Inclusion Criteria: 

• Male and female patients must be 18 to 65 years of age, inclusive, at the time of signing informed consent. 
• Patient has completed the daily electronic diary on at least 6 of the 7 days during the week prior to randomization AND at least 11 of the 14 days during the 2 weeks prior to randomization. Patients have up to 3 weeks to meet these criteria.
• Patient meets the diagnosis of IBS based on the Rome IV diagnostic criteria (Lacy et al., 2016):*
  • Recurrent abdominal pain occurring, on average, at least 1 day per week and associated with 2 or more of the following:
  • Related to defecation;
  • Associated with a change in frequency of bowel movements;
  • Associated with a change in form (appearance) of stool;
    • * These criteria must be fulfilled for the last 3 months prior to randomization and onset must have occurred at least 6 months prior to randomization.
• Patient meets the diagnosis of IBS-D subtype based on Rome IV diagnostic criteria (Lacy et al., 2016). On days when the patient experiences IBS symptoms:
  • At least 25% of stools are loose or watery; AND
  • Fewer than 25% of stools are hard.
• Over the final 7 days of the run-in period, the patient has an average of WAP scores in the prior 24 hours of 3.0 to 8.0 (on a 0 to 10 numerical rating scale, where 0 indicates no pain and 10 indicates worst pain imaginable).
• Over the final 7 days of the run-in period, the patient has an average daily BSFS score ≥ 5.0 (on a 1 to 7 scale, where 1 = hard, lumpy stools, and 7 = watery, liquid stools), and there must be at least 2 days with stool consistency of Type ≥ 6.
• Patient is not planning to change his or her usual diet and lifestyle during the course of the study.
• Patient must undergo or previously have undergone:
  • an appropriate evaluation for their IBS symptoms, including an evaluation for organic/structural etiologies (if in the presence of alarm symptoms); and
  • age-appropriate screening for colorectal cancer, if applicable.
• If at least one of the following alarm features are present, then the patient must have had a colonoscopy that should include biopsy since the onset of symptoms or within the past 5 years (whichever is less):
  • Documented and unexplained weight loss of 10% within the past 6 months;
  • Nocturnal diarrhea;
  • Blood mixed with stool (except hemorrhoidal bleeding, defined as occasional blood found on the toilet paper only or limited dripping of blood into the toilet bowl after defecation;
  • Unexplained iron-deficiency anemia.
• If no alarm features are present, then the patient must have had a colonoscopy or other appropriate exam, based on criteria as outlined below (Colorectal cancer screening tests other than colonoscopy are considered second-tier and can be discussed with the sponsor [):
  • Age ≥ 50 (≥ 45 if African-American): Colonoscopy within the past 10 years;
  • First‑degree relative (FDR) diagnosed with colorectal cancer under age 60 OR 2 FDRs diagnosed with colorectal cancer at any age: Colonoscopy within past 5 years, beginning 10 years before age of youngest FDR (at time of diagnosis);
  • Age ≥ 40 AND FDR diagnosed with colorectal cancer (at any age):
    • Colonoscopy within past 10 years.
• Patient is negative for serum tissue transglutaminase IgA antibody (tTG-IgA) plus has evidence of detectable serum IgA within the normal reference range.
• Body mass index (BMI) within the range 16 to 39 kg/m^2 (inclusive). 
• Male and female patients are eligible if: 
  • Male patients:
    • A male patient must agree to use contraception during the treatment period and for at least 14 weeks after the last dose of investigational product. Patients must also agree to refrain from donating sperm during this period. 
  • Female patients:  
    • A female patient is eligible to participate if she is not pregnant, not breastfeeding, and at least 1 of the following conditions applies: 
      • Not a woman of childbearing potential (WOCBP); or
      • A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 5 weeks after the last dose of investigational product.
• Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the Informed Consent Form (ICF) and in this protocol. 
• Patient is willing to be compliant with study procedures, including completing the daily electronic diary during the Run-in Period and throughout the study.

Exclusion Criteria:

Gastrointestinal-related Medical Conditions 

• At the time of screening, patient has a diagnosis of an IBS subtype other than IBS-D, based on Rome IV criteria (Lacy et al., 2016). Based on stool patterns on days that the patient experiences symptoms, other IBS subtypes are defined as follows:  
  • IBS-C: hard or lumpy stools ≥ 25% of bowel movements and loose or watery stools ≤ 25% of bowel movements;
  • IBS-M: hard or lumpy stools ≥ 25% of bowel movements and loose or watery stools ≥ 25% of bowel movements;
  • IBS-U: hard or lumpy stools ≤ 25% of bowel movements and loose or watery stools ≤ 25% of bowel movements.
• Patient has a history of inflammatory or immune-mediated GI disorders including (but not limited to) inflammatory bowel disease (i.e., Crohn's disease, ulcerative colitis, microscopic colitis, and celiac disease).
• Patient has had an episode of diverticulitis within 3 months prior to Screening.
• Patient has a history of intestinal obstruction, stricture, toxic megacolon, GI perforation, fecal impaction, gastric banding, bariatric surgery, adhesions, ischemic colitis, or impaired intestinal circulation (e.g., aortoiliac occlusive disease).
• Patient has any of the following surgical history:
  • Cholecystectomy with ANY history of post-cholecystectomy biliary tract pain. A successful cholecystectomy with no postoperative biliary tract pain is not exclusionary;
  • Any abdominal surgery within the 3 months prior to Screening;
  • Major gastric, esophageal, hepatic, pancreatic, or intestinal surgery (appendectomy, hemorrhoidectomy, or polypectomy greater than 3 months post-surgery are allowed).
• Patient has a history or current evidence of laxative abuse.

Other Medical Conditions

• Patient has a history of a cardiovascular event, including stroke, myocardial infarction, congestive heart failure, or transient ischemic attack within 6 months prior to Screening.
• Patient has a history of malignancy within 5 years prior to Screening (except squamous and basal cell carcinomas of the skin and cervical carcinoma in situ).
• Patient has a history of alcohol abuse or binge drinking.
• Patient has uncontrolled hypertension, defined as systolic blood pressure > 180 mmHg or a diastolic blood pressure > 100 mmHg at the time of Screening.
• Patient has a history of significant hypersensitivity, intolerance, or allergy to any drug compound, food, or other substance, unless approved by the Investigator.

Laboratory Assessments

• Fecal calprotectin > 150μg/g (Walsham and Sherwood, 2016).
• Hemoglobin A1c level ≥ 8.0% or a confirmed fasting plasma glucose level ≥ 180 mg/dL.
• Confirmed alanine aminotransferase (ALT) upper limit of normal (ULN).
• Confirmed total bilirubin > ULN, unless the patient has a documented history of Gilbert’s syndrome.
• Confirmed QT interval corrected by Fridericia’s formula (QTcF) or QT interval corrected by Bazett’s formula (QTcB) > 500 msec.
• Evidence of active hepatitis B virus (HBV) infection, based on a positive hepatitis B surface antigen (HBsAg) screen.
• Evidence of hepatitis C virus (HCV) infection based on a positive HCV antibody screen. Patients with a positive HCV antibody at screening may be eligible if confirmatory testing (i.e., Recombinant Immunoblot Assay [RIBA], or HCV RNA viral load) provided by the study site is negative. Patients who have been successfully treated for HCV are eligible if an undetectable HCV viral load at least 6 months after completion of treatment can be demonstrated.
• Human immunodeficiency virus (HIV)-1 or HIV-2 antibody positive.

Prior/Concomitant Therapy 

• Within 14 days of randomization, patient has used either of the following:
  • 5-hydroxytriptamine (5-HT)3 or 5‑HT4 receptor antagonists (e.g., alosetron, ondansetron, or ramosetron);
  • Eluxadoline;
  • Any of the strong inhibitors of P-glycoprotein.
• Within 14 days of randomization, patient has used any of the following:
  • Loperamide;
    • Note: loperamide can be used during the study as rescue medication based on protocol specified guidelines.
  • Bile acid sequestrants such as cholestyramine, colestipol, or colesevelam*
  • Aspirin or aspirin-containing medications (> 325 mg of aspirin per day) or nonsteroidal anti-inflammatory drugs, when taken specifically for the symptoms of IBS;
  • Narcotic- or opioid‑containing agents;
  • Cannabis-containing products;
  • Docusate;
  • Enemas;
  • GI preparations (including antacids containing aluminum or magnesium, antidiarrheal agents, antispasmodic agents, bismuth, peppermint oil, IBgard, FDgard, or prokinetic agents).
  • * Patients with diagnosis of or suspected to have bile acid malabsorption are not specifically excluded given the challenge of diagnosing these patients; however, use of bile acid sequestrants are prohibited.
• Within 14 days of randomization, receipt of any prescribed or over-the-counter, systemic, herbal (including St. John’s wort), or topical medication, or any expectation of requiring use of such medication while participating in the study that, in the opinion of the Investigator, would interfere with study procedures, compromise safety, or the scientific integrity of the data.
• Patient has used, or is expected to use, the following antibiotics:
  • Rifaximin within 90 days prior to randomization;
  • Other oral antibiotics within 28 days of randomization (with the exception of topical antibiotics or a 1-day course with an antibiotic).
• However, a patient will be allowed to remain in the study should unplanned use of antibiotics other than rifaximin occur after the patient has been randomly assigned to study drug.
• Within 3 months prior to randomization, patient has had significant changes to his or her antidepressant regimen (i.e., addition of a new agent, discontinuation of a prior agent, significant modifications to the dose of a current medication). Patients on chronic stable doses of antidepressants will be allowed to participate in the study. As‑needed use of buspirone and benzodiazepines for anxiety is permitted during the study;
• Within 30 days prior to randomization (or 5 half-lives, if known), the patient has received an investigational drug, or is currently enrolled in an investigational study.

Other Exclusions 

• Patient is unable to swallow solid oral dosage forms whole with the aid of liquid (patients may not chew, divide, dissolve, or crush the study drug).
• Patient has an elective surgery planned or expects to need elective surgery at any time during the study.
• Patient is pregnant or breastfeeding.
• Patient has any medical or psychological disorder or condition that, in the opinion of the Investigator, would compromise the wellbeing of the patient or the study or prevent the patient from meeting or performing study requirements.
• Patient has poor peripheral venous access.
• Patient is an employee of the Investigator or study center with direct involvement in the proposed study or other studies under the direction of that Investigator or study center, as well as family members of the employees or the Investigator.