Clinical trial NCT00911612: Does Welchol (Colesevelam Hydrochloride) Improve Colonic Transit in Diarrhea-predominant Irritable Bowel Syndrome (D-IBS)?
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Irritable Bowel Syndrome
Diarrhea
Keywords: bile acid
malabsorption
permeability
diarrhea
IBS
stool
Lead sponsor: Mayo Clinic
Sponsor class: OTHER
Collaborators: name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
First posted: 2009-06-02
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Colonic Transit, Geometric Center at 24 Hours
timeFrame: After 12-14 days treatment
measure: Ascending Colon Emptying T1/2
timeFrame: After 12-14 days' treatment
Secondary outcomes:
measure: Colonic Permeability as Measured by Cumulative Urinary Excretion of Mannitol 8-24 Hours
timeFrame: after 12-14 days' treatment
measure: Colonic Transit, Geometric Center at 48 Hours
timeFrame: After 12-14 days' treatment
measure: Stool Consistency
timeFrame: After 12-14 days' treatment
Other outcomes:
Locations:
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
Study officials:
affiliation: Mayo Clinic
name: Michael L. Camilleri, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Fernandez-Banares F, Esteve M, Salas A, Alsina M, Farre C, Gonzalez C, Buxeda M, Forne M, Rosinach M, Espinos JC, Maria Viver J. Systematic evaluation of the causes of chronic watery diarrhea with functional characteristics. Am J Gastroenterol. 2007 Nov;102(11):2520-8. doi: 10.1111/j.1572-0241.2007.01438.x. Epub 2006 Aug 4.
citation: Odunsi-Shiyanbade ST, Camilleri M, McKinzie S, Burton D, Carlson P, Busciglio IA, Lamsam J, Singh R, Zinsmeister AR. Effects of chenodeoxycholate and a bile acid sequestrant, colesevelam, on intestinal transit and bowel function. Clin Gastroenterol Hepatol. 2010 Feb;8(2):159-65. doi: 10.1016/j.cgh.2009.10.020. Epub 2009 Oct 30.