Diarrhea, Irritable Bowel Syndrome
Conditions
Keywords
bile acid, malabsorption, permeability, diarrhea, IBS, stool
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.
Interventions
DRUGColesevelam
Welchol (Colesevelam HCL) 1.875 gram twice daily for 12-14 days
DRUGPlacebo
Inert capsule matching the study drug, given twice daily
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Mayo Clinic
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
Countries
United States
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.
Participants by arm
| Arm | Count |
|---|---|
| Colesevelam Participants received colesevelam 1.875 g twice daily | 12 |
| Placebo Participants received an inert capsule matching the study drug twice daily, as prepared by the Mayo Clinic research pharmacy | 12 |
| Total | 24 |
Baseline characteristics
| Characteristic | Placebo | Total | Colesevelam |
|---|---|---|---|
| Age Continuous | 43.3 years STANDARD_DEVIATION 3.7 | 42.8 years STANDARD_DEVIATION 13 | 42.1 years STANDARD_DEVIATION 4 |
| Baseline Colonic Geometric Center at 24 hours | 3.4 units on a scale STANDARD_DEVIATION 0.3 | 3.4 units on a scale STANDARD_DEVIATION 0.2 | 3.4 units on a scale STANDARD_DEVIATION 0.3 |
| Body Mass Index | 28.9 kg/m^2 STANDARD_DEVIATION 1.8 | 30.4 kg/m^2 STANDARD_DEVIATION 5.7 | 31.8 kg/m^2 STANDARD_DEVIATION 1.5 |
| Fasting Serum 7 alpha-HCO | 38.2 ng/mL STANDARD_DEVIATION 14.7 | 35.0 ng/mL STANDARD_DEVIATION 36.5 | 31.8 ng/mL STANDARD_DEVIATION 5.9 |
| Region of Enrollment United States | 12 participants | 24 participants | 12 participants |
| Sex: Female, Male Female | 12 Participants | 24 Participants | 12 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 12 / 12 | 9 / 12 |
| serious Total, serious adverse events | 0 / 12 | 0 / 12 |
Outcome results
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.
Time frame: After 12-14 days' treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Colesevelam | Ascending Colon Emptying T1/2 | 18.85 hours | Standard Error 2.88 |
| Placebo | Ascending Colon Emptying T1/2 | 14.9 hours | Standard Error 3.58 |
Comparison: An analysis of covariance was used to compare drug with placebo adjusting for BMI and 7 alpha HCO.p-value: 0.02ANCOVA
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.
Time frame: After 12-14 days treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Colesevelam | Colonic Transit, Geometric Center at 24 Hours | 2.68 units on a scale | Standard Error 0.32 |
| Placebo | Colonic Transit, Geometric Center at 24 Hours | 3.30 units on a scale | Standard Error 0.33 |
Comparison: An analysis of covariance was used to compare drug with placebo adjusting for baseline geometric center at 24 hours , BMI, and 7 alpha CHO.p-value: 0.22ANCOVA
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.
Time frame: after 12-14 days' treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Colesevelam | Colonic Permeability as Measured by Cumulative Urinary Excretion of Mannitol 8-24 Hours | 64.3 mg | Standard Error 13.3 |
| Placebo | Colonic Permeability as Measured by Cumulative Urinary Excretion of Mannitol 8-24 Hours | 45.8 mg | Standard Error 8.8 |
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.
Time frame: After 12-14 days' treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Colesevelam | Colonic Transit, Geometric Center at 48 Hours | 4.65 units on a scale | Standard Error 0.13 |
| Placebo | Colonic Transit, Geometric Center at 48 Hours | 4.47 units on a scale | Standard Error 0.2 |
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.
Time frame: After 12-14 days' treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Colesevelam | Stool Consistency | 3.78 units on a scale | Standard Error 0.27 |
| Placebo | Stool Consistency | 4.57 units on a scale | Standard Error 0.35 |