Does Welchol (Colesevelam Hydrochloride) Improve Colonic Transit in Diarrhea-predominant Irritable Bowel Syndrome (D-IBS)?

Study Overview
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Brief Summary
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Our hypothesis is that the medication approved for treatment of high blood cholesterol levels, Colesevelam HCl (WELCHOL), decreases colonic transit and permeability in patients with diarrhea due to irritable bowel syndrome. This effect is thought to result from the effect of the medication on bile acids, which can cause diarrhea.

Detailed Description
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Background: Irritable bowel syndrome (IBS) affects about 15% of the U.S. population, about 5% having predominant diarrhea; current treatment is suboptimal as it may not be tolerated, lead to side effects or insufficient benefit. Bile acid malabsorption (BAM) is recognized as a cause of chronic diarrhea and has been investigated as a mechanism for the phenotype of diarrhea predominant IBS (D-IBS). Increased exposure of the colon to bile acids which may result from accelerated small bowel transit or abnormal function of the apical sodium bile acid transporter (ASBT) has been postulated to cause functional diarrhea or symptoms of D-IBS by a number of mechanisms, such as increase colonic secretion, and mucosal permeability. Recent preliminary data suggest that doses of chenodeoxycholate (CDC) that are approved for the dissolution of gall stones are associated with accelerated colonic emptying and looser stool consistency. Hypothesis: The bile acid binding agent, Colesevelam HCl, decreases colonic transit and permeability in patients with D-IBS. Specific Aim: To investigate the effect of Colesevelam, which binds bile acids in the small intestine and reduces the concentration of bile acids in the colon, on colonic transit, permeability and the bowel function of patients with D-IBS. Methods: Twenty-four D-IBS participants will be randomized to placebo or treatment with Welchol (Colesevelam HCL) 1.875 gram b.i.d. for 12-14 days. A baseline colon transit, 24 hour urine for colon permeability, and blood for serum 7 alpha-hydroxy-4-cholesten-3-one (7 alpha-HCO) will be measured and venous blood DNA will be collected and stored. The measurement of serum 7 alpha-hydroxy-4-cholesten-3-one (7 alpha-HCO), which is a measurement of hepatic cholesterol synthesis, is closely related to the fecal loss of bile acids, and is a validated method for screening for BAM. Following treatment for 12 days, transit and permeability studies will be repeated. Bowel function symptoms will be recorded for the duration of the study.

Official Title
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A Phase IIB Study to Evaluate the Effects of Welchol (Colesevelam Hydrochloride) on Colonic Transit, Intestinal Permeability and Bowel Function in Diarrhea-predominant Irritable Bowel Syndrome (D-IBS)

Conditions
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Irritable Bowel Syndrome, Diarrhea

Intervention / Treatment
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* Drug: Colesevelam
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with D-IBS Aged 18-65 years No abdominal surgery (except appendectomy or cholecystectomy as long as patients IBS-diarrhea symptoms preceded the cholecystectomy Exclusion Criteria: Participants with known chronic liver disease or Aspartate aminotransferase (AST) or Alanine transaminase (ALT) > 2.0 X upper limit of normal Hypertriglyceridemia and pancreatitis by history Diabetes or hypoglycemia Significant coagulation disorder History of bowel obstruction Serum triglycerides >500 mg/dL History of vitamin A, D, E, or K deficiencies

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Colesevelam<br>Participants received colesevelam 1.875 g twice daily | Drug: Colesevelam<br>* Welchol (Colesevelam HCL) 1.875 gram twice daily for 12-14 days<br>* Other names: Welchol;|
| Placebo Comparator: Placebo<br>Participants received an inert capsule matching the study drug twice daily, as prepared by the Mayo Clinic research pharmacy | Drug: Placebo<br>* Inert capsule matching the study drug, given twice daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Colonic Transit, Geometric Center at 24 Hours | The scintigraphic method is used to measure colonic transit. An isotope is adsorbed on activated charcoal particles and delivered to the colon in a delayed release capsule. Anterior and posterior gamma images are taken hourly. The geometric center (GC) is the weighted average of counts in the different colonic regions. The scale ranges from 1 to 5; a high GC implies faster colonic transit. A GC of 1 implies all isotope is in the ascending colon, and a GC of 5 implies all isotope is in the stool. | After 12-14 days treatment | 
| Ascending Colon Emptying T1/2 | The half time for the ascending colon emptying (T1/2) was measured by the scintigraphic method. An isotope is adsorbed on activated charcoal particles and delivered to the colon in a delayed release capsule that is swallowed by the subject. Anterior and posterior gamma images are taken hourly. From the hourly scans, a time-activity curve is plotted using linear interpolation between time points when content was measured. The time taken to empty 50% of the isotope from the ascending colon is read from this time-activity curve. | After 12-14 days' treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Colonic Permeability as Measured by Cumulative Urinary Excretion of Mannitol 8-24 Hours | Colonic permeability is measured through differential excretion of urine saccharides. The subject ingests a methacrylate-coated capsule that contains saccharides (mannitol 1g and lactulose 5 g powder). The capsule provides a means to protect the sugars from absorption, until the sugars are delivered to the colon by means of a standard delayed release capsule. The value reported is the mean for each arm of the total amount of mannitol excreted over the 8-24 hour time period. | after 12-14 days' treatment | 
| Colonic Transit, Geometric Center at 48 Hours | The scintigraphic method is used to measure colonic transit. An isotope is adsorbed on activated charcoal particles and delivered to the colon in a delayed release capsule. Anterior and posterior gamma images are taken hourly. The geometric center (GC) is the weighted average of counts in the different colonic regions. The scale ranges from 1 to 5; a high GC implies faster colonic transit. A GC of 1 implies all isotope is in the ascending colon, and a GC of 5 implies all isotope is in the stool. | After 12-14 days' treatment | 
| Stool Consistency | The subjects rated their stool consistency using the Bristol Stool Scale. The Bristol Stool Scale is a medical aid designed to classify the form of human feces into seven categories or types. Types 1 and 2 indicate constipation with 3 and 4 being the ideal stools especially the latter, as they are the easiest to defecate, and 5-7 tending towards diarrhea. | After 12-14 days' treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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bile acid, malabsorption, permeability, diarrhea, IBS, stool