This study will evaluate the efficacy and safety of eluxadoline 100 milligrams (mg) twice a day (BID) versus placebo for the treatment of patients with Irritable Bowel Syndrome with Diarrhea (IBS-D) who report that the use of loperamide in the prior 12 months failed to provide control of their IBS-D symptoms.

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.