Trial to Understand Efficacy of Colesevelam in Diarrhea Predominant IBS Patients With Bile Acid Malabsorption

• Sponsor: Mayo Clinic (Other)
• Overall Status: Completed
• CT.gov ID: NCT03270085
• Collaborator: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH)
• Enrollment: 30
• Location: 1
• Arms: 2
• Actual Duration (Months): 17.7
• Patients Per Site Per Month: 1.7

Study Details

Study Description

Brief Summary

To compare with a randomized trial (n=15 per treatment group), effects of colesevelam and placebo treatment, on colonic transit, bowel functions, permeability and tight junction expression in rectosigmoid mucosa of IBS-D with Bile Acid Malabsorption.

Condition or Disease	Intervention/Treatment	Phase
Chronic Diarrhea; Irritable Bowel Syndrome With Diarrhea; Bile Acid Malabsorption	Drug: Colesevelam; Other: Placebo	Phase 2

Detailed Description

Compare the effects of Colesevelam versus the placebo on diabetic subjects with chronic diarrhea. In this study, diabetic subjects will get either the Colesevelam or the placebo, not both.

The plan is to have about 30 subjects complete this study at Mayo Clinic.

Study Design

• Study Type: Interventional
• Actual Enrollment: 30 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: This is the third specific aim of a program on IBS-D with increased fecal bile acid excretion.This is the third specific aim of a program on IBS-D with increased fecal bile acid excretion.
• Masking: Triple (Participant, Care Provider, Investigator)
• Masking Description: 30 subjects with irritable bowel syndrome and diarrhea and bile acid malabsorption will be randomized into 15 people per group in 4-week double-blind, parallel-group trial to Colesevelam or placebo.
• Primary Purpose: Other
• Official Title: Randomized, Double Blinded, Placebo Controlled Trial to Understand Efficacy of Colesevelam in Diarrhea Predominant IBS Patients With Bile Acid Malabsorption
• Actual Study Start Date: Dec 7, 2017
• Actual Primary Completion Date: May 31, 2019
• Actual Study Completion Date: May 31, 2019

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Colesevelam Once randomized, subjects will have baseline testing period, treatment period, and treatment testing period the study drug. This consists of nine visits and will be over a period of five to nine weeks. Baseline testing period consists of: transit test, 4 day high fat diet with 48 hour stool collection, blood samples, rectosigmoid biopsies, one week stool diary, and medication pick up. Treatment period will have subject take the study drug 1875 mg of medication orally twice daily with lunch and supper for 4-5 weeks. The last period, is the treatment testing period. This consists of a full transit & urine permeability test, 4 day high fat diet with 48 hour stool collection, blood samples, one week stool diary collection, and the return of the unused medication.	Drug: Colesevelam; Colesevelam (Welchol) is approved by the Food and Drug Administration (FDA) for the treatment of high blood cholesterol levels and to treat type 2 diabetes however, Colesevelam is not approved for the use proposed in this study and is considered investigational.
Placebo Comparator: Placebo Once randomized, subjects will have a baseline testing period, treatment period and treatment testing period with the placebo. This consists of nine visits and will be over a period of five to nine weeks. The last period, is the treatment testing period. This consists of a full transit & urine permeability test, 4 day high fat diet with 48 hour stool collection, blood samples, one week stool diary collection, and the return of the unused placebo.	Other: Placebo; A placebo looks exactly like the study drug, but it contains no active ingredient. This is used to learn if the effects seen in research participants are truly from the study drug.

Outcome Measures

Primary Outcome Measures

1. Total Fecal Bile Acid (BA) Excretion [Treatment day 28]

   Total fecal BA excretion was measured using High Performance Liquid Chromatography (HPLC)/tandem mass spectrometry (MS) where single stool samples obtained at baseline and end of treatment were prepared by assay by HPLC/MS by methanol extraction and results are presented as micromoles per gram (μmoles/g) of stool.

2. Stool Consistency [Treatment days 1 through 28]

   Stool consistency as reported by the participant via daily bowel diaries. Stool consistency was based on Bristol Stool Form Scale (BSFS) where 1 - hard lumps, 2 - lumpy sausage, 3 - cracked sausage, 4 - smooth sausage, 5 - soft lumps, 6 - mushy, and 7 - watery. Stool consistency was averaged for the 28 day treatment period.

Secondary Outcome Measures

1. Number of Stools Per Day [Treatment days 1 through 28]

   The total number of bowel movements as reported by the participant via daily bowel diaries. The number of bowel movements were averaged for the 28 day treatment period.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Females and males age 18 -75.

• An IBS diagnosis based on the Rome III criteria for at least 3 months, with onset at least 6 months previously, of recurrent abdominal pain or discomfort.

• Biomarkers serum alpha C4 ≥ 40 ng/mL or FGF19 ≤ 80 pg/mL or fecal bile acid >2000 micromoles/48h

Exclusion Criteria:

• IBS patients with known clinically-relevant inflammation.

• IBS patient with known bleeding diathesis

• History of abdominal surgery

Patients participating will not take any of the following disallowed medications for at least 7 days prior to and during the remainder of the study:

• Any treatment specifically taken for IBS-D, including loperamide, cholestyramine, alosetron

• Drugs with a known pharmacological activity at 5-HT4, 5-HT2b or 5-HT3 receptors

• All narcotics

• Anti-cholinergic agents

• Tramadol

• Oral anticoagulants

• Antimuscarinics

• Peppermint oil

• Systemic antibiotics, as well as antibiotics directed at colonic flora such as rifaximin and metronidazole

Gastrointestinal preparations:

• Anti-nausea agents

• Osmotic laxative agents

• Prokinetic agents

• 5-HT3 antagonists

Contacts and Locations

Locations

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

Sponsors and Collaborators

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

Investigators

• Principal Investigator: Michael Camilleri, Mayo Clinic

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Oct 15, 2018

More Information

Additional Information:

• Mayo Clinic Clinical Trials

Publications

None provided.

• Responsible Party: Michael Camilleri, MD, Michael Camilleri, M.D. Professor of Medicine, Pharmacology and Physiology, Atherton and Winifred W. Bean Professor, College of Medicine Consultant, Division of Gastroenterology and Hepatology, Mayo Clinic
• ClinicalTrials.gov Identifier: NCT03270085
• Other Study ID Numbers: 17-004639; R01DK115950; UL1TR000135
• First Posted: Sep 1, 2017
• Last Update Posted: Apr 27, 2020
• Last Verified: Mar 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Irritable Bowel Syndrome; Malabsorption Syndromes; Diarrhea; Colesevelam Hydrochloride

Study Results

Participant Flow

Arm/Group Title	Colesevelam	Placebo
Arm/Group Description	Once randomized, subjects will have baseline testing period, treatment period, and treatment testing period the study drug. This consists of nine visits and will be over a period of five to nine weeks. Baseline testing: transit test, 4 day high fat diet with 48 hour stool collection, blood samples, rectosigmoid biopsies, one week stool diary, medication pick up. Treatment period: subject takes study drug 1875 mg orally twice daily with lunch and supper for 4-5 weeks. Treatment testing period: full transit & urine permeability test, 4 day high fat diet with 48 hour stool collection, blood samples, one week stool diary collection, and the return of the unused medication. Colesevelam: Colesevelam (Welchol) is approved by the Food and Drug Administration (FDA) for the treatment of high blood cholesterol levels and to treat type 2 diabetes however, Colesevelam is not approved for the use proposed in this study and is considered investigational.	Once randomized, subjects will have a baseline testing period, treatment period and treatment testing period with the placebo. This consists of nine visits and will be over a period of five to nine weeks. Treatment testing period: full transit & urine permeability test, 4 day high fat diet with 48 hour stool collection, blood samples, one week stool diary collection, and the return of the unused placebo. Placebo: A placebo looks exactly like the study drug, but it contains no active ingredient. This is used to learn if the effects seen in research participants are truly from the study drug.
Period Title: Overall Study
STARTED	15	15
COMPLETED	14	15
NOT COMPLETED	1	0

Baseline Characteristics

Arm/Group Title	Colesevelam	Placebo	Total
Arm/Group Description	Once randomized, subjects will have baseline testing period, treatment period, and treatment testing period the study drug. This consists of nine visits and will be over a period of five to nine weeks. Baseline testing: transit test, 4 day high fat diet with 48 hour stool collection, blood samples, rectosigmoid biopsies, one week stool diary, medication pick up. Treatment period: subject takes study drug 1875 mg orally twice daily with lunch and supper for 4-5 weeks. Treatment testing period: full transit & urine permeability test, 4 day high fat diet with 48 hour stool collection, blood samples, one week stool diary collection, and the return of the unused medication. Colesevelam: Colesevelam (Welchol) is approved by the Food and Drug Administration (FDA) for the treatment of high blood cholesterol levels and to treat type 2 diabetes however, Colesevelam is not approved for the use proposed in this study and is considered investigational.	Once randomized, subjects will have a baseline testing period, treatment period and treatment testing period with the placebo. This consists of nine visits and will be over a period of five to nine weeks. Treatment testing period: full transit & urine permeability test, 4 day high fat diet with 48 hour stool collection, blood samples, one week stool diary collection, and the return of the unused placebo. Placebo: A placebo looks exactly like the study drug, but it contains no active ingredient. This is used to learn if the effects seen in research participants are truly from the study drug.	Total of all reporting groups
Overall Participants	15	15	30
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	44	56	50
Sex: Female, Male (Count of Participants)
Female	11 73.3%	13 86.7%	24 80%
Male	4 26.7%	2 13.3%	6 20%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	13 86.7%	15 100%	28 93.3%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	2 13.3%	0 0%	2 6.7%
Region of Enrollment (participants) [Number]
United States	15 100%	15 100%	30 100%
Body Mass Index (kg/m2) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [kg/m2]	33.2	33.6	33.4

Outcome Measures

1. Primary Outcome

Title	Total Fecal Bile Acid (BA) Excretion
Description	Total fecal BA excretion was measured using High Performance Liquid Chromatography (HPLC)/tandem mass spectrometry (MS) where single stool samples obtained at baseline and end of treatment were prepared by assay by HPLC/MS by methanol extraction and results are presented as micromoles per gram (μmoles/g) of stool.
Time Frame	Treatment day 28

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Colesevelam	Placebo
Arm/Group Description	Once randomized, subjects will have baseline testing period, treatment period, and treatment testing period the study drug. This consists of nine visits and will be over a period of five to nine weeks. Baseline testing: transit test, 4 day high fat diet with 48 hour stool collection, blood samples, rectosigmoid biopsies, one week stool diary, medication pick up. Treatment period: subject takes study drug 1875 mg orally twice daily with lunch and supper for 4-5 weeks. Treatment testing period: full transit & urine permeability test, 4 day high fat diet with 48 hour stool collection, blood samples, one week stool diary collection, and the return of the unused medication. Colesevelam: Colesevelam (Welchol) is approved by the Food and Drug Administration (FDA) for the treatment of high blood cholesterol levels and to treat type 2 diabetes however, Colesevelam is not approved for the use proposed in this study and is considered investigational.	Once randomized, subjects will have a baseline testing period, treatment period and treatment testing period with the placebo. This consists of nine visits and will be over a period of five to nine weeks. Treatment testing period: full transit & urine permeability test, 4 day high fat diet with 48 hour stool collection, blood samples, one week stool diary collection, and the return of the unused placebo. Placebo: A placebo looks exactly like the study drug, but it contains no active ingredient. This is used to learn if the effects seen in research participants are truly from the study drug.
Measure Participants	15	15
Median (Inter-Quartile Range) [μmoles/g]	10.7	3.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Colesevelam, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

2. Primary Outcome

Title	Stool Consistency
Description	Stool consistency as reported by the participant via daily bowel diaries. Stool consistency was based on Bristol Stool Form Scale (BSFS) where 1 - hard lumps, 2 - lumpy sausage, 3 - cracked sausage, 4 - smooth sausage, 5 - soft lumps, 6 - mushy, and 7 - watery. Stool consistency was averaged for the 28 day treatment period.
Time Frame	Treatment days 1 through 28

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Colesevelam	Placebo
Arm/Group Description	Once randomized, subjects will have baseline testing period, treatment period, and treatment testing period the study drug. This consists of nine visits and will be over a period of five to nine weeks. Baseline testing: transit test, 4 day high fat diet with 48 hour stool collection, blood samples, rectosigmoid biopsies, one week stool diary, medication pick up. Treatment period: subject takes study drug 1875 mg orally twice daily with lunch and supper for 4-5 weeks. Treatment testing period: full transit & urine permeability test, 4 day high fat diet with 48 hour stool collection, blood samples, one week stool diary collection, and the return of the unused medication. Colesevelam: Colesevelam (Welchol) is approved by the Food and Drug Administration (FDA) for the treatment of high blood cholesterol levels and to treat type 2 diabetes however, Colesevelam is not approved for the use proposed in this study and is considered investigational.	Once randomized, subjects will have a baseline testing period, treatment period and treatment testing period with the placebo. This consists of nine visits and will be over a period of five to nine weeks. Treatment testing period: full transit & urine permeability test, 4 day high fat diet with 48 hour stool collection, blood samples, one week stool diary collection, and the return of the unused placebo. Placebo: A placebo looks exactly like the study drug, but it contains no active ingredient. This is used to learn if the effects seen in research participants are truly from the study drug.
Measure Participants	15	15
Median (Inter-Quartile Range) [units on a scale]	4.6	4.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Colesevelam, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.81
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

3. Secondary Outcome

Title	Number of Stools Per Day
Description	The total number of bowel movements as reported by the participant via daily bowel diaries. The number of bowel movements were averaged for the 28 day treatment period.
Time Frame	Treatment days 1 through 28

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Colesevelam	Placebo
Arm/Group Description	Once randomized, subjects will have baseline testing period, treatment period, and treatment testing period the study drug. This consists of nine visits and will be over a period of five to nine weeks. Baseline testing: transit test, 4 day high fat diet with 48 hour stool collection, blood samples, rectosigmoid biopsies, one week stool diary, medication pick up. Treatment period: subject takes study drug 1875 mg orally twice daily with lunch and supper for 4-5 weeks. Treatment testing period: full transit & urine permeability test, 4 day high fat diet with 48 hour stool collection, blood samples, one week stool diary collection, and the return of the unused medication. Colesevelam: Colesevelam (Welchol) is approved by the Food and Drug Administration (FDA) for the treatment of high blood cholesterol levels and to treat type 2 diabetes however, Colesevelam is not approved for the use proposed in this study and is considered investigational.	Once randomized, subjects will have a baseline testing period, treatment period and treatment testing period with the placebo. This consists of nine visits and will be over a period of five to nine weeks. Treatment testing period: full transit & urine permeability test, 4 day high fat diet with 48 hour stool collection, blood samples, one week stool diary collection, and the return of the unused placebo. Placebo: A placebo looks exactly like the study drug, but it contains no active ingredient. This is used to learn if the effects seen in research participants are truly from the study drug.
Measure Participants	15	15
Median (Inter-Quartile Range) [number of stools per day]	3.1	2.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Colesevelam, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.91
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Adverse Events

Time Frame	Adverse events were collected for each subject from baseline to the end of the study, approximately 10 weeks, for a total study duration of approximately 18 months.
Arm/Group Title	Colesevelam		Placebo
Arm/Group Description	Once randomized, subjects will have baseline testing period, treatment period, and treatment testing period the study drug. This consists of nine visits and will be over a period of five to nine weeks. Baseline testing: transit test, 4 day high fat diet with 48 hour stool collection, blood samples, rectosigmoid biopsies, one week stool diary, medication pick up. Treatment period: subject takes study drug 1875 mg orally twice daily with lunch and supper for 4-5 weeks. Treatment testing period: full transit & urine permeability test, 4 day high fat diet with 48 hour stool collection, blood samples, one week stool diary collection, and the return of the unused medication. Colesevelam: Colesevelam (Welchol) is approved by the Food and Drug Administration (FDA) for the treatment of high blood cholesterol levels and to treat type 2 diabetes however, Colesevelam is not approved for the use proposed in this study and is considered investigational.		Once randomized, subjects will have a baseline testing period, treatment period and treatment testing period with the placebo. This consists of nine visits and will be over a period of five to nine weeks. Treatment testing period: full transit & urine permeability test, 4 day high fat diet with 48 hour stool collection, blood samples, one week stool diary collection, and the return of the unused placebo. Placebo: A placebo looks exactly like the study drug, but it contains no active ingredient. This is used to learn if the effects seen in research participants are truly from the study drug.
All Cause Mortality
	Colesevelam		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		0/15 (0%)
Serious Adverse Events
	Colesevelam		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		0/15 (0%)
Other (Not Including Serious) Adverse Events
	Colesevelam		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		0/15 (0%)

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.