Controlling Anal Incontinence by Performing Anal Exercises With Biofeedback or Loperamide (CAPABLe)

Study Overview
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Brief Summary
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The study is a multi-center, randomized, placebo controlled trial with participants randomized into one of four groups: placebo/usual care (educational pamphlet) loperamide/usual care (educational pamphlet) placebo/anal exercises with biofeedback loperamide/anal exercises with biofeedback The primary outcome, change from baseline in St. Marks (Vaizey) Score at 24 weeks, will be compared between treatment groups using linear regression.

Detailed Description
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The goals of this trial are to compare the use of loperamide to oral placebo and to compare the use of anal sphincter exercise training with biofeedback to usual care (educational pamphlet) in the treatment of women suffering from fecal incontinence (FI). We will test the following null hypotheses: there is no difference in outcomes between women randomized to loperamide and women randomized to oral placebo for treatment of FI; there is no difference in outcomes between women randomized to anal sphincter exercises with biofeedback and women randomized to usual care (educational pamphlet) for FI treatment; there is no difference between women randomized to both treatments together and women randomized to either FI treatment alone; and there is no correlation between anal manometry measurements and digital anal squeeze strength or measures of FI severity and bother. A supplemental study, Stool Metabolome and Microbiome in Women with Fecal Incontinence in CAPABLe, will evaluate the stool metabolome and microbiome in women with fecal incontinence and unaffected age matched controls.

Official Title
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Controlling Anal Incontinence by Performing Anal Exercises With Biofeedback or Loperamide (CAPABLe): a Randomized Placebo Controlled Trial

Conditions
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Fecal Incontinence

Intervention / Treatment
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* Drug: Loperamide
* Drug: Placebo
* Behavioral: Anal exercises with biofeedback
* Behavioral: Usual Care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 years Fecal incontinence defined as any uncontrolled loss of liquid or solid fecal material that occurs at least monthly over the last 3 months that is bothersome enough to desire treatment Exclusion Criteria: Stool consistency over the last 3 months that includes items 1 or 7 based on the Bristol Stool form scale Current or past diagnosis of colorectal or anal malignancy Diagnosis of inflammatory bowel disease Current or history of rectovaginal fistula or cloacal defect Rectal prolapse (mucosal or full thickness) Prior removal or diversion of any portion of colon or rectum Prior pelvic floor or abdominal radiation Refusal or inability to provide written consent Inability to conduct telephone interviews conducted in English or Spanish Fecal impaction by exam Untreated pelvic organ prolapse beyond the hymen; Patients with prolapse beyond the hymen who are currently using a pessary are eligible Incontinence only to flatus Has taken any loperamide (Imodium®) or diphenoxylate plus atropine (Lomotil®) in the last 30 days Previously received and failed treatment of fecal incontinence using loperamide (Imodium®) or diphenoxylate plus atropine (Lomotil®) over the last 3 months Current supervised anal sphincter exercise/pelvic floor muscle training with biofeedback Previously received and failed treatment of fecal incontinence using supervised anal sphincter exercise/pelvic floor muscle training with biofeedback Previous allergy or intolerance to loperamide Pregnant, nursing, or planning to become pregnant before the end of the study follow-up period. Childbirth within the last 3 months Currently taking anti-retroviral drugs Neurological disorders known to affect continence, including spinal cord injury, advanced multiple sclerosis or Parkinson's disease and debilitating stroke Known diagnosis of hepatic impairment Chronic abdominal pain in the absence of diarrhea

Ages Eligible for Study
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Minimum Age: 18 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: Factorial Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo - Exercise plus Biofeedback<br>Placebo and biofeedback intervention. Placebo doses range from 2mg every other day to 8mg per day. Capsules are taken by mouth once a day for 24 weeks. Anal exercises with biofeedback intervention is a total of six sessions with trained personnel occurring every 2 weeks over a 12-week period. Sessions are held at the following study visits: baseline, 2, 4, 6, 9, and 12 week visits. | Drug: Placebo<br>* Participants randomized to the placebo arm will begin the a dose of one capsule per day and will be dose increased or dose decreased using the same algorithm described for the loperamide arm.<br>* Other names: Inactive Drug;Behavioral: Anal exercises with biofeedback<br>* Participants will receive a formal anal exercises training program that can be easily applied in an office setting with minimal participant burden. Participants will attend six anal exercises with biofeedback sessions with trained personnel over a 12-week period for the 24-week study. Sessions will include introduction, standard patient education, and exercises using anal manometry-assisted biofeedback introducing concepts such as shaping, generalization and termination. The protocol uses strength and sensory training including urge resistance training. During the final twelve weeks, participants will perform anal exercises on their own. The sessions with interventionists will occur every other week for 12 weeks (total 6 supervised sessions).<br>|
| Experimental: Loperamide - Exercise plus Biofeedback<br>Loperamide and biofeedback intervention. Loperamide doses range from 2mg every other day to 8mg per day. Capsules are taken by mouth once a day for 24 weeks. Anal exercises with biofeedback intervention is a total of six sessions with trained personnel occurring every 2 weeks over a 12-week period. Sessions are held at the following study visits: baseline, 2, 4, 6, 9, and 12 week visits. | Drug: Loperamide<br>* Participants randomized to the loperamide group will begin with 2mg of loperamide/day. The participant will be administered the Patient Global Symptom Control rating scale (PGSC) to determine dose escalation. Participants who report inadequate control of stool leakage on the PGSC will be instructed to increase the daily dose of loperamide by 2 mg up to a maximum of 8 mg per day (1-4 capsules). Bothersome adverse events and resulting dose reduction will be based exclusively on the result of the Patient Global Tolerability Scale (PGTS). The daily dose will be decreased by 2mg to a minimum of 2mg every other day. If a PGSC score indicates inadequate control of stool leakage combined with a PGTS score indicating bothersome side effects, the participant will discontinue the study medication.<br>* Other names: Imodium;Behavioral: Anal exercises with biofeedback<br>* Participants will receive a formal anal exercises training program that can be easily applied in an office setting with minimal participant burden. Participants will attend six anal exercises with biofeedback sessions with trained personnel over a 12-week period for the 24-week study. Sessions will include introduction, standard patient education, and exercises using anal manometry-assisted biofeedback introducing concepts such as shaping, generalization and termination. The protocol uses strength and sensory training including urge resistance training. During the final twelve weeks, participants will perform anal exercises on their own. The sessions with interventionists will occur every other week for 12 weeks (total 6 supervised sessions).<br>|
| Placebo Comparator: Placebo - Education Only<br>Placebo and education (usual care). Placebo doses range from 2mg every other day to 8mg per day. Capsules are taken by mouth once a day for 24 weeks. Participants receive education and a NIDDK Bowel Control Educational pamphlet. | Drug: Placebo<br>* Participants randomized to the placebo arm will begin the a dose of one capsule per day and will be dose increased or dose decreased using the same algorithm described for the loperamide arm.<br>* Other names: Inactive Drug;Behavioral: Usual Care<br>* Usual care consists of patients receiving an educational pamphlet on fecal incontinence created by the National Institute of Diabetes and Digestive and Kidney Diseases.<br>|
| Experimental: Loperamide - Education Only<br>Loperamide and education (usual care). Loperamide doses range from 2mg every other day to 8mg per day. Capsules are taken by mouth once a day for 24 weeks. Participants receive education and a NIDDK Bowel Control Educational pamphlet. | Drug: Loperamide<br>* Participants randomized to the loperamide group will begin with 2mg of loperamide/day. The participant will be administered the Patient Global Symptom Control rating scale (PGSC) to determine dose escalation. Participants who report inadequate control of stool leakage on the PGSC will be instructed to increase the daily dose of loperamide by 2 mg up to a maximum of 8 mg per day (1-4 capsules). Bothersome adverse events and resulting dose reduction will be based exclusively on the result of the Patient Global Tolerability Scale (PGTS). The daily dose will be decreased by 2mg to a minimum of 2mg every other day. If a PGSC score indicates inadequate control of stool leakage combined with a PGTS score indicating bothersome side effects, the participant will discontinue the study medication.<br>* Other names: Imodium;Behavioral: Usual Care<br>* Usual care consists of patients receiving an educational pamphlet on fecal incontinence created by the National Institute of Diabetes and Digestive and Kidney Diseases.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline St. Mark's (Vaizey) Score | The primary outcome measure for all study arms is the change from baseline in St. Mark's (Vaizey) Score 24 weeks after treatment initiation to compare the marginal outcomes of anal exercise with biofeedback to usual care and loperamide to placebo. The St. Mark's (Vaizey) score, published in 1999, is commonly used in clinical studies and reports and was based on the Jorge-Wexner score but added two further items for assessment: the use of constipating medication and the presence of fecal urgency. Minimum score is 0 = perfect continence; maximum score is 24 = totally incontinent. | 12 and 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Quality of Life on Colorectal-Anal Distress Inventory (CRADI) | The Pelvic Floor Distress Inventory is a 20-question, validated, self-reported instrument used to evaluate pelvic floor symptoms. It consists of an overall scale (range: 0-300) comprised of 3 sub-scales: 1) Pelvic Organ Prolapse Distress Inventory (range: 0-100), 2) Colorectal Anal Distress Inventory (range: 0-100), and 3) Urinary Distress Inventory (range: 0-100). The range of responses on the CRADI is 1-4 with (1) Not at all, (2) Somewhat, (3) Moderately, and (4), Quite a bit. Scores are calculated by multiplying the mean value of all questions answered by 25 for the scale. The range of responses is: 0-100 with 0 (least distress) to 100 (most distress). Change = (Week [12, 24] Score - Baseline Score). Lower scores indicate better function / fewer symptoms. | 12 and 24 weeks | 
| Change in Colorectal-Anal Subscale of the Pelvic Floor Impact Questionnaire Short Form (CRAIQ) Score | The Pelvic Floor Impact Questionnaire short form (PFIQ-7) measuring the impact of bladder, bowel, and vaginal symptoms on a woman's daily activities, relationships and emotions is composed of 3 scales of 7 questions each: the Urinary Impact Questionnaire (UIQ; range 0-100), the Pelvic Organ Prolapse Impact Questionnaire (POPIQ; range 0-100), and the Colorectal-Anal Impact Questionnaire (CRAIQ; range 0-100). The range of responses on the CRAIQ is 0-3 with (0) Not at all, (1) Somewhat, (2) Moderately, and (3), Quite a bit. Scores are calculated by multiplying the mean value of all answered questions for a scale by 100 divided by 3. The range of responses is: 0-100 with 0 (least negative impact) to 100 (most negative impact). Change = (Week [12, 24] Score - Baseline Score). Lower scores indicate better function / fewer symptoms. | 12 and 24 weeks | 
| Change From Baseline Accident-free Days at 12 and 24 Weeks | Based on data collected from participant-completed diaries at baseline and 12 and 24 weeks, the outcome variable is computed as the difference in number of accident-free days at 12 and 24 weeks and the number of accident-free days at baseline. Only valid diaries were included in the analyses (e.g. completion of all 7 days for baseline and at least 3 complete days, not necessarily consecutive, for follow-up diaries). | 12 and 24 weeks | 
| Change From Baseline Pad-change Leaks Per Day at 12 and 24 Weeks | Based on data collected from participant-completed diaries at baseline and 12 and 24 weeks, the outcome variable is computed as the difference in number of fecal incontinence episodes per day resulting in a change in pad, clothes or underwear at 12 and 24 weeks and the number of fecal incontinence episodes resulting in a change in pad, clothes or underwear at baseline. Only valid diaries were included in the analyses (e.g. completion of all 7 days for baseline and at least 3 complete days, not necessarily consecutive, for follow-up diaries). | 12 and 24 weeks | 
| Change From Baseline Pad-change Leaks Per Week at 12 and 24 Weeks | Based on data collected from participant-completed diaries at baseline and 12 and 24 weeks, the outcome variable is computed as the difference in number of fecal incontinence episodes per week resulting in a change in pad, clothes or underwear at 12 and 24 weeks and the number of fecal incontinence episodes resulting in a change in pad, clothes or underwear at baseline. Only valid diaries were included in the analyses (e.g. completion of all 7 days for baseline and at least 3 complete days, not necessarily consecutive, for follow-up diaries). | 12 and 24 weeks | 
| Change From Baseline Total Number of Leaks Per Day at 12 and 24 Weeks | Based on data collected from participant-completed diaries at baseline and 12 and 24 weeks, the outcome variable is computed as the difference in daily average FI episodes at 12 and 24 weeks and the daily average FI episodes at baseline. Only valid diaries were included in the analyses (e.g. completion of all 7 days for baseline and at 3 complete days, not necessarily consecutive, for follow-up diaries). | 12 and 24 weeks | 
| Change in Fecal Incontinence Severity Index (FISI) Score | The Modified Manchester Health Questionnaire (MMHQ) includes the 4-item Fecal Incontinence Severity Index (FISI), which measures the severity of liquid, solid, mucus, or gas incontinence that occurs from 2 or more times per day, once per day, 2 or more times per week, once a week, to 1-3 times per month. Patient-weighted scores were used to determine severity and scores ranged from 0-61, with higher scores indicating worse fecal incontinence (FI) severity. An FISI score of 0 indicated continence. | 12 and 24 weeks | 
| Participants With Improvement in Patient Global Impression of Improvement (PGI-I) Score | The Patient Global Impression of Improvement (PGI-I) is a patient-reported measure of perceived improvement with treatment, as assessed on a scale of 1 (very much better) to 7 (very much worse). Included here are participants who had improvement as indicated by a rating of 1 (very much better), 2 (much better), or 3 (a little better). | 12 and 24 Weeks | 
| Change From Baseline Resting Anal Canal Pressures (mm of Hg) at 2 cm, 1 cm, and 0 cm Insertion at 12 and 24 Weeks | Based on data collected from the manometry form, the outcome variable is computed as the difference in resting anal canal pressures (mm Hg) at 2 cm, 1 cm, and 0 cm insertion at 12 and 24 weeks and resting anal canal pressures (mm Hg) at 2 cm, 1 cm, and 0 cm insertion at baseline | 12 and 24 weeks | 
| Change From Baseline Volume of Air (mL) at First Sensation for Perception of Rectal Distention at 12 and 24 Weeks | Based on data collected from the manometry form, the outcome variable is computed as the difference in volume of air (mL) at first sensation for perception of rectal distention at 12 and 24 weeks and volume of air (mL) at first sensation for perception of rectal distention at baseline. | 12 and 24 weeks | 
| Change From Baseline Volume of Air (mL) at Urge to Defecate at 12 and 24 Weeks | Based on data collected from the manometry form, the outcome variable is computed as the difference in maximum tolerable rectal volume of air (mL) at 12 and 24 weeks and maximum tolerable rectal volume of air (mL) at baseline. | 12 and 24 weeks | 
| Change From Baseline Maximum Anal Pressures During Squeeze With the Catheter at the HPZ at 12 and 24 Weeks | Based on data collected from the manometry form, the outcome variable will be computed as the difference in maximum anal pressures during squeeze with the catheter at the high pressure zone (HPZ) at 12 and 24 weeks and maximum anal pressures during squeeze with the catheter at the HPZ at baseline. | 12 and 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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anal exercises, Fecal incontinence, Loperamide, biofeedback