Irritable Bowel Syndrome With Diarrhea (IBS-D) Rifaximin Re-Treatment Study

It is important in chronic conditions to have information about how a product that is
intended for short course administration in order to confer prolonged benefit should be
administered beyond the first cycle of use once symptoms reappear. This Phase 3 study will
evaluate the efficacy and safety of repeat treatment with rifaximin 550 mg three times daily
(TID) for 14 days in subjects with IBS-D who respond to an initial treatment course with
rifaximin 550 mg TID for 14 days.

This study consists of several treatment phases outlined below:

Screening/Treatment 1 Phase. Subjects will receive single-blind placebo TID for 7-13 days and
answer daily IBS symptom-related questions.

Treatment 2 Phase. Eligible subjects will receive open-label rifaximin 550 mg TID for 2 weeks
with a 4-week treatment-free follow-up. Responders will continue into Maintenance Phase 1.
Nonresponders will withdraw from the study.

Maintenance Phase 1. Subjects will continue the treatment-free follow-up period for up to 18
weeks until either: 1) they experience recurrence or 2) enrollment is met in the Treatment 3
Phase (Double Blind Repeat Treatment Phase). Subjects who do not meet recurrence criteria by
the end of the Maintenance Phase 1 will withdraw from the study.

Treatment 3 Phase/ Double Blind Repeat Treatment Phase. Subjects who meet criteria for
recurrence will be randomized 1:1 to receive either rifaximin 550 mg TID or placebo TID for 2
weeks with a 4-week treatment-free follow-up.

Primary efficacy analysis will be performed at the end of the Treatment 3 Phase (at Week 6 of
the double-blind period).

Maintenance Phase 2. All subjects continued into an additional treatment-free follow-up
period of up to 6 weeks (Maintenance Phase 2).

Treatment 4 Phase/Second Repeat Treatment Phase. Subjects will receive the same double-blind
treatment as previously assigned in the Treatment 3 Phase for 2 weeks with a 4-week
treatment-free follow-up.

A lactulose breath test sub-study will be conducted at select sites.

Inclusion Criteria:

- IBS confirmed by Rome III diagnostic criteria.

- At least 18 years of age.

- Colonoscopy within the past 10 years to rule out inflammatory bowel disease; or
flexible sigmoidoscopy if < 50 years of age or previous colonoscopy > 10 years prior.

- Willing to maintain a stable diet. including vitamins, supplements, and
nutraceuticals.

Exclusion Criteria:

- Diabetes (Type 1 or 2).

- Lactose intolerance and not controlled by a lactose-free diet.

- Pregnant or planning to become pregnant or is lactating.

- History of HIV or hepatitis B or C.

- Participation in investigational study within past 30 days.

- Taking rifaximin or any other antibiotic within past 60 days.

- Unstable cardiovascular or pulmonary disease, with change in treatment in last 30 days
due to worsening disease condition.

- History of GI surgery.