Effects of Eluxadoline (Viberzi®) 100 mg Twice Daily on Diarrhea-Associated Fecal Incontinence

Study Overview
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Brief Summary
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Accidental bowel leakage (fecal incontinence) increases in people who have diarrhea and sensations of urgency to have a bowel movement. Drugs such as loperamide (Imodium) that reduce diarrhea improve accidental bowel leakage, but loperamide has disadvantages: it is difficult to find a dose that does not cause constipation, and it does not reduce urge sensations. Eluxadoline is a new drug that is effective for reducing diarrhea, abdominal pain, and urgency in patients with irritable bowel syndrome, and it may be less likely than loperamide to cause severe constipation. Therefore, eluxadoline may help patients manage accidental bowel leakage caused by diarrhea. The chemical name for Viberzi® is eluxadoline. The primary aims of this study are to find out if eluxadoline at a dose of 100 mg orally twice a day will reduce the average number of days the patient has accidental bowel leakage, and to see if the rate of accidental bowel leakage increases when the patient stops taking eluxadoline. Additional goals are to find out if eluxadoline decreases diarrhea and urge sensations. This is a small (pilot) study to show whether eluxadoline is an effective way of treating accidental bowel leakage. If the study shows this, a larger study will be needed. There are three phases to this 12-week study: (1) A two-week run-in period to see if the patient meets the inclusion criteria. (2) Two months for treatment including one month on eluxadoline and one on placebo (sugar pills) twice a day. (3) A two-week follow-up to see what happens when you stop taking eluxadoline. To participate in the study, patients should be aged 18 or older. Patients with inflammatory bowel disease, anal fissures, or congenital malformations will be excluded. The primary outcome is the average number of days per week with any solid or liquid bowel accidents. Additional information includes: (1) Number of days per week the patient takes loperamide, (2) days per week with loose or watery stools, (3) days per week with moderate to strong urge sensations, and (4) questionnaires to measure the severity of accidental bowel leakage, quality of life, anxiety, and depression. There will be up to 38 patients in the study.

Official Title
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Treatment of Diarrhea-Associated Fecal Incontinence With Eluxadoline

Conditions
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Fecal Incontinence, Accidental Bowel Leakage, Anal Incontinence, Diarrhea, Urge Incontinence

Intervention / Treatment
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* Drug: Eluxadoline 100 mg
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: At least 18 years of age. Any gender, race, or ethnicity. Must self-report an average of at least 2 episodes of solid or liquid FI per week for the previous month. Must self-report an average of at least 2 bowel movements (BMs) per week that are Bristol Types 6 or 7 (mushy or liquid stools). Subjects must have access to the internet at home and be willing to enter symptom data each night before sleeping. Exclusion Criteria: Patients with inflammatory bowel disease, anal fissure, or congenital malformations as a cause of FI will be excluded. Subjects who start the study and do not experience at least 4 episodes of solid or liquid FI and at least 4 BMs that are Bristol Stool types 6 or 7 during the first two weeks will be withdrawn from the study. Subjects who do not provide at least 4 days of valid stool diary data per week during the first two weeks will be withdrawn from the study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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: Crossover Assignment
Interventional Model Description: Patients will be randomized to 1 of 2 sequences. Each sequence includes 4 periods: Run-in, Treatment Period 1, Treatment Period 2, and Follow-Up. In Sequence A, Eluxadoline will be given 100 mg BID in Treatment Period 1 and Placebo will be given in Treatment Period 2. In Sequence B, Placebo will be given in Treatment Period 1 and Eluxadoline will be given in Treatment Period 2. Placebo will be given during Baseline and Follow-Up of both arms.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Eluxadoline followed by Placebo<br>Following a 2-week run-in period, patients will receive Eluxadoline 100 mg twice daily for 4 weeks then placebo tablets taken twice daily for 4 weeks followed by a 2-week follow-up period during which placebo will be administered twice daily. | Drug: Eluxadoline 100 mg<br>* 100 mg capsule-shaped tablet by mouth taken twice per day<br>* Other names: Viberzi®;Other: Placebo<br>* Matching capsule-shaped placebo tablets taken by mouth twice per day<br>* Other names: sugar pill;|
| Other: Placebo followed by Eluxadoline<br>Following a 2-week run-in period, patients will receive placebo twice daily for 4 weeks then Eluxadoline 100 mg twice daily for 4 weeks followed by a 2-week follow-up period during which placebo will be administered twice daily. | Drug: Eluxadoline 100 mg<br>* 100 mg capsule-shaped tablet by mouth taken twice per day<br>* Other names: Viberzi®;Other: Placebo<br>* Matching capsule-shaped placebo tablets taken by mouth twice per day<br>* Other names: sugar pill;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Run-in days per week with fecal incontinence | If there are less than 5 days in a 7-day period that have complete diary data, the subject will be excluded. The number of days per week with fecal incontinence (i.e., a score >0) will be counted and divided by 7 to obtain a rate per week. The range of scores is 0 to 7 with 7 being the most severe fecal incontinence. | Baseline Period, starting on Day 1 and ending at the conclusion of Day 14 | 
| Treatment Period 1 days per week with fecal incontinence | If there are less than 5 days in a 7-day period that have complete diary data in weeks 5 and 6, the Treatment Period 1 variable will be missing. The number of days per week with fecal incontinence (i.e., a score >0) will be counted and divided by 7 to obtain a rate per week. The range of scores is 0 to 7 with 7 being the most severe fecal incontinence. | Treatment Period 1 (measured across Weeks 5 and 6) | 
| Treatment Period 2 days per week with fecal incontinence | If there are less than 5 days in a 7-day period that have complete diary data in weeks 9 and 10, the Treatment Period 2 variable is missing. The number of days per week with fecal incontinence (i.e., a score >0) will be counted and divided by 7 to obtain a rate per week. The range of scores is 0 to 7 with 7 being the most severe fecal incontinence. | Treatment Period 2 (measured across Weeks 9 and 10) | 
| Follow-up days per week with fecal incontinence | If there are less than 5 days in a 7-day period that have complete diary data in weeks 11 and 12, the Follow-Up variable is missing. The number of days per week with fecal incontinence (i.e., a score >0) will be counted and divided by 7 to obtain a rate per week. The range of scores is 0 to 7 with 7 being the most severe fecal incontinence. | Follow-up period (measured across Weeks 11 and 12) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Days per week with loperamide (escape medication) | For eligibility analysis, Run-in (Weeks 1 and 2) will determine if there are 5 to 7 days in each week that can be evaluated; if less than one week, the subject is excluded. For treatment assessment, Treatment Period 1 (Weeks 5 and 6) and Treatment Period 2 (Weeks 9 and 10) will determine if there are 5 to 7 days that can be evaluated; if less than one week per period, the subject will be excluded from analysis. For evaluation of drug withdrawal, Follow-up (Weeks 11 and 12) will be examined to determine if there are 5 to 7 days that can be evaluated; if less than one week, the data is missing. In all analyses, count the number of days in each period with any loperamide used. The range of scores is 0 to 7 with 7 being the greatest amount of rescue medication used. | Weeks 1, 2, 5, 6, 9, 10, 11, and 12 | 
| Days per week patient described bowel movements as 6 or 7 on the Bristol Stool Scale | For eligibility analysis, Run-in (Weeks 1 and 2) will determine if there are 5 to 7 days in each week that can be evaluated; if less than one week, the subject is excluded. For treatment assessment, Treatment Period 1 (Weeks 5 and 6) and Treatment Period 2 (Weeks 9 and 10) will determine if there are 5 to 7 days that can be evaluated; if less than one week per period, the subject will be excluded from analysis. For evaluation of drug withdrawal, Follow-up (Weeks 11 and 12) will be examined to determine if there are 5 to 7 days that can be evaluated; if less than one week, the data is missing. In all analyses, count the number of days in each period with any Bristol Stool Scale score of 6 or 7. The range of scores is 0 to 7 days with 7 being the most severe diarrhea. | Weeks 1, 2, 5, 6, 9, 10, 11, and 12 | 
| Days per week patient reported strong urge sensations | For eligibility analysis, Run-in (Weeks 1 and 2) will determine if there are 5 to 7 days in each week that can be evaluated; if less than one week, the subject is excluded. For treatment assessment, Treatment Period 1 (Weeks 5 and 6) and Treatment Period 2 (Weeks 9 and 10) will determine if there are 5 to 7 days that can be evaluated; if less than one week per period, the subject will be excluded from analysis. For evaluation of drug withdrawal, Follow-up (Weeks 11 and 12) will be examined to determine if there are 5 to 7 days that can be evaluated; if less than one week, the data is missing. In all analyses, count the number of days in each period with any moderate to strong urge sensations . The range of scores is 0 to 7 days with 7 being the most severe urgency to defecate. | Weeks 1, 2, 5, 6, 9, 10, 11, and 12 | 
| Fecal Incontinence Severity Score (FISS) over time | For clinic visits in Weeks 2, 6, 10, and 12, compute the score for the 4 components of the FISS. These components are frequency of leaks, type of leakage, amount that leaked, and urgency vs. passive incontinence. These individual items are added together to form a total score which ranges from 3 to 13, with 13 representing the most severe form of fecal incontinence (FI). If items are not completed or are not correct, the FISS score is missing. | Weeks 2, 6,10, and 12 | 
| Fecal Incontinence Quality of Life Scale Score for Lifestyle (FIQOL-Lifestyle) | For clinic visits in Weeks 2, 6, 10, and 12, compute the scale score for lifestyle. If more than half of the items in the scale are present, the score is based on the average for those items; otherwise the FIQOL-Lifestyle scale score is missing. Scores range from 0 to 4 with 4 representing the greatest impairment in FIQOL-Lifestyle. | Weeks 2, 6, 10, and12 | 
| Fecal Incontinence Quality of Life Scale Score for Coping/Behavior (FIQOL-Coping/Behavior) | For clinic visits in Weeks 2, 6, 10, and 12, compute the scale score for Coping/Behavior. If more than half of the items in the scale are present, the score is based on the average for those items; otherwise the FIQOL-Coping/Behavior scale score is missing. Scores range from 0 to 4 with 4 representing the greatest impairment in FIQOL-Coping/Behavior. | Weeks 2, 6, 10, and 12 | 
| Fecal Incontinence Quality of Life Scale Score for Depression/Self-Perception (FIQOL-Depression/Self-Perception) | For clinic visits in Weeks 2, 6, 10, and 12, compute the scale score for Depression/Self-Perception. If more than half of the items in the scale are present, the score is based on the average for those items; otherwise the FIQOL-Depression/Self-Perception scale score is missing. Scores range from 0 to 4 with 4 representing the greatest impairment in FIQOL-Depression/Self-Perception. | Weeks 2, 6, 10, and 12 | 
| Fecal Incontinence Quality of Life Scale Score for Embarrassment (FIQOL-Embarrassment) | For clinic visits in Weeks 2, 6, 10, and 12, compute the scale score for Embarrassment. If more than half of the items in the scale are present, the score is based on the average for those items; otherwise the FIQOL-Embarrassment scale score is missing. Scores range from 0 to 4 with 4 representing the greatest impairment in FIQOL-Embarrassment. | Weeks 2, 6, 10, and 12 | 
| Brief Symptom Inventory-18 Anxiety Score (BSI-Anxiety) | For each visit to the clinic, compute the previous week's BSI scores for anxiety. If more than two items are not answered, the score is not valid. Scores of 0 to 4 are added across items with missing items being replaced by the average for the present items, and the summary score is transformed into a T-score in which the average score is 50 and 10 is equivalent to a standard deviation in the reference sample. A score of 60 represents one standard deviation above the population mean for severity of anxiety. | Weeks 2, 6, 10, and 12 | 
| Brief Symptom Inventory-18 Depression Score (BSI-Depression) | For each visit to the clinic, compute the previous week's BSI scores for depression. If more than two items are not answered, the score is not valid. Scores of 0 to 4 are added across items with missing items being replaced by the average for the present items, and the summary score is transformed into a T-score in which the average score is 50 and 10 is equivalent to a standard deviation in the reference sample. A score of 60 represents one standard deviation above the population mean for severity of depression. | Weeks 2, 6, 10, and 12 | 
| Preference for study drug vs. loperamide | On Week 6 and 10, subject will be asked to compare the study drug to loperamide for the previous 4 weeks. The choices are -2=strongly prefer loperamide, -1=somewhat prefer loperamide, 0=no preference, 1=somewhat prefer study drug, and 2=strongly prefer study drug. The range of scores is -2 to +2, with +2 being equivalent to a strong preference for the study drug over loperamide. | Weeks 6, and 10 | 
| Preference for eluxadoline or placebo | At week 10, subjects will be asked to compare the second study drug to the first study drug for the previous 8 weeks. For subjects randomized to the Eluxadoline followed by Placebo group, the first study drug is eluxadoline; for subjects in the Placebo followed by Eluxadoline group the second study drug is eluxadoline. To estimate the preference of subjects for eluxadoline, the preference of the first group for the first study period and the preferences of the second group for the second study period will be averaged. The range of outcome scores is -2 to +2 with +2 representing a strong preference for eluxadoline over placebo. (The excluded groups are available as a way to assess whether order effects interfere with the measurement of preferences for eluxadoline vs. placebo.) | Week 10 |