Efficacy of Eluxadoline in the Treatment of Irritable Bowel Syndrome With Diarrhea in Patients With Inadequate Control of Symptoms With Prior Loperamide Use

Inclusion Criteria:

- Has a diagnosis of IBS-D, defined by the Rome III criteria as loose (mushy) or watery
stools ≥25% and hard or lumpy stools ≤25% of bowel movements.

- Has had a colonoscopy performed within 5 years prior to Screening if they are at least
50 years of age, OR if they meet any of the following alarm features:

1. Has documented weight loss within the past 6 months; or

2. Has nocturnal symptoms; or

3. Has a familial history of colon cancer; or

4. Has blood mixed with their stool (excluding any blood from hemorrhoids)

- Patient reports use of loperamide in the 12 months prior to Screening for IBS-D
symptoms and that loperamide did not provide adequate control of IBS-D symptoms.

- Has not used any loperamide rescue medication within 14 days prior to randomization.

Exclusion Criteria:

- Has a diagnosis of Irritable Bowel Syndrome (IBS) with a subtype of constipation IBS,
mixed IBS, or unsubtyped IBS.

- Has a history of inflammatory or immune-mediated gastrointestinal (GI) disorders
including inflammatory bowel disease (i.e., Crohn's disease, ulcerative colitis),
microscopic colitis, or celiac disease.

- Has a history of diverticulitis within 3 months prior to screening.

- Has a documented history of lactose intolerance.

- Has a documented history of bile-acid malabsorption.

- Has a history of chronic or severe constipation or intestinal obstruction, stricture,
toxic megacolon, GI perforation, fecal impaction, gastric banding, bariatric surgery,
adhesions.

- Has any of the following surgical history:

1. Cholecystectomy or previously documented agenesis of gallbladder; or

2. Any abdominal surgery within the 3 months prior to screening; or

3. Major gastric, hepatic, pancreatic, or intestinal surgery (appendectomy,
hemorrhoidectomy, or polypectomy greater than 3 months post-surgery are allowed).

- Has a history of cholecystitis within 6 months before screening.

- Has a history of pancreatitis or structural diseases of the pancreas, including known
or suspected pancreatic duct obstruction.

- Has a history of known or suspected biliary duct obstruction or sphincter of Oddi
disease or dysfunction, excluding a history of gallstones.

- Has a history or current evidence of laxative abuse within 5 years prior to screening.

- Has documented evidence of cirrhosis.

- Has a history of cardiovascular events, including stroke, myocardial infarction,
congestive heart failure, or transient ischemic attack within 6 months prior to
screening.

- Has an unstable renal, hepatic, metabolic, or hematologic condition.

- Has a history of malignancy within 5 years before screening (except squamous and basal
cell carcinomas and cervical carcinoma in situ).

- Has a history of human immunodeficiency virus infection.

- Has a history of Diagnostic and Statistical Manual of Mental Disorders, 4th Edition,
Text Revision-defined substance dependency, excluding nicotine and caffeine, within 2
years prior to screening.

- Has a history of alcohol abuse, alcohol addiction, and alcoholism or drinks more than
3 alcoholic beverages per day.

- Has used aspirin or aspirin-containing medications (>325 mg of aspirin per day) or
nonsteroidal anti-inflammatory drugs, when taken specifically for the symptoms of IBS,
within 14 days of randomization.

- Has current (within 14 days of randomization) or expected use of any narcotic or
opioid-containing agents, tramadol, docusate, enemas, GI preparations (including
antacids containing aluminum or magnesium, antidiarrheal agents [except loperamide
rescue medication after randomization]), antinausea agents, antispasmodic agents,
bismuth, or prokinetic agents.

- Has current (within 28 days of randomization) use of rifaximin or other antibiotics
(with the exception of topical antibiotics or a 1-day course with an antibiotic).
Expected use of rifaximin or other antibiotics during the course of the study that is
known at the time of randomization.

- Has an elective surgery planned or expects to need elective surgery at any time during
the study.