Bile Acid Malabsorption, Fecal Incontinence
Conditions
Keywords
Incontinence, Diarrhea, Bile acid, Microbiome
Brief summary
Compare the effects of a combination of colesevelam and clonidine to placebo on bowel symptoms in patients with urge or combined type of FI.
Detailed description
Fecal incontinence (FI) is a common symptom that can significantly impair quality of life. There is very limited, mostly uncontrolled, evidence to support the approaches currently used to manage FI. The alpha-2 adrenergic agonist clonidine decreased the frequency of loose stools in FI patients with diarrhea. Among patients with diarrhea, clonidine decreased the proportion of days with FI; however results were not statistically significant. Uncontrolled studies suggest that the bile acid binding resin colesevelam also increased stool consistency in patients with functional diarrhea. In this study, the investigators propose to compare the effects of a combination of colesevelam and clonidine to placebo on bowel symptoms in patients with urge or combined type of FI.
Interventions
DRUGColesevelam
Participants who satisfy symptom criteria in Phase 2 will be randomized in a 1:1 ratio to receive either a combination of colesevelam (1.875 gm twice daily) and clonidine (0.1 mg oral twice daily) or an identical placebo for 4 weeks.
DRUGClonidine
Participants who satisfy symptom criteria in Phase 2 will be randomized in a 1:1 ratio to receive either a combination of colesevelam (1.875 gm twice daily) and clonidine (0.1 mg oral twice daily) or an identical placebo for 4 weeks.
OTHERPlacebo
Placebo will be identical in appearance to the active drug.
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
National Center for Research Resources (NCRR)
Mayo Clinic
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
A. Phase 1 Inclusion Criteria: i) Females aged 18-80 years with urge predominant or combined (i.e. urge plus passive) FI, as defined by a validated questionnaire, for at least 1 year duration will be eligible to participate.
Exclusion criteria
(i) History of clinically serious cardiovascular or pulmonary disease or EKG showing 2nd degree atrioventricular block or higher. (ii) Current or past history of rectal cancer, scleroderma, inflammatory bowel disease, small bowel obstruction, congenital anorectal abnormalities, Grade 2 rectal prolapse, history of rectal resection or pelvic irradiation (iii) Neurological disorders - Spinal cord injuries, dementia (Mini-Mental status score \<21), multiple sclerosis, Parkinson's disease, peripheral neuropathy (iv) Conditions precluding safe use of clonidine, i.e., symptomatic hypotension, or systolic blood pressure of \<100 mm Hg on initial visit in Phase 1 of study (v) Currently pregnant or nursing women (vi) Prior history of intolerance to clonidine or colesevelam (vii) Medications Absolute - opioid analgesics. Relative - other antihypertensive agents (i.e. if there is concern about synergistic effects and hypotension). Patients using drugs with anticholinergic effects will be excluded if they are used at high doses (e.g. nortriptyline greater than 50 mg/day or amitriptyline greater than 25 mg/day). Patients who use lower doses will be eligible to participate provided the dose will be stable during the study B. Phase 2 Inclusion Criteria: i) Females aged 18-80 years with urge predominant or combined (i.e. urge plus passive) FI for at least 1 year, as defined by questionnaire
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants to Report a 50% or Greater Reduction in Weekly Fecal Incontinence (FI) Episodes | 4 weeks | The number of participants that report a 50% or greater reduction in weekly incontinent episodes as measured by self-reported bowel diaries. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Stool Consistency | 4 weeks | Stool consistency as measured by self-reported bowel diaries. Expressed in terms of the Bristol Stool Form Scale, where: 1= separate hard lumps; 2= lumpy sausage-shape; 3= cracked sausage; 4= smooth and soft sausage; 5=soft blobs; 6=mushy, fluffy pieces; 7= watery, no solid pieces. |
| Number of Semi-Formed Stools Per Week | 4 weeks | The number of stools per week measured by self-reported bowel diaries where the Bristol stool score was 5, 6, or 7. (5=soft blobs; 6=mushy, fluffy pieces; 7= watery, no solid pieces) |
| Delay of Bowel Movement | 4 weeks | The time in minutes a bowel movement can be delayed after sense of urgency to defecate as measured by self-reported bowel diaries. |
| Total Fecal Incontinence Episodes | 4 weeks | The total number of fecal incontinence episodes per week as measured by self-reported bowel diaries. |
| Volume of Fecal Incontinence | 4 weeks | The volume of fecal incontinence measured as the number of incontinent episodes per week as categorized by small (staining only), moderate (requiring change of underwear) or large (requiring change of all clothes) in self-reported bowel diaries. |
| Percent of Incontinent Bowel Movements Pre-treatment | baseline | The percentage of bowel movements that were incontinent prior to treatment initiation, per self-reported bowel diaries. |
| Daily Stool Frequency | 4 weeks | The number of bowel movements daily measured by self-reported bowel diaries. |
| Percent of Incontinent Bowel Movements to be Semi-Formed Stools Pre-Treatment | baseline | The percentage of incontinent bowel movements where the Bristol stool score was 5, 6 or 7. (5=soft blobs; 6=mushy, fluffy pieces; 7= watery, no solid pieces), pre-treatment, per self-reported bowel diaries. |
| Percent of Incontinent Bowel Movements to be Semi-Formed Stools During Treatment | 4 weeks | The percentage of incontinent bowel movements where the Bristol stool score was 5, 6 or 7. (5=soft blobs; 6=mushy, fluffy pieces; 7= watery, no solid pieces) during treatment, per self-reported bowel diaries. |
| Severity of Bowel Symptoms | 4 weeks | The Fecal Incontinence Symptom Severity (FISS) score is based on five questions; (1) the frequency of FI; (2) the type of FI (stool only, liquid or mucus only, both liquid/mucus and stool, or gas only); (3) the amount of stool leaked (small, moderate, or large); (4) the frequency of having to rush to the toilet; and (5) the frequency of having stool leak without warning. Questions 4 & 5 are merged to determine if the participant has passive FI (FI without warning), urge FI, both, or neither. The responses to the questions are assigned physician-derived weights and added together for a total score of 4 to 13. The higher the score the more severe the FI symptoms. |
| Severity of Fecal Incontinence | 4 weeks | Measured by the Fecal Incontinence Severity Index (FISI). It is a validated 4-item scale used to assess the frequency (never, 1-3 times a month, once a week, 2 or more times per week but not daily, once a day, 2 or more times per day) of 4 different types of FI (gas, mucus, liquid stool, solid stool). Each of the four types of FI is awarded a number of points, depending on the frequency at which that type of incontinence is experienced. The points are totaled and the scores can range from 0 to 61, where the higher the score, the higher the perceived severity of the fecal incontinence. |
| Fecal Incontinence Quality of Life (FI-QoL) | 4 weeks | The Fecal Incontinence Quality of Life questionnaire measures specific quality of life issues expected to affect patients with fecal incontinence. The questions are grouped into four categories: lifestyle (10 questions), coping (9 questions), depression (7 questions), and embarrassment (3 questions). Each category is scored from 1 to 4. The scale scores are calculated by adding the numerical values of all responses in that specific scale and then dividing by its number of items. Higher scores indicate a better quality of life. |
| Loperamide Tablets Per Week | 4 weeks | The number of tablets of loperamide used, per self-reported bowel diaries. |
| Percent of Incontinent Bowel Movements During Treatment | 4 weeks | The percentage of bowel movements that were incontinent during treatment, per self-reported bowel diaries. |
Countries
United States
Participant flow
Pre-assignment details
Eighty-eight (88) participants were enrolled but thirty-two (32) withdrew from the study before beginning any study procedures.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants in this arm will receive placebo for 4 weeks.
Placebo: Placebo will be identical in appearance to the active drug. | 32 |
| Colesevelam and Clonidine Participants in this arm will receive a combination of colesevelam (1.875 gm twice daily) and clonidine (0.1 mg oral twice daily) for 4 weeks.
Colesevelam: Participants who satisfy symptom criteria in Phase 2 will be randomized in a 1:1 ratio to receive either a combination of colesevelam (1.875 gm twice daily) and clonidine (0.1 mg oral twice daily) or an identical placebo for 4 weeks.
Clonidine: Participants who satisfy symptom criteria in Phase 2 will be randomized in a 1:1 ratio to receive either a combination of colesevelam (1.875 gm twice daily) and clonidine (0.1 mg oral twice daily) or an identical placebo for 4 weeks. | 24 |
| Total | 56 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 2 | 2 |
Baseline characteristics
| Characteristic | Placebo | Total | Colesevelam and Clonidine |
|---|---|---|---|
| Age, Continuous | 47 years STANDARD_DEVIATION 26 | 50 years STANDARD_DEVIATION 27 | 53 years STANDARD_DEVIATION 29 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 32 Participants | 56 Participants | 24 Participants |
| Region of Enrollment United States | 32 participants | 56 participants | 24 participants |
| Sex: Female, Male Female | 32 Participants | 56 Participants | 24 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 | 0 / 32 | 0 / 24 |
| other Total, other adverse events | 4 / 32 | 6 / 24 |
| serious Total, serious adverse events | 0 / 32 | 0 / 24 |
Outcome results
Primary
Number of Participants to Report a 50% or Greater Reduction in Weekly Fecal Incontinence (FI) Episodes
The number of participants that report a 50% or greater reduction in weekly incontinent episodes as measured by self-reported bowel diaries.
Time frame: 4 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants to Report a 50% or Greater Reduction in Weekly Fecal Incontinence (FI) Episodes | 17 Participants |
| Colesevelam and Clonidine | Number of Participants to Report a 50% or Greater Reduction in Weekly Fecal Incontinence (FI) Episodes | 13 Participants |
p-value: 0.85ANCOVA
Secondary
Daily Stool Frequency
The number of bowel movements daily measured by self-reported bowel diaries.
Time frame: 4 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Daily Stool Frequency | 2.4 bowel movements per day | Standard Deviation 2.3 |
| Colesevelam and Clonidine | Daily Stool Frequency | 2.1 bowel movements per day | Standard Deviation 2 |
Comparison: Approximately 4 weeksp-value: 0.24ANCOVA
Secondary
Delay of Bowel Movement
The time in minutes a bowel movement can be delayed after sense of urgency to defecate as measured by self-reported bowel diaries.
Time frame: 4 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Delay of Bowel Movement | 2.8 minutes | Standard Deviation 7.8 |
| Colesevelam and Clonidine | Delay of Bowel Movement | 3.6 minutes | Standard Deviation 8.4 |
Comparison: Approximately 4 weeksp-value: 0.56ANCOVA
Secondary
Fecal Incontinence Quality of Life (FI-QoL)
The Fecal Incontinence Quality of Life questionnaire measures specific quality of life issues expected to affect patients with fecal incontinence. The questions are grouped into four categories: lifestyle (10 questions), coping (9 questions), depression (7 questions), and embarrassment (3 questions). Each category is scored from 1 to 4. The scale scores are calculated by adding the numerical values of all responses in that specific scale and then dividing by its number of items. Higher scores indicate a better quality of life.
Time frame: 4 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Fecal Incontinence Quality of Life (FI-QoL) | Lifestyle score | 2.7 score on a scale | Standard Deviation 0.9 |
| Placebo | Fecal Incontinence Quality of Life (FI-QoL) | Coping score | 2.0 score on a scale | Standard Deviation 0.6 |
| Placebo | Fecal Incontinence Quality of Life (FI-QoL) | Depression Score | 3.1 score on a scale | Standard Deviation 0.6 |
| Placebo | Fecal Incontinence Quality of Life (FI-QoL) | Embarrassment score | 2.6 score on a scale | Standard Deviation 0.9 |
| Colesevelam and Clonidine | Fecal Incontinence Quality of Life (FI-QoL) | Embarrassment score | 2.5 score on a scale | Standard Deviation 0.9 |
| Colesevelam and Clonidine | Fecal Incontinence Quality of Life (FI-QoL) | Lifestyle score | 2.7 score on a scale | Standard Deviation 0.9 |
| Colesevelam and Clonidine | Fecal Incontinence Quality of Life (FI-QoL) | Depression Score | 3.1 score on a scale | Standard Deviation 0.8 |
| Colesevelam and Clonidine | Fecal Incontinence Quality of Life (FI-QoL) | Coping score | 2.1 score on a scale | Standard Deviation 0.8 |
Comparison: Lifestyle Scorep-value: 0.67ANCOVA
Comparison: Coping Scorep-value: 0.8ANCOVA
Comparison: Depression Scorep-value: 0.49ANCOVA
Comparison: Embarrassment Scorep-value: 0.6ANCOVA
Secondary
Loperamide Tablets Per Week
The number of tablets of loperamide used, per self-reported bowel diaries.
Time frame: 4 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Loperamide Tablets Per Week | 1.9 tablets per week | Standard Deviation 2 |
| Colesevelam and Clonidine | Loperamide Tablets Per Week | 6 tablets per week | Standard Deviation 5 |
Comparison: Approximately 4 weeks post-treatmentp-value: 0.78ANCOVA
Secondary
Number of Semi-Formed Stools Per Week
The number of stools per week measured by self-reported bowel diaries where the Bristol stool score was 5, 6, or 7. (5=soft blobs; 6=mushy, fluffy pieces; 7= watery, no solid pieces)
Time frame: 4 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Number of Semi-Formed Stools Per Week | 1.0 number of stools per week | Standard Deviation 0.7 |
| Colesevelam and Clonidine | Number of Semi-Formed Stools Per Week | 1.2 number of stools per week | Standard Deviation 1.1 |
p-value: 0.35ANCOVA
Secondary
Percent of Incontinent Bowel Movements During Treatment
The percentage of bowel movements that were incontinent during treatment, per self-reported bowel diaries.
Time frame: 4 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent of Incontinent Bowel Movements During Treatment | 27 percent of incontinent bowel movements | Standard Deviation 8 |
| Colesevelam and Clonidine | Percent of Incontinent Bowel Movements During Treatment | 28 percent of incontinent bowel movements | Standard Deviation 9 |
p-value: 0.04ANCOVA
Secondary
Percent of Incontinent Bowel Movements Pre-treatment
The percentage of bowel movements that were incontinent prior to treatment initiation, per self-reported bowel diaries.
Time frame: baseline
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent of Incontinent Bowel Movements Pre-treatment | 45 percent of incontinent bowel movements | Standard Deviation 9 |
| Colesevelam and Clonidine | Percent of Incontinent Bowel Movements Pre-treatment | 40 percent of incontinent bowel movements | Standard Deviation 10 |
p-value: 0.18ANCOVA
Secondary
Percent of Incontinent Bowel Movements to be Semi-Formed Stools During Treatment
The percentage of incontinent bowel movements where the Bristol stool score was 5, 6 or 7. (5=soft blobs; 6=mushy, fluffy pieces; 7= watery, no solid pieces) during treatment, per self-reported bowel diaries.
Time frame: 4 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent of Incontinent Bowel Movements to be Semi-Formed Stools During Treatment | 67 percent of semi-formed stools | Standard Deviation 8 |
| Colesevelam and Clonidine | Percent of Incontinent Bowel Movements to be Semi-Formed Stools During Treatment | 61 percent of semi-formed stools | Standard Deviation 10 |
p-value: 0.39ANCOVA
Secondary
Percent of Incontinent Bowel Movements to be Semi-Formed Stools Pre-Treatment
The percentage of incontinent bowel movements where the Bristol stool score was 5, 6 or 7. (5=soft blobs; 6=mushy, fluffy pieces; 7= watery, no solid pieces), pre-treatment, per self-reported bowel diaries.
Time frame: baseline
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent of Incontinent Bowel Movements to be Semi-Formed Stools Pre-Treatment | 61 percent of semi-formed stools | Standard Deviation 8 |
| Colesevelam and Clonidine | Percent of Incontinent Bowel Movements to be Semi-Formed Stools Pre-Treatment | 76 percent of semi-formed stools | Standard Deviation 8 |
p-value: 0.29ANCOVA
Secondary
Severity of Bowel Symptoms
The Fecal Incontinence Symptom Severity (FISS) score is based on five questions; (1) the frequency of FI; (2) the type of FI (stool only, liquid or mucus only, both liquid/mucus and stool, or gas only); (3) the amount of stool leaked (small, moderate, or large); (4) the frequency of having to rush to the toilet; and (5) the frequency of having stool leak without warning. Questions 4 & 5 are merged to determine if the participant has passive FI (FI without warning), urge FI, both, or neither. The responses to the questions are assigned physician-derived weights and added together for a total score of 4 to 13. The higher the score the more severe the FI symptoms.
Time frame: 4 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Severity of Bowel Symptoms | 6 score on a scale | Standard Deviation 3.2 |
| Colesevelam and Clonidine | Severity of Bowel Symptoms | 4.6 score on a scale | Standard Deviation 3.6 |
p-value: 0.07ANCOVA
Secondary
Severity of Fecal Incontinence
Measured by the Fecal Incontinence Severity Index (FISI). It is a validated 4-item scale used to assess the frequency (never, 1-3 times a month, once a week, 2 or more times per week but not daily, once a day, 2 or more times per day) of 4 different types of FI (gas, mucus, liquid stool, solid stool). Each of the four types of FI is awarded a number of points, depending on the frequency at which that type of incontinence is experienced. The points are totaled and the scores can range from 0 to 61, where the higher the score, the higher the perceived severity of the fecal incontinence.
Time frame: 4 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Severity of Fecal Incontinence | 28 score on a scale | Standard Deviation 15 |
| Colesevelam and Clonidine | Severity of Fecal Incontinence | 22 score on a scale | Standard Deviation 18 |
p-value: 0.12ANCOVA
Secondary
Stool Consistency
Stool consistency as measured by self-reported bowel diaries. Expressed in terms of the Bristol Stool Form Scale, where: 1= separate hard lumps; 2= lumpy sausage-shape; 3= cracked sausage; 4= smooth and soft sausage; 5=soft blobs; 6=mushy, fluffy pieces; 7= watery, no solid pieces.
Time frame: 4 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Stool Consistency | 4.1 score on a scale | Standard Deviation 1.9 |
| Colesevelam and Clonidine | Stool Consistency | 3.2 score on a scale | Standard Deviation 1.5 |
Comparison: Approximately 4 weeksp-value: 0.44ANCOVA
Secondary
Total Fecal Incontinence Episodes
The total number of fecal incontinence episodes per week as measured by self-reported bowel diaries.
Time frame: 4 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Total Fecal Incontinence Episodes | 4.2 incontinence episodes per week | Standard Deviation 4.4 |
| Colesevelam and Clonidine | Total Fecal Incontinence Episodes | 4.8 incontinence episodes per week | Standard Deviation 3.7 |
p-value: 0.55ANCOVA
Secondary
Volume of Fecal Incontinence
The volume of fecal incontinence measured as the number of incontinent episodes per week as categorized by small (staining only), moderate (requiring change of underwear) or large (requiring change of all clothes) in self-reported bowel diaries.
Time frame: 4 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Volume of Fecal Incontinence | Small (staining only) | 2.4 incontinent episodes per week | Standard Deviation 1.8 |
| Placebo | Volume of Fecal Incontinence | Moderate (requires change of underwear) | 0.9 incontinent episodes per week | Standard Deviation 1.7 |
| Placebo | Volume of Fecal Incontinence | Large (requires complete change of clothes | 1.3 incontinent episodes per week | Standard Deviation 2.2 |
| Colesevelam and Clonidine | Volume of Fecal Incontinence | Small (staining only) | 3.3 incontinent episodes per week | Standard Deviation 3 |
| Colesevelam and Clonidine | Volume of Fecal Incontinence | Moderate (requires change of underwear) | 2.0 incontinent episodes per week | Standard Deviation 2.6 |
| Colesevelam and Clonidine | Volume of Fecal Incontinence | Large (requires complete change of clothes | 2.4 incontinent episodes per week | Standard Deviation 6.2 |
Comparison: Small (staining only)p-value: 0.11ANCOVA
Comparison: Moderate (requires change of underwear)p-value: 0.06ANCOVA
Comparison: Large (requires complete change of clothes)p-value: 0.36ANCOVA