Diarrhea Predominant Irritable Bowel Syndrome
Conditions
Brief summary
The investigators' hypothesis is that therapy with Colesevelam, reduces fecal bile acid excretion in patients with Irritable Bowel Syndrome (IBS)-diarrhea with prior evidence of increased fecal 48 hour total bile acid excretion. The investigators aim to study the ability of the HPLC assay for fecal bile acids to demonstrate responsiveness after treatment with Colesevelam.
Detailed description
This study will evaluate whether Colesevelam, a bile acid sequestrant, is able to reduce fecal bile acids and improve bowel function in patients with IBS-diarrhea and Mayo's HPLC method can demonstrate a response to the Colesevelam. The study design will be a single center, unblinded, single dose trial to study the ability to identify the effect of taking 1875 mg (3 tablets \[625 mg/tablet\]) of Colesevelam orally twice daily for ten days on fasting serum 7alphaC4 and total 48 hour fecal bile acid excretion. Stool and fasting serum samples will be collected predose and during final 48 hours' dosing for assessment. Participants will also fill out an 8-day stool diary assessing frequency, consistency, ease of passage of bowel movements before and during treatment with Colesevelam.
Interventions
DRUGColesevelam
Subjects will receive 1875 mg of Colesevelam orally twice daily for 10 days
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Mayo Clinic
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
Patients with IBS-diarrhea with prior evidence of increased fecal 48 hour total bile acid and increased fasting serum 7alphaC4 who meet the following: INCLUSION CRITERIA * Bowel disease questionnaire (BDQ) - IBS symptoms: Positive by Rome lll criteria * No restrictions on Hospital Anxiety/Depression Score (HADS). * Gender: Men or women. Women of childbearing potential will have a negative pregnancy test before initiation of medication.
Exclusion criteria
* Use of drugs or agents within the past 1 week or planned use in the subsequent 2 weeks during the study period (Birth control pill, estrogen replacement therapy, and thyroxine replacement are permissible exceptions): * Agents that alter GI transit including opioids, narcotics, anticholinergics, tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors (SNRI) antidepressants. * Analgesic drugs including opiates, nonsteroidal anti-inflammatory drugs (NSAID), cyclooxygenase-2 (COX 2) inhibitors * Intake of medication that could interfere with the interpretation of the study. * Female subjects who are pregnant or breast-feeding. Females must be either surgically sterilized, postmenopausal (\>12 months since last menses), or, if of childbearing potential, using reliable methods of contraception as determined by the physician. * Abdominal surgery (except Appendectomy) * Patients with known chronic liver disease or history of elevated aspartate aminotransferase (AST)/ alanine transaminase (ALT) 2.0 X upper limit of normal. * Bile acid (BA) synthesis and possible false positive or negative fecal bile acid or serum 7alpha-hydroxy-4-cholesten-3-one (7alphaC4) result. If there is no AST or ALT values in the medical record, the study physicians will determine if the tests need to be run.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Total 48 Hour Fecal Bile Acids (BA) From Baseline in Response to Treatment With Colesevelam | baseline, 10 days | Stool 48 hour collections (for BAs) were collected during baseline before treatment, and then during days 9-10 of the 10 days of colesevelam dosing for fecal BAs. Total fecal BA were measured using HPLC/tandem mass spectrometry. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Stool Frequency (Number of Stools Per Week) | baseline, 10 days | Change in stool frequency from baseline in response to treatment with colesevelam. |
| Change in Fasting Serum C4 | baseline, 10 days | Change in fasting serum C4 from baseline in response to treatment with colesevelam. |
| Change in Fecal Fat Excretion | baseline, 10 days | Change in fecal fat excretion from baseline in response to treatment with colesevelam |
| Change in Stool Consistency | baseline, 10 days | The subjects rated their stool consistency using the Bristol Stool Form Scale. The Bristol Stool Form 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. |
| Concordance Correlation Coefficients of the Relative Composition of Stool Total and the Main Individual Bile Acids (BA) | baseline, 10 days | Stool 48 hour collections (for BAs) were collected during baseline before treatment, and then during days 9-10 of the 10 days of colesevelam dosing for fecal BAs. Relative composition of the main individual bile acids (cholic acid (CA), chenodeoxycholic acid (CDCA), deoxycholic acid (DCA), lithocholic acid (LCA) and ursodeoxycholic acid (UDCA)) in 48 hour stool collection after colesevelam treatment were compared to baseline values. The concordance correlation coefficient (rc) measures agreement between two variables. The concordance correlation satisfies -1 ≤ rc ≤ +1. A value of rc = +1 corresponds to perfect agreement. A value of rc = -1 corresponds to perfect negative agreement, and a value of rc = 0 corresponds to no agreement. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited from the Mayo Clinic in Rochester, Minnesota.
Pre-assignment details
13 subjects were accrued. One subject withdrew from the study after the pre-drug activities, but before the treatment activities.
Participants by arm
| Arm | Count |
|---|---|
| Colesevelam 1875 mg of Colesevelam orally twice daily for 10 days | 12 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Colesevelam |
|---|---|
| Age, Continuous | 43.1 years STANDARD_DEVIATION 3.7 |
| Mean Body Mass Index (BMI) | 31.1 kg/m^2 STANDARD_DEVIATION 2.4 |
| Region of Enrollment United States | 12 participants |
| Sex: Female, Male Female | 11 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 2 / 12 |
| serious Total, serious adverse events | 0 / 12 |
Outcome results
Primary
Change in Total 48 Hour Fecal Bile Acids (BA) From Baseline in Response to Treatment With Colesevelam
Stool 48 hour collections (for BAs) were collected during baseline before treatment, and then during days 9-10 of the 10 days of colesevelam dosing for fecal BAs. Total fecal BA were measured using HPLC/tandem mass spectrometry.
Time frame: baseline, 10 days
Population: 13 subjects were accrued. One subject withdrew from the study after the pre-drug activities, but before the treatment activities. Only the 12 participants with complete data at both baseline and after 10 days of treatment are included in the Outcome Measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Colesevelam | Change in Total 48 Hour Fecal Bile Acids (BA) From Baseline in Response to Treatment With Colesevelam | Baseline | 1662 uM | Standard Error 234.7 |
| Colesevelam | Change in Total 48 Hour Fecal Bile Acids (BA) From Baseline in Response to Treatment With Colesevelam | After 10 days treatment with colesevelam | 3496 uM | Standard Error 709.2 |
Comparison: Comparison of on-treatment total fecal bile acid excretion with baseline total fecal bile acid excretion.p-value: 0.012Wilcoxon (Mann-Whitney)
Secondary
Change in Fasting Serum C4
Change in fasting serum C4 from baseline in response to treatment with colesevelam.
Time frame: baseline, 10 days
Population: 13 subjects were accrued. One subject withdrew from the study after the pre-drug activities, but before the treatment activities. Only the 12 participants with complete data at both baseline and after 10 days of treatment are included in the Outcome Measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Colesevelam | Change in Fasting Serum C4 | Baseline | 24.7 ng/mL | Standard Error 4.2 |
| Colesevelam | Change in Fasting Serum C4 | After 10 days treatment with colesevelam | 72.3 ng/mL | Standard Error 12.2 |
Secondary
Change in Fecal Fat Excretion
Change in fecal fat excretion from baseline in response to treatment with colesevelam
Time frame: baseline, 10 days
Population: 13 subjects were accrued. One subject withdrew from the study after the pre-drug activities, but before the treatment activities. Only the 12 participants with complete data at both baseline and after 10 days of treatment are included in the Outcome Measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Colesevelam | Change in Fecal Fat Excretion | Baseline | 6.4 g/day | Standard Error 1.2 |
| Colesevelam | Change in Fecal Fat Excretion | After 10 days treatment with colesevelam | 6.8 g/day | Standard Error 0.9 |
Secondary
Change in Stool Consistency
The subjects rated their stool consistency using the Bristol Stool Form Scale. The Bristol Stool Form 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: baseline, 10 days
Population: 13 subjects were accrued. One subject withdrew from the study after the pre-drug activities, but before the treatment activities. Only the 12 participants with complete data at both baseline and after 10 days of treatment are included in the Outcome Measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Colesevelam | Change in Stool Consistency | Baseline | 4.8 units on a scale | Standard Error 0.3 |
| Colesevelam | Change in Stool Consistency | After 10 days treatment with colesevelam | 4.4 units on a scale | Standard Error 0.3 |
Secondary
Change in Stool Frequency (Number of Stools Per Week)
Change in stool frequency from baseline in response to treatment with colesevelam.
Time frame: baseline, 10 days
Population: 13 subjects were accrued. One subject withdrew from the study after the pre-drug activities, but before the treatment activities. Only the 12 participants with complete data at both baseline and after 10 days of treatment are included in the Outcome Measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Colesevelam | Change in Stool Frequency (Number of Stools Per Week) | Baseline | 17.6 Number of stools per week | Standard Error 0.4 |
| Colesevelam | Change in Stool Frequency (Number of Stools Per Week) | After 10 days treatment with colesevelam | 15.1 Number of stools per week | Standard Error 1.9 |
Secondary
Concordance Correlation Coefficients of the Relative Composition of Stool Total and the Main Individual Bile Acids (BA)
Stool 48 hour collections (for BAs) were collected during baseline before treatment, and then during days 9-10 of the 10 days of colesevelam dosing for fecal BAs. Relative composition of the main individual bile acids (cholic acid (CA), chenodeoxycholic acid (CDCA), deoxycholic acid (DCA), lithocholic acid (LCA) and ursodeoxycholic acid (UDCA)) in 48 hour stool collection after colesevelam treatment were compared to baseline values. The concordance correlation coefficient (rc) measures agreement between two variables. The concordance correlation satisfies -1 ≤ rc ≤ +1. A value of rc = +1 corresponds to perfect agreement. A value of rc = -1 corresponds to perfect negative agreement, and a value of rc = 0 corresponds to no agreement.
Time frame: baseline, 10 days
Population: 13 subjects were accrued. One subject withdrew from the study after the pre-drug activities, but before the treatment activities. Only the 12 participants with complete data at both baseline and after 10 days of treatment are included in the Outcome Measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Colesevelam | Concordance Correlation Coefficients of the Relative Composition of Stool Total and the Main Individual Bile Acids (BA) | Total BAs at Baseline | 0.53 concordance correlation coefficient | Standard Error 0.13 |
| Colesevelam | Concordance Correlation Coefficients of the Relative Composition of Stool Total and the Main Individual Bile Acids (BA) | Total BAs 48 hour collection after colesevelam | 0.54 concordance correlation coefficient | Standard Error 0.15 |
| Colesevelam | Concordance Correlation Coefficients of the Relative Composition of Stool Total and the Main Individual Bile Acids (BA) | CA at Baseline | 0.84 concordance correlation coefficient | Standard Error 0.08 |
| Colesevelam | Concordance Correlation Coefficients of the Relative Composition of Stool Total and the Main Individual Bile Acids (BA) | CA 48 hour collection after colesevelam | 0.83 concordance correlation coefficient | Standard Error 0.06 |
| Colesevelam | Concordance Correlation Coefficients of the Relative Composition of Stool Total and the Main Individual Bile Acids (BA) | DCA at Baseline | 0.68 concordance correlation coefficient | Standard Error 0.14 |
| Colesevelam | Concordance Correlation Coefficients of the Relative Composition of Stool Total and the Main Individual Bile Acids (BA) | DCA 48 hour collection after colesevelam | 0.85 concordance correlation coefficient | Standard Error 0.07 |
| Colesevelam | Concordance Correlation Coefficients of the Relative Composition of Stool Total and the Main Individual Bile Acids (BA) | UDCA at Baseline | 0.96 concordance correlation coefficient | Standard Error 0.2 |
| Colesevelam | Concordance Correlation Coefficients of the Relative Composition of Stool Total and the Main Individual Bile Acids (BA) | UDCA 48 hour collection after colesevelam | 0.54 concordance correlation coefficient | Standard Error 0.2 |
| Colesevelam | Concordance Correlation Coefficients of the Relative Composition of Stool Total and the Main Individual Bile Acids (BA) | CDCA at Baseline | 0.88 concordance correlation coefficient | Standard Error 0.05 |
| Colesevelam | Concordance Correlation Coefficients of the Relative Composition of Stool Total and the Main Individual Bile Acids (BA) | CDCA 48 hour collection after colesevelam | 0.90 concordance correlation coefficient | Standard Error 0.06 |
| Colesevelam | Concordance Correlation Coefficients of the Relative Composition of Stool Total and the Main Individual Bile Acids (BA) | LCA at Baseline | 0.44 concordance correlation coefficient | Standard Error 0.21 |
| Colesevelam | Concordance Correlation Coefficients of the Relative Composition of Stool Total and the Main Individual Bile Acids (BA) | LCA 48 hour collection after colesevelam | 0.88 concordance correlation coefficient | Standard Error 0.07 |