Randomized, Double-Blind, Placebo-Controlled Phase 2 Trial of BEKINDA (Ondansetron 12 mg Bimodal Release Tablets) for Diarrhea Predominant Irritable Bowel Syndrome (IBS-D)

All patients will undergo baseline evaluation including full history and physical, with
particular attention to gastrointestinal symptomatology and findings, a standard set of
safety laboratory examinations (CBC and platelet count, biochemical profile, urinalysis,
serum thyroid-stimulating hormone (TSH) and free T4, INR), and 12-lead ECG. In addition, the
following studies will be performed to exclude other causes of gastrointestinal symptoms:

- Serum testing for C-reactive protein and gluten sensitivity

- Colonoscopy if required per protocol

- Patients with a history of positive tests for ova, parasites or Clostridium difficile
must undergo repeat testing, which must be negative, during the screening period.
Starting during the baseline observation phase, all patients will keep diaries of
symptomatology and stool frequency and consistency. Stool consistency will be assessed
according to the Bristol Stool Form scale (Lewis and Heaton, 1997).

Patients will keep diaries of stool frequency and consistency, symptoms, study medication
compliance, and use of all medications, including rescue medications, throughout the study.

Serum electrolyte assays (bicarbonate, calcium, chloride, magnesium, potassium, and sodium)
will be performed at week 3 on study. Safety laboratory examinations will be performed during
and after the treatment period in accordance with the study procedures schedule below.

Patients will be questioned periodically regarding concomitant medication use and the
occurrence of adverse events.

Patients must complete at least 12 days of all baseline diary entries within the 14 day
screening period to be eligible to participate in the study. Patients completing fewer than
12 days of diary entries may, at the investigator's discretion, repeat the screening period
diary. As long as the patent can complete and enter the study within 6 weeks, baseline
laboratory studies need not be repeated. If repeating the 2 weeks' baseline diary will result
in a period longer than 6 weeks from consent to start of treatment, the medical monitor must
be consulted prior to randomization.

Inclusion Criteria:

1. Male and female patients age≥18 years (with a minimum of 35% males in the study)

2. Patient meets FDA guidance and Rome III criteria for IBS-D:

a. Recurrent abdominal pain or discomfort over ≥6 months, with frequency ≥3 days/month
in the last 3 months associated with ≥2 of the following: i. Improvement with
defecation ii. Onset associated with a change in frequency of stool iii. Onset
associated with a change in the form of stool b. Loose or watery stools (Bristol stool
form scale 6 or 7) ≥2 days per week

3. Average worst daily pain intensity ≥3.0 for each of the two baseline weeks

4. Major laboratory parameters within the following limits (no worse than grade 1
abnormalities per NCI-CTCAE v4):

a. Adequate hematologic function, as demonstrated by i. Hemoglobin ≥10 g/dL ii.
Absolute neutrophil count (ANC) 1.5-10 x 10^9/L iii. Platelets ≥100 x 10^9/L b.
Adequate liver and renal function as demonstrated by i. Aspartate transaminase (AST)
and Alanine transaminase (ALT) each ≤ 3.0 x upper limit of normal (ULN) ii. Total
bilirubin ≤1.5 x ULN iii. Creatinine ≤1.5 X ULN c. Euthyroid based on
thyroid-stimulating hormone (TSH) and free T4 levels

5. Patients on thyroid hormone replacement must be on a stable dose for at least one
month prior to study entry.

6. C-reactive protein ≤2 x ULN for lab

7. Patients of childbearing potential and male patients with partners of childbearing
potential must utilize effective contraceptive measures Women of childbearing
potential are women who have menstruated in the past 12 months, with the exception of
women who have undergone surgical sterilization

8. All patients must sign informed consent.

Exclusion Criteria:

1. Evidence of other cause for bowel disease:

1. Relevant abnormalities seen on colonoscopy if previously performed or if required
per this protocol. These include but are not limited to Crohn's disease,
ulcerative colitis, diverticulitis, ischemic colitis, microscopic colitis.

2. History of and/or positive serologic test for celiac disease

3. Known or suspected lactose intolerance.

2. History of abdominal surgery other than appendectomy or cholecystectomy at any time

3. Any elective major surgery (of any organ) planned for the period of the study,
including follow-up

4. History of organic abnormalities of the GI tract including but not limited to
intestinal obstruction, stricture, toxic megacolon, GI perforation, fecal impaction,
gastric banding, adhesions or impaired intestinal circulation (e.g., aortoiliac
disease)

5. Current or previous diagnosis of neoplasia (except non-GI neoplasia in complete
remission ≥5 years, squamous and basal cell carcinomas). With approval of the medical
monitor patients with curatively treated neoplasm in complete remission <5 years may
be entered in the study.

6. Patients with a history of positive tests for ova or parasites or Clostridium
difficile must be retested during the screening period and tests for the relevant
agents must be negative

7. Use of any 5-HT3 antagonist (5hydroxytryptamine receptor antagonists) within 4 weeks
of the start of baseline data collection.

8. Use of rifaximin within 4 months of the start of baseline data collection.

9. Use of any other agent specific for IBS (such as alosetron or eluxadoline) or for
symptomatic treatment of IBS (such as antispasmotics and antidiarrheals other than
loperamide) within 2 weeks of the start of baseline data collection.

10. Uses of any investigational agent for any indication within 4 weeks of the start of
baseline data collection.

11. Congestive heart failure, bradyarrhythmia (baseline pulse<55/min), known long QT
syndrome

12. Patients who have Corrected QT interval (QTc) prolongation>450 msec noted on screening
ECG, or who are taking medication known to cause QT prolongation

Note: For current list of medications known to cause QT prolongation see:

https://www.crediblemeds.org/healthcare-providers/drug-list/ There are several risk
categories. Use the list showing those drugs known to cause torsade de pointes (TdP)

13. Hypersensitivity or other known intolerance to ondansetron or other 5-HT3 antagonists

14. Patient has taken apomorphine within 24 hours of screening

15. Pregnant or lactating

16. Patients with other major illnesses, either physical or psychiatric, or social
situations which may interfere with participation in the study or interpretation of
results

17. Patients with severe hepatic impairment, defined as Child-Pugh score ≥10 at baseline