A Study of Colesevelam in Fecal Incontinence

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Placebo Controlled Study of Colesevelam in Fecal Incontinence

Conditions
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Fecal Incontinence, Bile Acid Malabsorption

Intervention / Treatment
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* Drug: Colesevelam
* Drug: Clonidine
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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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 Exclusion criteria: (i) Positive urine pregnancy screen C. Phase 3 Inclusion criteria: (i) Completion of at least 5 out of 7 days of the diary in the preceding week and 10 out of 14 in the preceding 2 weeks (ii) At least 1 episode of FI per week averaged over 2 weeks (iii) Average Bristol stool score of 3 or higher (iv) Average stool frequency of ≥1/day Exclusion criteria (if at least one is satisfied): (i) Missing data in bowel diaries, i.e. if patient did not record bowel symptoms data for more than 2 days in 1 week or 4 days over 2 weeks (ii) Greater than 6 liquid [Bristol 6 or 7]) stools daily (iii) Average of less than 1 bowel movement daily (iv) Average Bristol stool score <3 as assessed from analysis of bowel diaries D. Phase 4 Inclusion criteria: (i) All patients who complete at least 1 week of treatment with study drugs or placebo Exclusion criteria: (i) Patients who completed less than 1 week of treatment with study drugs or placebo

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Participants in this arm will receive placebo for 4 weeks. | Other: Placebo<br>* Placebo will be identical in appearance to the active drug.<br>|
| Active Comparator: Colesevelam and Clonidine<br>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. | Drug: Colesevelam<br>* 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.<br>* Other names: Welchol;Drug: Clonidine<br>* 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.<br>* Other names: Catapres;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Daily Stool Frequency | The number of bowel movements daily measured by self-reported bowel diaries. | 4 weeks | 
| 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. | 4 weeks | 
| 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) | 4 weeks | 
| 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. | 4 weeks | 
| Total Fecal Incontinence Episodes | The total number of fecal incontinence episodes per week as measured by self-reported bowel diaries. | 4 weeks | 
| 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. | 4 weeks | 
| Percent of Incontinent Bowel Movements Pre-treatment | The percentage of bowel movements that were incontinent prior to treatment initiation, per self-reported bowel diaries. | baseline | 
| Percent of Incontinent Bowel Movements During Treatment | The percentage of bowel movements that were incontinent during treatment, per self-reported bowel diaries. | 4 weeks | 
| 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. | baseline | 
| 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. | 4 weeks | 
| 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. | 4 weeks | 
| 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. | 4 weeks | 
| 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. | 4 weeks | 
| Loperamide Tablets Per Week | The number of tablets of loperamide used, per self-reported bowel diaries. | 4 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Incontinence, Diarrhea, Bile acid, Microbiome