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| ID | Type | Description | Link |
|---|---|---|---|
| R01DK054681 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) | NIH |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Colesevelam | Experimental | Participants received colesevelam 1.875 g twice daily |
|
| Placebo | Placebo Comparator | Participants received an inert capsule matching the study drug twice daily, as prepared by the Mayo Clinic research pharmacy |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Colesevelam | Drug | Welchol (Colesevelam HCL) 1.875 gram twice daily for 12-14 days |
|
| 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 |
| 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. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Michael L. Camilleri, M.D. | Mayo Clinic | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Mayo Clinic | Rochester | Minnesota | 55905 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 17680846 | Background | 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. | |
| 19879973 | Result | 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. |
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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.
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| ID | Title | Description |
|---|---|---|
| FG000 | Colesevelam | Participants received colesevelam 1.875 g twice daily |
| FG001 | Placebo | Participants received an inert capsule matching the study drug twice daily, as prepared by the Mayo Clinic research pharmacy |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Colesevelam | Participants received colesevelam 1.875 g twice daily |
| BG001 | Placebo | Participants received an inert capsule matching the study drug twice daily, as prepared by the Mayo Clinic research pharmacy |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | Posted | Mean | Standard Error | units on a scale | After 12-14 days treatment |
|
Adverse events were collected from randomization through the 12-14 day treatment period (colesevelam HCL or placebo) and the 2 day testing period.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Colesevelam | Participants received colesevelam 1.875 g twice daily |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Uterine cramps | Reproductive system and breast disorders | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Michael Camilleri | Mayo Clinic | 507-266-2306 | camilleri.michael@mayo.edu |
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| ID | Term |
|---|---|
| D043183 | Irritable Bowel Syndrome |
| D003967 | Diarrhea |
| D008286 | Malabsorption Syndromes |
| ID | Term |
|---|---|
| D003109 | Colonic Diseases, Functional |
| D003108 | Colonic Diseases |
| D007410 | Intestinal Diseases |
| D005767 | Gastrointestinal Diseases |
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| ID | Term |
|---|---|
| D000069472 | Colesevelam Hydrochloride |
| ID | Term |
|---|---|
| D000499 | Allylamine |
| D000588 | Amines |
| D009930 | Organic Chemicals |
| D000498 | Allyl Compounds |
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| Placebo | Drug | Inert capsule matching the study drug, given twice daily |
|
| 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 |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Body Mass Index | Mean | Standard Deviation | kg/m^2 |
|
| Baseline Colonic 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. | Mean | Standard Deviation | units on a scale |
|
| Fasting Serum 7 alpha-HCO | The measurement of serum 7 alpha-hydroxy-4-cholesten-3-one (7 alpha-HCO) 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 bile acid malabsorption (BAM). | Mean | Standard Deviation | ng/mL |
|
Participants received an inert capsule matching the study drug twice daily, as prepared by the Mayo Clinic research pharmacy
|
|
|
| Primary | 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. | Posted | Mean | Standard Error | hours | After 12-14 days' treatment |
|
|
|
|
| Secondary | 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. | Posted | Mean | Standard Error | mg | after 12-14 days' treatment |
|
|
|
| Secondary | 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. | Posted | Mean | Standard Error | units on a scale | After 12-14 days' treatment |
|
|
|
| Secondary | 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. | Posted | Mean | Standard Error | units on a scale | After 12-14 days' treatment |
|
|
|
| 0 |
| 12 |
| 12 |
| 12 |
| EG001 | Placebo | Participants received an inert capsule matching the study drug twice daily, as prepared by the Mayo Clinic research pharmacy | 0 | 12 | 9 | 12 |
| Headache | Nervous system disorders | Non-systematic Assessment |
|
| Upper respiratory infection | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
|
| Lower abdominal cramps | Gastrointestinal disorders | Non-systematic Assessment |
|
| Flatulence | Gastrointestinal disorders | Non-systematic Assessment |
|
| Green-colored stools | Gastrointestinal disorders | Non-systematic Assessment |
|
| Nausea | Gastrointestinal disorders | Non-systematic Assessment |
|
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| D004066 | Digestive System Diseases |
| D012817 | Signs and Symptoms, Digestive |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D000475 |
| Alkenes |
| D006839 | Hydrocarbons, Acyclic |
| D006838 | Hydrocarbons |