatment of bacterial overgrowth. 13 Doxycycline and amoxicillin/clavulanate, like other systemically available antibiotics, are best reserved for infections requiring systemically available agents rather than for enteric conditions that can more appropriately be treated with a minimally absorbed agent. Page 16

17 Protocol RFIB3007 CRP An ideal antibiotic for IBS is arguably one with negligible systemic absorption, minimal side effects, and good efficacy for controlling bacterial overgrowth. Rifaximin, a poorly absorbed antibiotic with excellent tolerability, has shown high eradication rates for bacterial overgrowth Rifaximin Background and Rationale for the Study Rifaximin is a novel, nonabsorbable, oral antibiotic derived from rifamycin, which has a broad spectrum of activity against gram-positive and gram-negative, aerobic, and anaerobic enterobacteria. 14 Rifaximin acts by inhibiting RNA synthesis in susceptible microorganisms. Rifaximin is particularly suited for the treatment of GI infections because of its low systemic bioavailability. When taken orally, less than 1% of the dose is absorbed from the GI tract. In May 2004, Salix received marketing approval from the FDA for XIFAXAN (rifaximin) tablets 200 mg for the treatment of traveler s diarrhea at a dosage regimen of 200 mg taken 3 times a day (TID) for 3 days in adults and children 12 years or older. Rifaximin tablets are approved for marketing in 24 countries by Alfa-Wasserman (Bologna, Italy). Rifaximin is available in Italy and other European countries for treatment of acute bacterial diarrhea, hepatic encephalopathy, 15 and small bowel bacterial overgrowth. 16,17,18 It is also licensed in Mexico, and in countries in Asia and Africa for treatment of acute diarrhea. The properties of rifaximin, including its broad range of activity against enterobacteria and low systemic availability, make it a good candidate for the treatment of IBS by targeting SIBO. Eradication rates for SIBO with rifaximin treatment have been shown to be as high as 70%. 17 Moreover, results from two dose ranging studies in the literature suggest that rifaximin is more effective in eradicating SIBO at progressively higher doses. In a European dose-ranging study evaluating 90 subjects, 23 rifaximin was significantly (p < 0.01) more effective in eradicating SIBO with a daily dose of 1200 mg compared with daily doses of 600 mg and 800 mg, respectively. In another randomized trial of 80 subjects, rifaximin at a daily dose of 1600 mg demonstrated significantly (p < 0.05) higher efficacy in treatment of SIBO compared with a1200 mg daily dose. 24 Recently published studies have also shown rifaximin to be effective in improving IBS 19, 20 symptoms. In a double-blind, placebo-controlled study conducted by Pimentel and colleagues in 87 subjects (44 placebo, 43 rifaximin) with IBS, rifaximin (1200 mg/day) resulted in significantly greater (p = 0.02) improvement in IBS symptoms compared with placebo. 20 Subjects treated with rifaximin experienced an average improvement of 36.4% compared with 21.0% for patients treated with placebo. Treatment with rifaximin also resulted in a significant improvement (p = 0.01) in bloating score over the 10-week treatment follow-up. Results from a Salix-sponsored phase 2 trial in subjects with diarrhea-predominant IBS (IBS-D) support the use of rifaximin in the treatment of IBS (RFIB2001). In the RFIB2001 study, a statistically significant difference was demonstrated between rifaximin treatment (550 mg twice a day [BID] for 2 weeks) and placebo for the co-primary endpoints of improvement in IBS symptoms (p = ) and improvement Page 17

18 Protocol RFIB3007 CRP in IBS bloating (p = ). In addition, 4 rifaximin treatment arms (doses ranging from 550 to 2200 mg/day for 2 to 4 weeks) were well tolerated in subjects with IBS-D, with a safety profile comparable to placebo. Safety results were generally consistent with expectations for the subject population under study. Findings from the RFIB2001 study and the literature suggest that rifaximin may provide clinically meaningful relief of IBS symptoms without the side effects associated with antidepressants, serotonin agents, or systemic antibiotics. The current protocol is intended to assess the clinical efficacy and safety of a 550 mg TID dosing regimen of rifaximin (1650 mg/day) compared with placebo in subjects with IBS who are not currently experiencing symptoms of constipation (non-constipation IBS). Page 18

19 Protocol RFIB3007 CRP OBJECTIVES AND ENDPOINTS 2.1. Objectives Primary Objective The primary objective of this trial is to evaluate the efficacy of a 14-day course of oral rifaximin at 550 mg TID (1650 mg/day) versus placebo in providing adequate relief from IBS symptoms over a 12-week study duration in subjects with non-constipation IBS Secondary Objectives The secondary objective of this study is to evaluate the safety of a 14-day course of rifaximin at 550 mg TID as compared with placebo in subjects with non-constipation IBS Endpoints Efficacy Endpoints Primary Efficacy Endpoint The proportion of subjects who achieve adequate relief of IBS symptoms for at least 2 of the first 4 weeks during the Follow-up Phase (ie, Weeks 3 through 6). Adequate relief of IBS symptoms is defined as a response of yes to the following weekly (every 7 days) subject global assessment (SGA) question: In regards to your IBS symptoms, compared to the way you felt before you started study medication, have you, in the past 7 days, had adequate relief of your IBS symptoms? [Yes/No] Achieving adequate relief is another way of saying that in comparison with your typical experience of the disease before you started taking your study medication, you feel that the symptoms of IBS have satisfactorily improved during the past 7 days Secondary Efficacy Endpoints Key secondary efficacy endpoint The proportion of subjects who achieve adequate relief of the IBS symptom of bloating for at least 2 of the first 4 weeks of the Follow-up Phase (ie, Weeks 3 through 6). Adequate relief of IBS symptom of bloating is defined as a response of yes to the following weekly (every 7 days) SGA question: In regards to your IBS symptom of bloating, compared to the way you felt before you started study medication, have you, in the past 7 days, had adequate relief of your IBS symptom of bloating? [Yes/No] Page 19

20 Protocol RFIB3007 CRP Additional secondary efficacy endpoints: The proportion of subjects who achieve adequate relief of IBS symptoms each week for the duration of the study The proportion of subjects who achieve adequate relief of the IBS symptom of bloating each week for the duration of the study The proportion of subjects who are IBS symptom-free monthly responders during the 12 week study duration Subject s relief of IBS symptoms will be rated daily using a 7-point scoring system based on subject response to the following question: In regards to all your symptoms of IBS; on a scale of 0-6, how bothersome were your symptoms of IBS today? 0 = not at all; 1 = hardly; 2 = somewhat; 3 = moderately; 4= a good deal; 5 = a great deal; 6 = a very great deal. IBS symptom-free monthly responders are defined as subjects who rate their relief of IBS symptom as either: o 0 (not at all) or 1(hardly) at least 50% of the days in a given month (ie, 14 of 28 days); OR o 0 (not at all) 1 (hardly) or 2 (somewhat) 100% of the days in a given month (i.e, 28 of 28 days). Change from baseline to each week during the 12 week study duration for the following IBS symptoms (assessed daily by the Interactive Voice Response System): o Number of stools o Stool consistency: 1=very hard; 2=hard; 3=formed; 4=loose; or 5=watery o Sense of urgency: Asked as: Have you felt or experienced a sense of urgency today? Yes/No o Abdominal pain and discomfort: 7-point scoring system based on subject response to the following question: In regards to your specific IBS symptom of abdominal pain and discomfort; on a scale of 0-6, how bothersome was your IBSrelated abdominal pain and discomfort today? 0 = not at all; 1 = hardly; 2 = somewhat; 3 = moderately; 4 = a good deal; 5 = a great deal; 6 = a very great deal. o Bloating: 7-point scoring system based on subject response to the following question: Page 20

21 Protocol RFIB3007 CRP In regards to your specific IBS symptom of bloating; on a scale of 0-6, how bothersome was your IBS-related bloating today? 0 = not at all; 1 = hardly; 2 = somewhat; 3 = moderately; 4 = a good deal; 5 = a great deal; 6 = a very great deal. Durability of adequate relief of IBS symptoms (ie, time to durable response for adequate relief of IBS symptoms [defined in Section ]) Durability of adequate relief of IBS symptom of bloating (ie, time to durable response for adequate relief of IBS symptom of bloating [defined in Section ]) Change from baseline in quality of life based on the IBS quality of life (IBS-QoL) questionnaire Patient Reported Outcomes Interactive voice response (IVR) system diaries will be utilized to collect the weekly SGA questions and the daily symptom questions (see Section and Appendix 2). The IBS-QoL questionnaire by Patrick, et al (see Appendix 3) will be completed by the subject and collected on Day 1 (prior to Randomization) and Weeks 4 (Day 28 ± 3 days), 8 (Day 56 ± 3 days), and 12 (Day 42 ± 3 days) Safety Endpoints The safety endpoints are as follows: Incidence of adverse events grouped by body system Changes in clinical laboratory parameters (hematology, clinical chemistry, urinalysis) Changes in vital sign measurements Changes from baseline in physical examination Page 21

22 Protocol RFIB3007 CRP INVESTIGATIONAL PLAN 3.1. Overview of Study Design This is a phase 3, randomized, double-blind, placebo-controlled, multi-center study to assess the efficacy and safety of rifaximin in subjects with non-constipation IBS. Subject eligibility will be based on inclusion and exclusion criteria (see Sections 4.1 and 4.2). Approximately 600 eligible subjects will be randomized to study treatment in a 1:1 ratio to receive either rifaximin 550 mg TID or placebo TID. The study will consist of the following phases: Screening phase Prospective subjects will be required to undergo screening procedures. The screening phase will include obtaining informed consent, screening assessments including colonoscopy (if necessary) and the diary eligibility period. The diary eligibility period will begin no earlier than 7 days after the colonoscopy and within 10± 3 days prior to randomization. During the diary eligibility period, subjects will be required to respond to SGA questions and daily IBS symptom related questions for at least 7 days in the IVR system. Treatment phase (Days 1 to 14+ 2) Starting on Day 1 (Randomization Visit), eligible subjects will receive blinded study drug according to the randomization schedule for 14 days. Interim clinic visits will occur at Week 1 (Day 7 ± 1) and Week 2 (Day ). Subjects will be instructed to continue to record their daily IBS symptoms and weekly SGA responses in the IVR system. Follow-up phase Randomized subjects will be followed after completion of treatment for 10 additional weeks. Interim clinic visits will occur at Week 4 (Day 28± 3) and Week 12 (Termination Visit; Day 84 ± 3). In addition, telephone contacts will occur at Weeks 6 (Day 42 ± 3), 8 (Day 56± 3), and 10 (Day 70 ± 3). Subjects will be instructed to continue to record their daily IBS symptoms and weekly SGA responses in the IVR system. Total duration of the study is approximately 14 weeks, depending if a colonoscopy is required. All randomized subjects will be encouraged to complete the 12 week study duration (following randomization). Periodic safety monitoring (including symptom directed physical examination, vital sign measurements, clinical laboratory testing, and recording of AEs and concomitant medications) will be performed during the study. Subjects who discontinue the study early due to an AE will be followed until resolution or stabilization of the event. The IBS- QoL will be assessed at the Randomization Visit and at Weeks 4, 8, and Treatment Assignment/Randomization There will be approximately 600 subjects randomized 1:1 to the following two treatment arms. Treatment A: Rifaximin 550 mg TID (14 days): 300 subjects Page 22

23 Protocol RFIB3007 CRP Treatment B: Placebo TID (14 days): 300 subjects Each center will randomize subjects to treatment groups using a randomization code generated by the IVR system that is independent of the randomization code of any other center in the study. This stratified blocked randomization is necessary in order to guarantee balance between the treatment groups within each of the study centers. 3.3 Procedures for Breaking the Blind Only in the case of an emergency, when knowledge of the study drug is essential for the clinical management or welfare of the subject, will the investigator be allowed to unblind a subject s treatment assignment. To discuss breaking of the blind or to break the blind please contact the study manager at Salix at: If the investigator breaks the blind for an individual subject, the reason must be recorded and the subject will be removed from the study. The investigator must not reveal the subject s treatment assignment to the clinical monitor. Page 23

24 Protocol RFIB3007 CRP SELECTION AND WITHDRAWAL OF SUBJECTS 4.1. Inclusion Criteria A subject will be eligible for inclusion in this study if he/she meets all of the following criteria: 1. Subject is 18 years of age 2. Male or female Females of childbearing (reproductive) potential must have a negative serum pregnancy test at screening and agree to use an acceptable method of contraception throughout their participation in the study. Acceptable methods of contraception include double barrier methods (condom with spermicide jelly or diaphragm with spermicide), hormonal methods (oral contraceptives, patches or medroxyprogesterone acetate), or an intrauterine device (IUD) with a documented failure rate of less than 1% per year. Abstinence may be considered an acceptable method of contraception at the discretion of the investigator. Note: Females who have been surgically sterilized (eg, hysterectomy or bilateral tubal ligation) or who are postmenopausal (total cessation of menses for >1 year) will not be considered females of childbearing potential. 3. Subject has IBS confirmed by the Rome II diagnostic criteria (below) At least 12 Weeks, which need not be consecutive, in the preceding 12 months of abdominal discomfort or pain associated with 2 or more of the following: Relieved with defecation; and/or Onset associated with a change in frequency of stool; and/or Onset associated with a change in form (appearance) of stool. Source: Thompson WG, Longstreth GF, Drossman DA, et al. Functional bowel disorders and functional abdominal pain. Gut. 1999; 45: During the Screening Phase the following average daily symptom scores for IBS symptoms are required for entry into the study: Average score of 2 to 4.5 (inclusive) for abdominal pain and discomfort; Average score of 2 to 4.5 (inclusive) for bloating; and At least 3.5 for stool consistency. 5. Subject does not have adequate relief of IBS symptoms and IBS bloating on the first day of screening and on the day of randomization based on subject response Page 24

25 Protocol RFIB3007 CRP to SGA questions during the Screening Phase (adequate relief is defined in Appendix 2). An example of a subject who would continue to be qualified for the study based on their responses to the SGA questions is provided below; any other combination of responses would deem the subject ineligible to be randomized. SGA Question Adequate Relief of IBS Symptoms Adequate Relief of IBS Symptom of Bloating Screening Day Response NO NO Randomization Day Response NO NO 6. Subject had a colonoscopy within the last 2 years as part of an evaluation for IBS or IBS symptoms (which excludes inflammatory or neoplastic disease), or, subject will have a colonoscopy scheduled and completed within 30 days of signing the informed consent form 7. Subject must maintain a stable diet for the duration of the study Subjects who are on stable treatment with a daily fiber supplementation or bulking agents may be enrolled provided that the administration schedule is intended to be maintained throughout the study and the subject has been on bulking therapy for at least 30 days prior to signing informed consent 8. Subject is capable of understanding the requirements of the study, is willing to comply with all study procedures, understands the language of the informed consent form, and is capable and willing to sign the informed consent form 4.2. Exclusion Criteria A subject will not be eligible for inclusion in this study if he/she meets any of the following criteria: 1. Subject presents with the following symptoms of constipation IBS: o Less than 3 bowel movements a week, o Hard or lumpy stools, and o Straining during a bowel movement. 2. Subject has failed to record at least 7 days of the daily diary assessments during the Screening Phase 3. Subject has current evidence of duodenal ulcer, gastric ulcer, diverticulitis, gastroesophageal reflux disease, or infectious gastroenteritis. Note: Subjects with gastroesophageal reflux disease controlled by stable doses of medication or diet are eligible to participate in the study 4. Subject has a history of inflammatory bowel disease (eg, Crohn s disease, ulcerative colitis, celiac disease), GI malignancy, GI obstruction, gastroparesis, Page 25

26 Protocol RFIB3007 CRP carcinoid syndrome, pancreatitis, amyloidosis, ileus or cholelithiasis (exception: the subject is eligible to participate if they had a cholecystectomy) 5. Subject has diabetes (Type 1 or Type 2) 6. Subject is a candidate for GI surgery or has a history of GI surgery (exceptions: appendectomy, cholecystectomy, benign polypectomy and inguinal hernia) 7. Subject has lactose intolerance not controlled by lactose free diet 8. Subject has a positive stool test for Yersinia enterocolitica, Campylobacter jejuni, Salmonella, Shigella, ovum and parasites, and/or Clostridium difficile (Note: Stool sample not required if negative test is obtained within 14 days of randomization. Results for these tests are not required prior to randomization, but should be confirmed within 7 days after randomization) 9. Subject has psychiatric disorders which are not controlled ( controlled is based on the Investigator s medical judgment); subjects with psychoses are excluded regardless of current therapy 10. Subject has current or recent history (within 12 months before signing informed consent) of drug or alcohol abuse 11. Subject is pregnant or lactating 12. Subject has a history of human immunodeficiency virus (HIV) or hepatitis (B or C) 13. Subject has a history of abnormal thyroid function not controlled by thyroid medications 14. Subject has hepatic disease manifested by twice the upper limit of normal (ULN) for any of the following liver function tests: alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, or total bilirubin (except in isolated elevation of unconjugated bilirubin) 15. Subject has renal disease manifested by 1.5 times the ULN of serum creatinine or blood urea nitrogen levels 16. Subject has unstable cardiovascular or pulmonary disease, categorized by a worsening in the disease condition that required a change in treatment or medical care within 1 month of randomization 17. Subject has any condition or circumstance that could cause noncompliance with treatment or visits 18. Subject has known allergy to rifaximin or rifampin or excipients 19. Subject has participated in an investigational drug or device study within the 30 days prior to signing informed consent 20. Subject has active malignancy within the last 5 years (exceptions: basal cell carcinomas of the skin, or if female, in situ cervical carcinoma that has been surgically excised) 21. Subject taking rifaximin within 60 days of signing informed consent Page 26

27 Protocol RFIB3007 CRP Subject taking any experimental drugs within 30 days of signing informed consent and subjects taking products specifically marketed as probiotics (standard food or yogurt products are allowed) after initiation of the diary eligibility period 23. Subject taking any antibiotic within 14 days prior to signing informed consent 24. Subject taking antipsychotic drugs, antispasmodics, antidiarrheals (eg, loperamide, lubiprostone and bismuth subsalicylate), lubiprostone, narcotics, prokinetic drugs, drugs indicated for IBS (eg, Alosetron), or warfarin after initiation of the diary eligibility period NOTE: Tricyclic antidepressants and serotonin re-uptake inhibitors are allowed if the subject is at stable doses for at least 6 weeks prior to signing informed consent and the dose will remain stable throughout the duration of the study Prohibited Medications The following concomitant medications are prohibited after initiation of the diary eligibility period and throughout the study: Rifaximin (other than the study drug) Any experimental drugs Probiotic supplements (with the exception of standard food or yogurt products); Examples of probiotics include but are not limited to: Align (bifidocaterium infantis), Cuturelle (Lactobacillus GG), Cultura (Lactobacillus casei F19), Yakult (lactobacillus casei Shirota), and Vifit (lactobacillus rhamnosus ATCC53013) Antibiotics Antipsychotic drugs Antispasmodics Antidiarrheals (eg, loperamide and bismuth subsalicylate) IBS drugs (e.g., Alosetron) Lubiprostone Laxatives, enemas. (NOTE: laxatives taken for endoscopic procedures are not prohibited; subjects who are on stable treatment with a daily fiber supplementation or bulking agents may be enrolled provided that the administration schedule is intended to be maintained throughout the study and the subject has been on bulking therapy for at least 30 days prior to signing informed consent) Narcotics (specifically opioid analgesics) Prokinetic drugs Warfarin Nonsteroidal anti-inflammatory drugs are prohibited if used for the treatment of IBS Sites are encouraged to consult with the medical monitor if there are any questions about prohibited medications. Page 27

28 Protocol RFIB3007 CRP Females of Reproductive Potential The study drug to be administered is classified as a Pregnancy Category C drug for which animal studies have shown an adverse effect. There are no adequate and wellcontrolled studies that have been conducted in pregnant women. If a female subject becomes pregnant while on this study, the study drug will be immediately discontinued and the subject will be followed until the outcome of the pregnancy is known. The pregnancy will be reported to Salix using the guidelines provided in Sections through Premature Subject Discontinuation A subject will be discontinued from the study for the following medical or administrative reasons: Occurrence of an AE, which, in the judgment of the Investigator, suggests an unacceptable risk to the subject. In such instances the Investigator will follow the subject until satisfactory resolution of the AE or until the AE is determined to be stable; Pregnancy; Subject request; and Noncompliance with study procedures. Subjects will be encouraged to complete the study; however, they may voluntarily withdraw at any time. The Investigator or Sponsor may discontinue individual subjects from the study at any time during the study. The Investigator must provide written documentation of the reason for discontinuation on the appropriate CRF. Regardless of the reason for withdrawal, all subjects will be asked to undergo study evaluations depending on the study phase in which the subject discontinues. Refer to Section to determine procedures required. Subjects who withdraw or are withdrawn will not be replaced under this protocol Study Contact Information The investigator may deem it necessary to perform special tests, to hospitalize the subject, or to prescribe new drugs. Your monitor should be your first point of contact concerning any questions regarding the study. In the event the investigator needs to consult with a Salix representative, please contact: 1700 Perimeter Park Drive Morrisville, NC USA Phone: Fax: Page 28

29 Protocol RFIB3007 CRP TREATMENT OF SUBJECTS 5.1. Formulation and Supply Study drug will be supplied by Salix as tablets containing either rifaximin or matching placebo. Rifaximin will be supplied as pink, coated, oval, biconvex tablets. Each rifaximin tablet will contain 550 mg rifaximin, and the following inactive ingredients: colloidal silicon dioxide, disodium edetate, glycerol palmitostearate, hypromellose, microcrystalline cellulose, propylene glycol, red iron oxide, sodium starch glycolate, talc, and titanium dioxide. Rifaximin tablets are approximately 10.4 mm x 19.0 mm in size. Matching placebo will be supplied as tablets that are identical in appearance to rifaximin tablets with inactive ingredients. The components used in the manufacture of the matching placebo tablets are: colloidal silicon dioxide, disodium edetate, glycerol palmitostearate, hypromellose, microcrystalline cellulose, propylene glycol, red iron oxide, sodium starch glycolate, talc, and titanium dioxide Packaging Salix will supply double-blind study drug in high density polypropylene bottles. Each bottle will contain study drug for 15 days of therapy (i.e., 45 tablets) Labeling The contents of the label will be in accordance with all applicable regulatory requirements. Each bottle of rifaximin/placebo will bear a label containing the following information: Federal law statement: Caution New Drug-Limited by United States Law to Investigational Use Study number Treatment number Quantity: 45 Tablets Dosing instructions: Take 1 tablet orally TID Storage information: Store tablets at C (68-77 F); excursions permitted to C (59-86 F) Manufactured for, Morrisville, NC Study drug, lot number, and expiration date Page 29