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

• Sponsor: Mayo Clinic (Other)
• Overall Status: Completed
• CT.gov ID: NCT00911612
• Collaborator: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH)
• Enrollment: 24
• Location: 1
• Arms: 2
• Duration (Months): 3.9
• Patients Per Site Per Month: 6.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Irritable Bowel Syndrome; Diarrhea	Drug: Colesevelam; Drug: Placebo	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 24 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• 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 Start Date: Jan 1, 2009
• Actual Primary Completion Date: May 1, 2009
• Actual Study Completion Date: May 1, 2009

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Colonic Transit, Geometric Center at 24 Hours [After 12-14 days treatment]

   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.

2. Ascending Colon Emptying T1/2 [After 12-14 days' treatment]

   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.

Secondary Outcome Measures

1. Colonic Permeability as Measured by Cumulative Urinary Excretion of Mannitol 8-24 Hours [after 12-14 days' treatment]

   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.

2. Colonic Transit, Geometric Center at 48 Hours [After 12-14 days' treatment]

   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.

3. Stool Consistency [After 12-14 days' treatment]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic	Rochester	Minnesota	United States	55905

Sponsors and Collaborators

• Mayo Clinic
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Investigators

• Principal Investigator: Michael L. Camilleri, M.D., Mayo Clinic

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Mayo Clinic Clinical Trials

Publications

• Fernández-Bañares F, Esteve M, Salas A, Alsina M, Farré C, González C, Buxeda M, Forné M, Rosinach M, Espinós 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. Epub 2006 Aug 4.

• ClinicalTrials.gov Identifier: NCT00911612
• Other Study ID Numbers: 08-007454; R01DK054681
• First Posted: Jun 2, 2009
• Last Update Posted: Apr 4, 2012
• Last Verified: Mar 1, 2012

• Keywords provided by , ,: bile acid; malabsorption; permeability; diarrhea; IBS; stool
• Additional relevant MeSH terms: Irritable Bowel Syndrome; Syndrome; Diarrhea; Colesevelam Hydrochloride

Study Results

Participant Flow

Recruitment Details	All participants were recruited from the Mayo Clinic in Rochester, Minnesota from January through May 2009. 31 subjects signed consent, 1 withdrew consent before the start of the study, 2 had concomitant illness and 4 did not qualify based on colon transit eligibility criteria. 24 subjects were randomized and were included in the analysis.

Arm/Group Title	Colesevelam	Placebo
Arm/Group Description	Participants received colesevelam 1.875 g twice daily	Participants received an inert capsule matching the study drug twice daily, as prepared by the Mayo Clinic research pharmacy
Period Title: Overall Study
STARTED	12	12
COMPLETED	12	12
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Colesevelam	Placebo	Total
Arm/Group Description	Participants received colesevelam 1.875 g twice daily	Participants received an inert capsule matching the study drug twice daily, as prepared by the Mayo Clinic research pharmacy	Total of all reporting groups
Overall Participants	12	12	24
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	42.1 (4.0)	43.3 (3.7)	42.8 (13.0)
Sex: Female, Male (Count of Participants)
Female	12 100%	12 100%	24 100%
Male	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	12 100%	12 100%	24 100%
Body Mass Index (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	31.8 (1.5)	28.9 (1.8)	30.4 (5.7)
Baseline Colonic Geometric Center at 24 hours (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	3.4 (0.3)	3.4 (0.3)	3.4 (0.2)
Fasting Serum 7 alpha-HCO (ng/mL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [ng/mL]	31.8 (5.9)	38.2 (14.7)	35.0 (36.5)

Outcome Measures

1. Primary Outcome

Title	Colonic Transit, Geometric Center at 24 Hours
Description	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.
Time Frame	After 12-14 days treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Colesevelam	Placebo
Arm/Group Description	Participants received colesevelam 1.875 g twice daily	Participants received an inert capsule matching the study drug twice daily, as prepared by the Mayo Clinic research pharmacy
Measure Participants	12	12
Mean (Standard Error) [units on a scale]	2.68 (0.32)	3.30 (0.33)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Colesevelam, Placebo
	Comments	An analysis of covariance was used to compare drug with placebo adjusting for baseline geometric center at 24 hours , BMI, and 7 alpha CHO.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.22
	Comments	Not adjusted since only one comparison was made.
	Method	ANCOVA
	Comments

2. Primary Outcome

Title	Ascending Colon Emptying T1/2
Description	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.
Time Frame	After 12-14 days' treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Colesevelam	Placebo
Arm/Group Description	Participants received colesevelam 1.875 g twice daily	Participants received an inert capsule matching the study drug twice daily, as prepared by the Mayo Clinic research pharmacy
Measure Participants	12	12
Mean (Standard Error) [hours]	18.85 (2.88)	14.9 (3.58)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Colesevelam, Placebo
	Comments	An analysis of covariance was used to compare drug with placebo adjusting for BMI and 7 alpha HCO.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.02
	Comments
	Method	ANCOVA
	Comments

3. Secondary Outcome

Title	Colonic Permeability as Measured by Cumulative Urinary Excretion of Mannitol 8-24 Hours
Description	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.
Time Frame	after 12-14 days' treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Colesevelam	Placebo
Arm/Group Description	Participants received colesevelam 1.875 g twice daily	Participants received an inert capsule matching the study drug twice daily, as prepared by the Mayo Clinic research pharmacy
Measure Participants	12	12
Mean (Standard Error) [mg]	64.3 (13.3)	45.8 (8.8)

4. Secondary Outcome

Title	Colonic Transit, Geometric Center at 48 Hours
Description	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.
Time Frame	After 12-14 days' treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Colesevelam	Placebo
Arm/Group Description	Participants received colesevelam 1.875 g twice daily	Participants received an inert capsule matching the study drug twice daily, as prepared by the Mayo Clinic research pharmacy
Measure Participants	12	12
Mean (Standard Error) [units on a scale]	4.65 (0.13)	4.47 (0.20)

5. Secondary Outcome

Title	Stool Consistency
Description	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.
Time Frame	After 12-14 days' treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Colesevelam	Placebo
Arm/Group Description	Participants received colesevelam 1.875 g twice daily	Participants received an inert capsule matching the study drug twice daily, as prepared by the Mayo Clinic research pharmacy
Measure Participants	12	12
Mean (Standard Error) [units on a scale]	3.78 (0.27)	4.57 (0.35)

Adverse Events

Time Frame	Adverse events were collected from randomization through the 12-14 day treatment period (colesevelam HCL or placebo) and the 2 day testing period.
Arm/Group Title	Colesevelam		Placebo
Arm/Group Description	Participants received colesevelam 1.875 g twice daily		Participants received an inert capsule matching the study drug twice daily, as prepared by the Mayo Clinic research pharmacy
All Cause Mortality
	Colesevelam		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Colesevelam		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/12 (0%)		0/12 (0%)
Other (Not Including Serious) Adverse Events
	Colesevelam		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/12 (100%)		9/12 (75%)
Gastrointestinal disorders
Lower abdominal cramps	2/12 (16.7%)	2	0/12 (0%)	0
Flatulence	3/12 (25%)	3	1/12 (8.3%)	1
Green-colored stools	2/12 (16.7%)	2	2/12 (16.7%)	2
Nausea	2/12 (16.7%)	2	3/12 (25%)	3
Nervous system disorders
Headache	5/12 (41.7%)	5	4/12 (33.3%)	4
Reproductive system and breast disorders
Uterine cramps	1/12 (8.3%)	1	2/12 (16.7%)	2
Respiratory, thoracic and mediastinal disorders
Upper respiratory infection	1/12 (8.3%)	1	4/12 (33.3%)	4

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.