Randomized, Double-Blind, Placebo-Controlled Phase 2 Trial of BEKINDA (Ondansetron 12 mg Bimodal Release Tablets) for Diarrhea Predominant Irritable Bowel Syndrome (IBS-D)
Condition: Irritable Bowel Syndrome With Diarrhea
MeSH terms: Irritable Bowel Syndrome; Syndrome; Diarrhea
Intervention: BEKINDA; Placebo
Intervention MeSH terms: Ondansetron
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Enrollment: 127.0
Sex: All
Minimum age: 18 Years
Maximum age: 80 Years
Healthy volunteers: No

Summary:

      This is a randomized, double-blind, placebo-controlled, 2-arm parallel group study. After
      qualifying for the study and signing informed consent, patients will undergo a two-week
      observation period during which stool consistency and frequency data and symptom data will be
      collected. Patients will then be randomized 60:40 to RHB-102 12 mg (BEKINDA) or placebo.
      Patients will continue on treatment for 8 weeks. Each medication will be given once daily.
    

Eligibility criteria:

        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