- Email: [email protected]
Impact of treatment for Fecal Incontinence on Constipation Symptoms
Journal Pre-proof Impact of treatment for Fecal Incontinence on Constipation Symptoms Uduak U. Andy, MD, J. Eric Jelovsek, MD, MMEd, Benjamin Carper, MS, Isuzu Meyer, MD, Keisha Y. Dyer, MD, MPH, Rebecca G. Rogers, MD, Donna Mazloomdoost, MD, Nicole B. Korbly, MD, Jessica C. Sassani, MD, Marie G. Gantz, PhD, on behalf of the Pelvic Floor Disorders Network PII:
S0002-9378(19)32635-3
DOI:
https://doi.org/10.1016/j.ajog.2019.11.1256
Reference:
YMOB 12973
To appear in:
American Journal of Obstetrics and Gynecology
Received Date: 26 July 2019 Revised Date:
17 October 2019
Accepted Date: 17 November 2019
Please cite this article as: Andy UU, Jelovsek JE, Carper B, Meyer I, Dyer KY, Rogers RG, Mazloomdoost D, Korbly NB, Sassani JC, Gantz MG, on behalf of the Pelvic Floor Disorders Network, Impact of treatment for Fecal Incontinence on Constipation Symptoms, American Journal of Obstetrics and Gynecology (2019), doi: https://doi.org/10.1016/j.ajog.2019.11.1256. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Elsevier Inc. All rights reserved.
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Impact of treatment for Fecal Incontinence on Constipation Symptoms
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Uduak U. Andy MD1, J. Eric Jelovsek MD, MMEd2, Benjamin Carper MS9, Isuzu Meyer MD3, Keisha Y. Dyer MD, MPH4, Rebecca G. Rogers MD7, Donna Mazloomdoost MD8, Nicole B. Korbly MD5, Jessica C. Sassani MD6, Marie G. Gantz PhD9 on behalf of the Pelvic Floor Disorders Network 1 Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, PA 2 Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC 3 Department of Obstetrics and Gynecology, University of Alabama at Birmingham, Birmingham, AL 4 Department of Obstetrics and Gynecology Kaiser Permanente, San Diego, CA 5 Department of Obstetrics and Gynecology, Alpert Medical School of Brown University, Providence, RI 6 Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh Medical Center, Pittsburgh, PA 7 Department of Women’s Health, Dell Medical School, University of Texas at Austin. Austin, TX and The University of New Mexico Health Sciences Center, Albuquerque NM. 8 The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 9 RTI International, Research Triangle Park, NC
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Disclosures: UUA and KYD received research funding from Pelvalon Inc, Sunnyvale, CA. RGR obtained royalties from UpToDate, travel grants from the American Board of Obstetrics and Gynecology and the American College of Obstetrics and Gynecology, stipend and travel for editor in chief from the International Urogynecological Association. MGG received research support on behalf of the Pelvic Floor Disorders Network from Medspira Inc, Minneapolis, MN and research funding from Boston Scientific, Marlborough, MA. The remaining authors report no conflict of interest. Financial Support: The study was supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (U10 HD054215, U10 HD041261, U10 HD054214, U10 HD041267, U10 HD069025, U10 HD069010, U10 HD069006, U10 HD069013, U01 HD069031) and the National Institutes of Health Office of Research on Women’s Health. Dr. UU Andy is supported by a grant from the National Institute on Aging (R03-AG-053277). ClinicalTrials.gov Identifier: NCT02008565 Presentation: American Urogynecologic Society 39th Annual Scientific Meeting. October 9-13. Chicago, IL.
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Corresponding Author:
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Uduak Andy, MD Department Obstetrics & Gynecology University of Pennsylvania Philadelphia, PA Tel: 215-662-7709 Fax: E-mail: [email protected]
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Words Count: Abstract- 476 ; Main Text – 2691 Condensation Improvements in constipation symptoms in women following treatment of fecal incontinence are small, and not significantly different whether or not they were treated with loperamide. Short version of title: Defecatory Symptoms and Fecal Incontinence AJOG at a Glance A. Why was this study conducted? • Loperamide, a medication widely used for the treatment of fecal incontinence, can worsen defecatory symptoms. The goal of this study was to compare changes in constipation symptoms in women undergoing treatment for fecal incontinence with education only, loperamide, anal sphincter exercises with biofeedback, or both loperamide and biofeedback. B. What are the key findings? • There were small improvements in constipation symptoms which were not different between treatment groups. • Women with improved fecal incontinence symptoms had greater improvement in constipation symptoms than women that did not have improvement in fecal incontinence symptoms. C. What does this study add to what is already known? • Findings of this study should reassure clinicians that among women with normal stool consistency, treatment of fecal incontinence with loperamide does not worsen constipation symptoms. Key Words: Fecal Incontinence, defecatory symptoms, constipation, anorectal disorders, loperamide, anal exercises with biofeedback,
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Abstract
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Objective: Defecatory symptoms, such as sense of incomplete emptying and straining with
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bowel movements, are paradoxically present in women with fecal incontinence (FI). Treatments
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for FI, such as loperamide and biofeedback, can worsen or improve defecatory symptoms,
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respectively. The primary aim of this study was to compare changes in constipation symptoms
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in women undergoing treatment for FI with education only, loperamide, anal muscle exercises
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with biofeedback, or both loperamide and biofeedback. Our secondary aim was to compare
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changes in constipation symptoms among responders and non-responders to FI treatment.
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Methods: This was a planned secondary analysis of a randomized controlled trial comparing 2
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first-line therapies for FI in a 2x2 factorial design. Women with at least monthly FI and normal
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stool consistency were randomized to 4 groups: 1) oral placebo plus education only, 2) oral
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loperamide plus education only, 3) placebo plus anorectal manometry-assisted biofeedback
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and 4) loperamide plus biofeedback. Defecatory symptoms were measured using the Patient
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Assessment of Constipation Symptoms (PAC-SYM) questionnaire at baseline, 12 weeks and 24
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weeks. The PAC-SYM consists of 12 items that contribute to a global score and 3 subscales:
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stool characteristics/symptoms (hardness of stool, size of stool, straining, inability to pass
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stool), rectal symptoms (burning, pain, bleeding, incomplete bowel movement), and abdominal
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symptoms (discomfort, pain, bloating, cramps). Scores for each subscale as well as the global
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score range from 0 (no symptoms) to 4 (maximum score), with negative change scores
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representing improvement in defecatory symptoms. Responders to FI treatment were defined
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as women with a minimally important clinical improvement of ≥5-points on the St. Mark’s
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(Vaizey) scale between baseline and 24 weeks. Intent-to-treat analysis was performed using a
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longitudinal mixed model, controlling for baseline scores, to estimate changes in PAC-SYM
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scores from baseline through 24 weeks.
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Results: At 24 weeks, there were small changes in PAC-SYM global scores in all four groups: oral
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placebo plus education (-0.3; 95% CI -0.5, -0.1), loperamide plus education (-0.1, 95% CI -0.3,
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0.0), oral placebo plus biofeedback (-0.3, 95% CI -0.4, -0.2), and loperamide plus biofeedback (-
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0.3, 95% CI -0.4, -0.2). No differences were observed in change in PAC-SYM scores between
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women randomized to placebo plus education and those randomized to loperamide plus
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education (p=0.17) or placebo plus biofeedback (p=0.82). Change in PAC-SYM scores in women
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randomized to combination loperamide plus biofeedback therapy was not different from that
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of women randomized to treatment with loperamide or biofeedback alone. Responders had
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greater improvement in PAC-SYM scores than non-responders (-0.4; 95% CI -0.5, -0.3 vs. -0.2;
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95% CI -0.3, -0.0, p<0.01, mean difference 0.2, 95% CI 0.1, 0.4).
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Conclusion: Change in constipation symptoms following treatment of FI in women are small and
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are not significantly different between groups. Loperamide treatment for FI does not worsen
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constipation symptoms among women with normal consistency stool. Women with clinically
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significant improvement in FI symptoms report greater improvement in constipation
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symptoms.
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Introduction Defecatory symptoms, especially those associated with constipation, are paradoxically
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common in women with fecal incontinence. In a series of 262 subjects, 36% of patients
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presenting primarily with constipation reported fecal incontinence while 34% of subjects
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presenting primarily with fecal incontinence reported symptoms of constipation (1). The
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quality of life of subjects with coexisting constipation and fecal incontinence is also significantly
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worse than either symptom alone (2). The presence of defecatory symptoms such as straining
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to defecate, feeling of incomplete bowel evacuation, digitation, sensation of blockage, and
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constipation indicate the presence of an underlying defecation dysfunction. Manometry studies
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have shown that potential markers of defecation dysfunction, such as poor rectal compliance,
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are common in women with FI (3). Thus, it is important that providers treating FI understand
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potential implications of therapies on commonly-coexisting defecatory symptoms.
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First line treatments for FI include constipating medications, such as loperamide, and
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pelvic floor physical therapy, with or without anorectal biofeedback. Loperamide has been
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shown to reduce incontinence episodes and improve symptoms and quality of life but can
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exacerbate constipation symptoms (4, 5). Pelvic floor physical therapy and anorectal
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biofeedback have been shown to improve defecatory symptoms such as such as straining and
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splinting for bowel movements (6). Despite the common coexistence of FI and defecatory
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symptoms and the potential impact of treatments of FI on defecatory symptoms, well-designed
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prospective studies exploring the relationship between defecatory symptoms and response to
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treatment for FI are lacking.
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We conducted a planned secondary analysis to the Controlling Anal incontinence by Performing
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Anal Exercises with Biofeedback or Loperamide (CAPABLe) trial (7) to determine the impact of
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first-line treatments for FI on constipation symptoms. Our primary aim was to compare the
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changes in constipation symptoms in women randomized to treatment for FI with education
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only, loperamide, anal muscle exercises with biofeedback, or both loperamide and biofeedback.
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Our secondary aim was to compare changes in constipation symptoms among women who
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reported improved FI symptoms and those who did not report improvement in FI symptoms
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following treatment.
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Materials and Methods The CAPABLe trial is a randomized controlled factorial trial conducted between April
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2014 and April 2016 at 8 sites participating in the Pelvic Floor Disorders Network, sponsored by
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Eunice Kennedy Shriver National Institute of Child Health and Human Development. The study
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design has been previously published (8). Women with bothersome FI occurring at least
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monthly over the preceding 3 months were invited to participate. Women who reported Type 1
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(hard) or Type 7 (watery) stool consistency over the last 3 months using the Bristol Stool Form
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were excluded. All sites received IRB approval and all participants gave written informed
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consent (Clinicaltrials.gov NCT02008565).
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Enrolled participants underwent a single randomization using a 0.5:1:1:1 allocation to
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one of four treatment combinations: 1) oral placebo plus education only, 2) oral loperamide
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plus education only, 3) oral placebo plus anal sphincter exercise training using manometry-
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assisted biofeedback, and 4) oral loperamide plus anal sphincter exercise training using
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manometry-assisted biofeedback. All participants were provided education consisting of the
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publicly available pamphlet from the National Institute of Diabetes and Digestive and Kidney
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Diseases (NIDDK) with deletion of a single reference to the drug loperamide. The pamphlet
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discusses symptoms, causes, diagnosis, and treatments including dietary treatment for bowel
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control problems.
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Participants not randomized to biofeedback had baseline, 12 and 24 week visits.
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Participants randomized to biofeedback had visits at baseline, 2, 4, 6, 9, 12 and 24 weeks.
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Participants randomized to the biofeedback group received an individualized program that
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included diagnostic anorectal manometry (ARM) evaluation, biofeedback strength training and
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sensory or urge resistance training (mcompass, Medspira, Minneapolis, MN). Biofeedback
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participants were prescribed a home exercise program based on their individual performance
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during the intervention visits. All study interventionists underwent standardized training (9).
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Participants initially received placebo or 2 mg of oral loperamide (1 capsule) per day
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with the option of dose escalation up to a maximum of 4 capsules daily and the option of dose
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reduction due to adverse effects to 1 capsule every other day. Dose escalation, maintenance or
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reduction was based on balancing efficacy and side effects of treatment using two Likert scales:
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the Patient Global Symptom Control rating scale (PGSC), “My current treatment is giving me
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adequate control of my stool leakage” and the Patient Global Tolerability rating Scale (PGTS),
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“My current medication is giving me bothersome side effects.” Responses on both scales ranged
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from 1, ‘disagree strongly’ to 5, ‘agree strongly.’ Those women reporting inadequate control of
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stool leakage and bothersome side effects were instructed to discontinue the study medication
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but were requested to remain in the study follow-up for the duration. Participants reporting
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deterioration in FI symptoms after discontinuing the study drug due to side effects were
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allowed to re-start study drug after an assessment by the site investigator.
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The primary outcome for CAPABLe was the change from baseline to 24 weeks in the St.
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Mark’s (Vaizey) FI severity scale. The primary outcome for this secondary study was change
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from baseline to 24 weeks in the Patient Assessment of Constipation Symptoms (PAC-SYM)
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global score (10). The PAC-SYM consists of 12 items that contribute to a global score and 3
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subscales: stool characteristics/ symptoms (hardness of stool, size of stool, straining, inability to
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pass stool), rectal symptoms (burning, pain, bleeding, incomplete bowel movement), and
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abdominal symptoms (discomfort, pain, bloating, cramps). Subscales and global scores range
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from 0 (no symptoms) to 4 (maximum score), with decreasing scores representing
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improvement in defecatory symptoms. The minimal important difference (MID) for the PAC-
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SYM questionnaire is -0.6 (21). Secondary outcomes included change from baseline to 24
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weeks in the PAC-SYM subscale scores. Throughout the study, outcome evaluators were
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masked to the treatment assignment for the biofeedback intervention. Participants and all
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study staff other than the research pharmacist were masked to the medication assignment.
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A responder-to-treatment was defined as any subject that showed the minimally
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important clinical difference, at least a 5-point decrease, in the St. Mark’s (Vaizey) score at 24
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weeks (11).
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Statistical Analysis
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Women who had constipation symptom outcome data at 12 or 24 weeks were included
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in analysis. The change from baseline in PAC-SYM global scores at 24 weeks was analyzed using
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a general linear mixed model. Independent variables included baseline PAC-SYM global score,
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treatment assignments, interactions between drug and exercise, week 12 or 24, interactions
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between week and treatment, and clinical site. The model accounted for the dependence
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between repeated measurements on the same subject by modeling the within-participant
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covariance structure. Combination treatment (oral loperamide plus anal sphincter exercise
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training using manometry-assisted biofeedback) was compared to oral loperamide plus
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education only or oral placebo plus biofeedback alone. Oral loperamide plus education only
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was compared to oral placebo plus education only, and oral placebo plus biofeedback was
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compared to oral placebo plus education only. Each comparison was evaluated at a type I error
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level of 0.05. Box plots were used to explore the relationship between baseline stool
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consistency (Bristol stool type) and change in PAC-SYM scores from baseline for each treatment
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group.
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The change from baseline in PAC-SYM global score at 24 weeks was also compared
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between responders-to-treatment and non-responders. The baseline PAC-SYM global score was
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first compared between responders and non-responders using a general linear model with
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responder status and clinical site as independent variables. The change from baseline in PAC-
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SYM global scores at 24 weeks was compared for responders and non-responders using a
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general linear mixed model with responder status, treatment assignments, week 12 or 24,
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clinical site, and interactions between drug and exercise, week and treatment, and responder
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status and week as independent variables. The model accounted for the dependence between
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repeated measurements on the same subject by modeling the within-participant covariance
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structure. Responders were compared to non-responders at a type I error level of 0.05.
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Subjects without 24-week data available for the St. Mark’s (Vaizey) score were excluded from
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the analysis comparing responders and non-responders. The other secondary outcomes, changes in PAC-SYM subscales, were evaluated similarly
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for both comparisons between treatments and between responders and non-responders.
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Primary and secondary outcomes were analyzed using a modified intent-to-treat principle, with
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the limitation that only observed outcomes at 12 and 24 weeks were included in analysis. No
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adjustments were made for performing multiple statistical tests.
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Results In the CAPABLe trial, 296 eligible women were randomized to the following groups: oral
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placebo plus education (n=42), loperamide plus education (n=86), oral placebo plus
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biofeedback (n=83) and the combined intervention of loperamide plus biofeedback (n=85).
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Over 83% of participants had defecatory symptom outcome data at 12 or 24 weeks and were
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included in analysis: oral placebo plus education 35/42 (83%), loperamide plus education 71/86
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(83%), oral placebo plus biofeedback 69/83 (83%), and loperamide plus biofeedback, 72/85
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(85%).
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Baseline demographic and clinical characteristics of participants included in this analysis
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are presented in Table 1. As expected in a randomized trial, women randomized to placebo plus
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education did not differ significantly from women randomized to loperamide plus education or
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oral placebo plus biofeedback. Similarly, baseline characteristics of women who received both
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active treatments (loperamide plus biofeedback) were not different from women who received
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one active treatment (loperamide plus education or placebo plus biofeedback) only. Baseline
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PAC-SYM scores were similar in all groups.
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All groups demonstrated small improvements in global PAC-SYM scores at 24 weeks:
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oral placebo plus education (-0.3, 95% CI -0.5, -0.1), loperamide plus education (-0.1, 95% CI -
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0.3, 0.0), oral placebo plus biofeedback (-0.3, 95% CI -0.4, -0.2) and loperamide plus
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biofeedback (-0.3, 95% CI -0.4, -0.2). No differences in improvement in PAC-SYM global scores
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between women randomized to placebo plus education and women randomized to loperamide
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plus education or oral placebo plus biofeedback were observed (Table 2). Improvement in PAC-
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SYM global scores in women randomized to combination loperamide plus biofeedback therapy
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was also not significantly different from improvement in women randomized to loperamide or
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biofeedback alone (Table 3). Likewise, no differences between groups were noted in the
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subscales of the PAC-SYM with the exception of the rectal subscale when comparing
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loperamide plus biofeedback to loperamide plus education. No associations or patterns that
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might support an association between baseline stool consistency and improvement or
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worsening of PAC-SYM scores for any of the treatment groups were observed in visual box plots
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(data not shown).
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Of the women with FI symptom outcome data at 24 weeks, 137 had clinically significant
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improvement in Vaizey score (responders) and 129 did not (non-responders). Of these women,
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124/137 (91%) of responders and 119/129 (92%) of non-responders had PAC-SYM defecatory
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symptom outcomes available at either 12 or 24 weeks. Responders had greater improvement in
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global PAC-SYM scores at 24 weeks than non-responders (-0.4; 95% CI -0.5, -0.3 vs. -0.2; 95% CI
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-0.3, -0.0, mean difference 0.2, 95% CI 0.1, 0.4) despite similar scores at baseline (Tables 4 and
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5). Responders had greater improvement in the all subscales of the PAC-SYM (Table 5).
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Comments
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Principal Findings
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We did not find differences in change in constipation symptoms among women with at
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least monthly FI and normal stool consistency randomized to loperamide and/or biofeedback
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compared to placebo plus education. Women who reported improvement in FI symptoms had
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greater improvement in constipation symptoms as measured by the PAC-SYM compared to
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those with no improvement in FI symptoms. These findings are useful in understanding the
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relationship between defecatory symptoms and FI treatments, and provide clinical reassurance
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that the use of loperamide in women with FI with normal stool consistency does not worsen
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constipation symptoms as all groups had small improvements in constipation symptoms.
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Results, Clinical and Research Implications
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Defecatory symptoms commonly co-exist in women with FI. Several retrospective or
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cross-sectional community-based studies and surveys in urogynecology clinics demonstrate a
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significant association between constipation that includes defecatory symptoms and FI (12-15).
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Studies have also demonstrated that coexisting constipation can modify the response to
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treatment for fecal incontinence. In a retrospective study of 145 patients treated for FI using
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biofeedback, symptoms such as straining with bowel movements, use of splinting, and
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abnormal rectal compliance on anorectal manometry were significantly more common in
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women who had poor response to treatment (6). Despite lack of controlled studies, clinical
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guidelines recommend treating women with co-existing FI and underlying evacuation disorders
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with interventions such as biofeedback to train patients to relax their pelvic floor (16).
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Unfortunately, these studies and recommendations have not been prospectively studied to
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assess treatment effect and did not use valid and reliable defecatory symptom-severity scales.
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In contrast, our study demonstrated that defecatory symptoms do not worsen with
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treatment with either loperamide or anal muscles exercises with biofeedback and suggest there
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may be marginal improvement. The biofeedback training protocol in this study included
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instruction on recto-anal coordination which may have improved evacuation of the rectum.
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However, it is unclear why women randomized to loperamide did not report higher defecatory
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symptom severity after treatment compared to women not taking loperamide. One possibility
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is that loperamide improved stool consistency and this improved efficiency of evacuation.
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However, we did not notice any association between baseline stool consistency and change in
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PAC-SYM score in women who received loperamide. Another possible explanation is that
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loperamide, which in addition to established effects on improving stool consistency, has been
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shown to affect rectal perception and increase anal sphincter resting and squeeze pressure
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impacts defecatory symptoms through these mechanisms.(17,18) When anal sphincter
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pressures are low, stool in the anorectum is sensed at lower volumes (18); thus our findings
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suggest that loperamide’s effect on increasing sphincter pressure may result in changes in
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visceral sensitivity leading to improvement in symptoms such as sense of incomplete emptying.
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Greater improvement in defecatory symptoms in responders compared to non-
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responders may suggest shared underlying mechanisms between FI and defecatory
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dysfunction. Women with FI have been shown to have poor rectal compliance indicating the
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presence of co-existing defecatory dysfunction (3). Additionally, women with symptoms of
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defecatory dysfunction such as straining for bowel movements and sense of incomplete
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evacuation, have weaker axial forces not only during expulsion but also during contraction of
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the pelvic floor muscles, suggesting an increased risk for FI (19). In women where treatments
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affect these underlying mechanisms, both FI and defecatory symptoms may improve.
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Alternatively, our finding may reflect the significant impact of functional anorectal disorders on
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quality of life. In a prior study examining the risk factors for constipation and FI, poor self-rated
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health and depression were found to be common risk factors for both conditions (20). Thus,
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women who had improvement in FI severity may have perceived overall subjective
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improvement in quality of life including defecatory symptoms.
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Strengths and Limitations
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The strengths of this study include the prospective study design of women randomly
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assigned to the two common conservative treatments for FI. Defecatory symptoms were
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evaluated using a valid, reliable and responsive questionnaire that has been used in other
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clinical trials to assess patient-reported defecatory dysfunction. Despite the large sample size
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adequately powered for the primary study (7), there was limited power to detect marginal
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differences between the combined versus individual treatments and single treatment versus
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control groups. The study findings are generalizable to women with normal stool consistency
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who are seeking treatment for FI rather than constipation symptoms and the study did not
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collect additional objective measures of defecatory dysfunction such as transit studies or
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balloon testing. Additionally, we excluded women with large rectoceles and we did not assess
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for high tone dysfunction, two conditions that could impact constipations symptoms and as
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such our data may not be generalizable to women with those conditions. Further, although all
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intervention groups as well as the responder group had defecatory symptom improvements
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compared to baseline, the change in scores did not meet the minimal important difference
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(MID, -0.6) for the PAC-SYM questionnaire (21). The concept of MID, the smallest difference in
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score associated with a clinically meaningful improvement, is frequently used in clinical trials to
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determine whether the difference observed is not only statistically significant but also clinically
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relevant. The proposed MID of 0.6 for the PAC-SYM was derived from trials evaluating the
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treatment efficacy of a medication for chronic constipation. Therefore, the improvement in
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defecatory symptoms observed in the current study may not have the same magnitude of
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change in symptoms compared to the clinical trials evaluating the treatment of constipation.
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Conclusion
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In summary, women seeking treatment for FI had modest improvements in defecatory
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symptoms, regardless of treatment group. These improvements were more marked in women
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who reported improvement in FI. In contrast to other studies, the addition of loperamide did
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not have a negative impact on defecatory symptoms.
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Acknowledgements
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We thank the Pelvic Floor Disorders Network Contributors who made this study possible: Cleveland Clinic Mathew D. Barber, Co-Investigator Marie Fidela R. Paraiso, Co-Investigator Mark D. Walters, Co-Investigator Beri Ridgeway, Co-Investigator Brooke Gurland, Co-Investigator Massarat Zutshi, Co-Investigator Geetha Krishnan, Research Nurse Ly Pung, Research Nurse Annette Graham, Research Nurse Alpert Medical School of Brown University-Women & Infant’s Hospital of Rhode Island Vivian W. Sung, Principal Investigator Deborah L. Myers, Co-Investigator Charles R. Rardin, Co-Investigator Cassandra Carberry, Co-Investigator B. Star Hampton, Co-Investigator Kyle Wohlrab, Co-Investigator Ann S. Meers, RN, Research Nurse Duke University Anthony Visco, Principal Investigator Cindy Amundsen, Co-Investigator Alison Weidner, Co-Investigator Nazema Siddiqui, Co-Investigator Amie Kawasaski, Co-Investigator Shantae McLean, Clinical Site Coordinator Nicole Longoria, Clinical Research Coordinator Jessica Carrington, Clinical Research Coordinator Niti Mehta, Clinical Research Specialist Ingrid Harm-Ernandes, Interventionist Jennifer Maddocks, Interventionist Amy Pannullo, Interventionist University of Alabama at Birmingham Alayne Markland, Primary Investigator Holly E. Richter, Co- investigator R. Edward Varner, Co-Investigator Robert Holley, Co-Investigator
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L. Keith Lloyd, Co-Investigator Tracy S. Wilson, Co-Investigator Alicia Ballard, Co-Investigator Jeannine McCormick, Interventionist Velria Willis, Research Nurse Nancy Saxon, Research Nurse Kathy Carter, Research Nurse Julie Burge, Research Coordinator Northwest Physician Group, Amarillo, TX Susan Meikle, Co-Investigator University of California, San Diego Charles Nager, Principal Investigator Michael Albo, Co-Investigator Emily Lukacz, Co-Investigator Cindy Furey, Interventionist Patricia Riley, Interventionist JoAnn Columbo, Research Coordinator Sherella Johnson, Research Coordinator Kaiser Permanente – San Diego Shawn Menefee, Co-Investigator Karl Luber, Co-Investigator Gouri Diwadkar, Co-Investigator Jasmine Tan-Kim, Co-Investigator University of New Mexico Yuko Komesu, Co-Investigator Gena Dunivan, Co-Investigator Peter Jeppson, Co-Investigator Sara Cichowski, Co-Investigator Christy Miller, Interventionist Erin Yane, Interventionist Julia Middendorf, Research Nurse Risela Nava, Research Coordinator RTI International Dennis Wallace, Alternate Principal Investigator Amanda Shaffer, Research Operations Manager Poonam Pande, Chemistry, Manufacturing, and Controls Project Leader Kelly Roney, Regulatory Project Leader Ryan E. Whitworth, Statistician Lauren Klein Warren, Statistician
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Kevin A. Wilson, Clinical Research Informatics Project Leader Brenda Hair, Clinical Research Informatics Manager Kendra Glass, Data Manager Daryl Matthews, Data Manager James W. Pickett, II, Programmer Yan Tang, Programmer Tamara L. Terry, Research Services Manager Lynda Tatum, Research Services Supervisor Barbara Bibb, Programmer Jutta Thornberry, Program Manager Kristin Zaterka-Baxter, Clinical Study Specialist Lindsay Morris, Research Coordinator University of Pennsylvania Lily Arya, Principal Investigator Ariana Smith, Co-Investigator Heidi Harve, Co-Investigator Pamela Levin, Co-Investigator Diane K. Newman, Co-Investigator Mary Wang, Interventionist Donna Thompson, Interventionist Teresa Carney, Interventionist Michelle Kinglee, Research Coordinator Lorraine Flick, Research Nurse University of Pittsburgh Halina M. Zyczynski MD, Principle Investigator Pam Moalli PhD, MD, Co-Investigator Gary Sutkin MD, Co-Investigator Jonathan Shepherd MD, Co-Investigator Michael Bonidie MD, Co-Investigator Steven Abo, MD Co-Investigator Janet Harrison MD, Co-Investigator Christopher Chermansky MD, Co-Investigator Lori Geraci, Research Coordinator Judy Gruss, Research Coordinator Karen Mislanovich, Research Coordinator Ellen Eline, Interventionist Beth Klump, Interventionist Susan E. George DPT, Interventionist University of North Carolina at Chapel Hill William E. Whitehead Ph.D., Co-Investigator
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References 1. Mohammed SD. Co-existence of constipation and fecal incontinence: a greatly underappreciated clinical problem. Neurogastroenterol Motil 2010;22(Suppl1): 37 2. Siproudhis L, Pigot F, Godeberge P, Damon H, Soudan D, Bigard MA. Defecation disorders: a French population survey. Dis Colon Rectum. 2006 Feb;49(2):219-27. 3. Andrews C, Bharucha AE, Seide B, Zinsmeister AR. Rectal sensorimotor dysfunction in women with fecal incontinence. Am J Physiol Gastrointest Liver Physiol 292: G282–G289, 2007. 4. Omar MI, Alexander CE. Drug Treatment for fecal incontinence in adults. Cochrane Database Syst Rev 2013 Jun 11;(6): CD 002116 5. Markland AD, Burgio KL, Whitehead WE, Richter HE, Wilcox CM, Redden DT, Beasley TM, Goode PS. Loperamide Versus Psyllium Fiber for Treatment of Fecal Incontinence: The Fecal Incontinence Prescription (Rx) Management (FIRM) Randomized Clinical Trial. Dis Colon Rectum. 2015 Oct;58(10):983-93. 6. Ferna´ndez-Fraga X, Azpiroz F, Aparici A, Casaus M, Malagelada JR. Predictors of response to biofeedback treatment in anal incontinence. Dis Colon Rectum 2003;46:1218–1225. 7. Jelovsek JE, Markland AD, Whitehead WE, Barber MD, Newman DK, Rogers RG, Dyer K, Visco AG, Sutkin G, Zyczynski HM, Carper B, Meikle SF, Sung VW, Gantz MG; National Institute of Child Health and Human Development Pelvic Floor Disorders Network. Controlling faecal incontinence in women by performing anal exercises with biofeedback or loperamide: a randomised clinical trial. Lancet Gastroenterol Hepatol. 2019 Jul 15. pii: S2468-1253(19)30193-1. doi: 10.1016/S2468-1253(19)30193-1. 8. Jelovsek JE, Markland AD, Whitehead WE, Barber MD, Newman DK, Rogers RG, Dyer K, Visco A, Sung VW, Sutkin G, Meikle SF, Gantz MG Pelvic Floor Disorders Network. Controlling anal incontinence in women by performing anal exercises with biofeedback or loperamide (CAPABLe) trial: Design and methods. Contemp Clin Trials. 2015;44(Sept):164– 174.
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9. Markland AD, Jelovsek JE, Whitehead WE, Newman DK, Andy UU, Dyer K, Harm-Ernandes I, Cichowski S, McCormick J, Rardin C, Sutkin G, Shaffer A, Meikle S; Pelvic Floor Disorders Network. Improving biofeedback for the treatment of fecal incontinence in women: implementation of a standardized multi-site manometric biofeedback protocol. Neurogastroenterol Motil. 2017 Jan;29(1).
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10. Frank L, Kleinman L, Farup C, Taylor L, Miner P,Jr. Psychometric validation of a constipation symptom assessment questionnaire. Scand J Gastroenterol. 1999 Sep;34(9):870-7. 11. Bols EM, Hendriks EJ, Deutekom M, et al. Inconclusive psychometric properties of the Vaizey score in fecally incontinent patients: A prospective cohort study. Neurourol Urodyn 2010;29:370–7.
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12. Damon H, Guye O, Seigneurin A, Long F, Sonko A, Faucheron JL, et al. Prevalence of anal incontinence in adults and impact on quality-of-life. Gastroenterol Clin Biol 2006 Jan;30(1):37-43. 13. Bharucha AE, Seide BM, Zinsmeister AR, Melton LJ, 3rd. Relation of bowel habits to fecal incontinence in women. Am J Gastroenterol 2008 Jun;103(6):1470-5.
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14. Bharucha AE, Zinsmeister AR, Schleck CD, Melton LJ, 3rd. Bowel disturbances are the most important risk factors for late onset fecal incontinence: a population-based case-control study in women. Gastroenterology 2010 Nov;139(5):1559-66.
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15. Boreham MK, Richter HE, Kenton KS, Nager CW, Gregory WT, Aronson MP, et al. Anal incontinence in women presenting for gynecologic care: prevalence, risk factors, and impact upon quality of life. Am J Obstet Gynecol 2005 May;192(5):1637-42.
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16. Wald A, Bharucha AE, Cosman BC, Whitehead WE. ACG clinical guideline: management of benign anorectal disorders. Am J Gastroenterol 2014 Aug;109(8):1141-57; (Quiz) 058.
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17. Read M, Read NW, Barber DC, Duthie HL. Effects of loperamide on anal sphincter function in patients complaining of chronic diarrhea with fecal incontinence and urgency. Dig Dis Sci. 1982;27(9):807-814.
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18. Fox M, Stutz B, Menne D, Fried M, Schwizer W, Thumshirn M. The effects of loperamide on continence problems and anorectal function in obese subjects taking orlistat. Dig Dis Sci. 2005;50(9):1576-1583. doi: 10.1007/s10620-005-2900-6.
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19. Bharucha AE, Croak AJ, Gebhart JB, Berglund LJ, Seide BM, Zinsmeister AR, An KN. Comparison of rectoanal axial forces in health and functional defecatory disorders. Am J Physiol Gastrointest Liver Physiol. 2006 Jun;290(6):G1164-9.
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20. Andy UU, Vaughan CP, Burgio KL, Alli FM, Goode PS, Markland AD. Shared Risk Factors for Constipation, Fecal Incontinence, and Combined Symptoms in Older U.S. Adults. J Am Geriatr Soc. 2016 Nov;64(11):e183-e188
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21. Yiannakou Y. et al. The PAC-SYM questionnaire for chronic constipation: defining the minimal important difference. Aliment Pharmacol Ther. 2017 Dec; 46(11-12): 1103–1111.
538 539
540 541
Table 1. Demographics: Baseline clinical and demographic characteristics of participants in placebo, individual treatment, and combined treatment groups. Placebo - Education Only (N=35)
Loperamide Education Only (N=71)
Placebo - Exercise plus Biofeedback (N=69)
Loperamide Exercise plus Biofeedback (N=72)
Baseline Characteristic
Baseline Characteristic
Baseline Characteristic
Baseline Characteristic
62.5 (10.5) [40.2, 83.3]
62.5 (10.7) [38.1, 83.3]
65.5 (10.3) [39.7, 93.4]
63.6 (12.4) [27.5, 87.6]
American Indian/Alaskan Native
2 (5.7)
0 (0.0)
1 (1.4)
0 (0.0)
Black/African American
6 (17.1)
10 (14.1)
10 (13.9)
9 (13.0)
More than one race
0 (0.0)
0 (0.0)
4 (5.6)
1 (1.4)
Other
2 (5.7)
2 (2.8)
1 (1.4)
2 (2.9)
White
25 (71.4)
59 (83.1)
56 (77.8)
57 (82.6)
2 (5.7)
7 (9.9)
7 (9.7)
7 (10.1)
32 (91.4)
63 (88.7)
64 (88.9)
61 (88.4)
1 (2.9)
1 (1.4)
1 (1.4)
1 (1.4)
Prior accidental bowel leakage surgery, No(%)
0 (0.0)
4 (5.6)
3 (4.2)
5 (7.2)
Prior rectal or anal surgery, No. (%)
7 (20.6)
6 (8.6)
12 (17.1)
8 (11.6)
BMI, mean (SD) [min, max]
30.5 (9.0) [20.2, 62.1]
31.0 (6.7) [20.2, 48.5]
29.9 (6.7) [19.5, 55.0]
28.8 (6.6) [17.1, 43.2]
Dietary Fiber Score, mean (SD) [min, max]
15.1 (7.3) [2.0, 33.0]
15.3 (6.3) [4.0, 31.0]
16.5 (6.4) [4.0, 41.0]
16.1 (5.8) [5.0, 29.0]
Daily fiber intake, mean (SD) [min, max]
14.6 (5.4) [4.9, 27.8]
14.7 (4.7) [6.4, 26.3]
15.6 (4.7) [6.4, 33.7]
15.3 (4.3) [7.1, 24.9]
Type 2. Sausage shaped but lumpy
6 (17.1)
6 (8.5)
16 (22.2)
5 (7.2)
Type 3. Like a sausage or snake but with cracks on
2 (5.7)
14 (19.7)
9 (12.5)
10 (14.5)
Type 4. Like a sausage or snake, smooth and soft
14 (40.0)
24 (33.8)
20 (27.8)
25 (36.2)
Type 5. Soft blobs with clear cut edges
5 (14.3)
13 (18.3)
12 (16.7)
15 (21.7)
Type 6. Fluffy pieces with ragged edges, a mushy s
8 (22.9)
14 (19.7)
15 (20.8)
14 (20.3)
5 (14.3)
14 (19.7)
14 (19.4)
15 (21.7)
Endpoint
Category
Age, mean (SD) [min, max], y Race, No. (%)
Ethnicity, No. (%)
Hispanic/Latina Not Hispanic/Not Latina Unknown/Not Reported
Bristol Stool Index, No. (%)
Rome III IBS Clinical Status, No. (%)
Endpoint PAC-SYM Scores, mean (SD) [min, max]
542 543
Placebo - Education Only (N=35)
Loperamide Education Only (N=71)
Placebo - Exercise plus Biofeedback (N=69)
Loperamide Exercise plus Biofeedback (N=72)
Baseline Characteristic
Baseline Characteristic
Baseline Characteristic
Baseline Characteristic
Stool Score
1.1 (0.8) [0.0, 2.6]
1.2 (0.8) [0.0, 2.8]
0.9 (0.9) [0.0, 3.8]
1.1 (0.8) [0.0, 2.8]
Rectal Score
0.8 (0.8) [0.0, 2.7]
0.7 (0.7) [0.0, 2.7]
0.9 (0.7) [0.0, 3.3]
0.7 (0.7) [0.0, 2.3]
Abdominal Score
1.0 (1.1) [0.0, 3.5]
1.1 (0.9) [0.0, 3.3]
1.1 (0.8) [0.0, 3.4]
0.9 (0.8) [0.0, 3.0]
Global Score
1.0 (0.7) [0.0, 2.7]
1.1 (0.7) [0.0, 2.6]
0.7 (0.8) [0.0, 3.0]
0.9 (0.6) [0.0, 2.5]
Category
544 545
Table 2. Change in PAC-SYM at 24 weeks for Placebo versus Loperamide and Placebo versus Biofeedback Placebo- Education (N=35)
Loperamide - Education (N=71)
Placebo - Biofeedback (N=69)
Change in PAC-SYM Score
Mean Change from Baseline(95% CI)
Mean Change from Baseline(95% CI)
P-value for Comparison
Mean Change from Baseline(95% CI)
P-value for Comparison
Change in PAC-SYM Abdominal Score
-0.4 (-0.7, -0.2)
-0.2 (-0.3, 0.0)
0.052
-0.3 (-0.5, -0.2)
0.537
Change in PAC-SYM Rectal Score
-0.3 (-0.5, -0.1)
-0.1 (-0.2, 0.0)
0.125
-0.3 (-0.5, -0.2)
0.677
Change in PAC-SYM Stool Score
-0.2 (-0.4, 0.0)
-0.2 (-0.3, 0.0)
0.878
-0.3 (-0.4, -0.1)
0.379
Change in PAC-SYM Global Score
-0.3 (-0.5, -0.1)
-0.1 (-0.3, 0.0)
0.169
-0.3 (-0.4, -0.2)
0.819
546 547 548 549
Table 3: Change in PAC-SYM at 24 weeks for Combined Loperamide and Biofeedback versus Loperamide only and Biofeedback only Loperamide Biofeedback (N=72)
550 551 552 553 554 555
Loperamide - Education (N=71)
Placebo - Biofeedback (N=69)
Change in PAC-SYM Score
Mean Change from Baseline(95% CI)
Mean Change from Baseline(95% CI)
P-value for Compa rison
Mean Change from Baseline(95% CI)
P-value for Compa rison
Change in PAC-SYM Abdominal Score
-0.3 (-0.5, -0.1)
-0.2 (-0.3, 0.0)
0.257
-0.3 (-0.5, -0.2)
0.616
Change in PAC-SYM Rectal Score
-0.4 (-0.5, -0.1)
-0.1 (-0.2, 0.0)
0.010
-0.3 (-0.5, -0.2)
0.862
Change in PAC-SYM Stool Score
-0.2 (-0.4, 0.0)
-0.2 (-0.3, 0.0)
0.549
-0.3 (-0.4, -0.1)
0.499
Change in PAC-SYM Global Score
-0.3 (-0.4, -0.2)
-0.1 (-0.3, 0.0)
0.147
-0.3 (-0.4, -0.2)
0.600
556
Table 4. Baseline PAC-SYM scores in responders and non-responders to treatment for FI Responders
Non-Responders
(N=124)
(N=119)
Baseline PAC-SYM Score
Mean (95% CI)
Mean(95% CI)
PAC-SYM Abdominal Score
1.06 (0.89, 1.23)
0.88 (0.70, 1.06)
0.127
PAC-SYM Rectal Score
0.67 (0.52, 0.81)
0.67 (0.52, 0.81)
0.992
PAC-SYM Stool Score
1.10 (0.95, 1.25)
1.14 (0.99, 1.30)
0.675
PAC-SYM Global Score
0.98 (0.85, 1.11)
0.94 (0.80, 1.07)
0.641
P-value for Comparison
557 558 559 560
Table 5. Change in PAC-SYM scores at 24 weeks in responders and non-responders to treatment for FI Responders
Non-Responders
(N=124)
(N=119)
Mean Change from Baseline (95% CI)
Mean Change from Baseline (95% CI)
Change in PAC-SYM Abdominal Score
-0.48 (-0.63, -0.32)
-0.17 (-0.33, -0.01)
0.005
Change in PAC-SYM Rectal Score
-0.37 (-0.50, -0.24)
-0.16 (-0.29, -0.03)
0.020
Change in PAC-SYM Stool Score
-0.34 (-0.47, -0.20)
-0.13 (-0.26, 0.01)
0.022
Change in PAC-SYM Global Score
-0.39 (-0.50, -0.28)
-0.15 (-0.26, -0.03)
0.002
Change in PAC-SYM Score
561 562 563 564 565 566
P-value for Comparison
S0002-9378(19)32635-3
DOI:
https://doi.org/10.1016/j.ajog.2019.11.1256
Reference:
YMOB 12973
To appear in:
American Journal of Obstetrics and Gynecology
Received Date: 26 July 2019 Revised Date:
17 October 2019
Accepted Date: 17 November 2019
Please cite this article as: Andy UU, Jelovsek JE, Carper B, Meyer I, Dyer KY, Rogers RG, Mazloomdoost D, Korbly NB, Sassani JC, Gantz MG, on behalf of the Pelvic Floor Disorders Network, Impact of treatment for Fecal Incontinence on Constipation Symptoms, American Journal of Obstetrics and Gynecology (2019), doi: https://doi.org/10.1016/j.ajog.2019.11.1256. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Elsevier Inc. All rights reserved.
1
Impact of treatment for Fecal Incontinence on Constipation Symptoms
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Uduak U. Andy MD1, J. Eric Jelovsek MD, MMEd2, Benjamin Carper MS9, Isuzu Meyer MD3, Keisha Y. Dyer MD, MPH4, Rebecca G. Rogers MD7, Donna Mazloomdoost MD8, Nicole B. Korbly MD5, Jessica C. Sassani MD6, Marie G. Gantz PhD9 on behalf of the Pelvic Floor Disorders Network 1 Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, PA 2 Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC 3 Department of Obstetrics and Gynecology, University of Alabama at Birmingham, Birmingham, AL 4 Department of Obstetrics and Gynecology Kaiser Permanente, San Diego, CA 5 Department of Obstetrics and Gynecology, Alpert Medical School of Brown University, Providence, RI 6 Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh Medical Center, Pittsburgh, PA 7 Department of Women’s Health, Dell Medical School, University of Texas at Austin. Austin, TX and The University of New Mexico Health Sciences Center, Albuquerque NM. 8 The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 9 RTI International, Research Triangle Park, NC
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Disclosures: UUA and KYD received research funding from Pelvalon Inc, Sunnyvale, CA. RGR obtained royalties from UpToDate, travel grants from the American Board of Obstetrics and Gynecology and the American College of Obstetrics and Gynecology, stipend and travel for editor in chief from the International Urogynecological Association. MGG received research support on behalf of the Pelvic Floor Disorders Network from Medspira Inc, Minneapolis, MN and research funding from Boston Scientific, Marlborough, MA. The remaining authors report no conflict of interest. Financial Support: The study was supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (U10 HD054215, U10 HD041261, U10 HD054214, U10 HD041267, U10 HD069025, U10 HD069010, U10 HD069006, U10 HD069013, U01 HD069031) and the National Institutes of Health Office of Research on Women’s Health. Dr. UU Andy is supported by a grant from the National Institute on Aging (R03-AG-053277). ClinicalTrials.gov Identifier: NCT02008565 Presentation: American Urogynecologic Society 39th Annual Scientific Meeting. October 9-13. Chicago, IL.
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Corresponding Author:
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Uduak Andy, MD Department Obstetrics & Gynecology University of Pennsylvania Philadelphia, PA Tel: 215-662-7709 Fax: E-mail: [email protected]
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Words Count: Abstract- 476 ; Main Text – 2691 Condensation Improvements in constipation symptoms in women following treatment of fecal incontinence are small, and not significantly different whether or not they were treated with loperamide. Short version of title: Defecatory Symptoms and Fecal Incontinence AJOG at a Glance A. Why was this study conducted? • Loperamide, a medication widely used for the treatment of fecal incontinence, can worsen defecatory symptoms. The goal of this study was to compare changes in constipation symptoms in women undergoing treatment for fecal incontinence with education only, loperamide, anal sphincter exercises with biofeedback, or both loperamide and biofeedback. B. What are the key findings? • There were small improvements in constipation symptoms which were not different between treatment groups. • Women with improved fecal incontinence symptoms had greater improvement in constipation symptoms than women that did not have improvement in fecal incontinence symptoms. C. What does this study add to what is already known? • Findings of this study should reassure clinicians that among women with normal stool consistency, treatment of fecal incontinence with loperamide does not worsen constipation symptoms. Key Words: Fecal Incontinence, defecatory symptoms, constipation, anorectal disorders, loperamide, anal exercises with biofeedback,
70 71
Abstract
72
Objective: Defecatory symptoms, such as sense of incomplete emptying and straining with
73
bowel movements, are paradoxically present in women with fecal incontinence (FI). Treatments
74
for FI, such as loperamide and biofeedback, can worsen or improve defecatory symptoms,
75
respectively. The primary aim of this study was to compare changes in constipation symptoms
76
in women undergoing treatment for FI with education only, loperamide, anal muscle exercises
77
with biofeedback, or both loperamide and biofeedback. Our secondary aim was to compare
78
changes in constipation symptoms among responders and non-responders to FI treatment.
79
Methods: This was a planned secondary analysis of a randomized controlled trial comparing 2
80
first-line therapies for FI in a 2x2 factorial design. Women with at least monthly FI and normal
81
stool consistency were randomized to 4 groups: 1) oral placebo plus education only, 2) oral
82
loperamide plus education only, 3) placebo plus anorectal manometry-assisted biofeedback
83
and 4) loperamide plus biofeedback. Defecatory symptoms were measured using the Patient
84
Assessment of Constipation Symptoms (PAC-SYM) questionnaire at baseline, 12 weeks and 24
85
weeks. The PAC-SYM consists of 12 items that contribute to a global score and 3 subscales:
86
stool characteristics/symptoms (hardness of stool, size of stool, straining, inability to pass
87
stool), rectal symptoms (burning, pain, bleeding, incomplete bowel movement), and abdominal
88
symptoms (discomfort, pain, bloating, cramps). Scores for each subscale as well as the global
89
score range from 0 (no symptoms) to 4 (maximum score), with negative change scores
90
representing improvement in defecatory symptoms. Responders to FI treatment were defined
91
as women with a minimally important clinical improvement of ≥5-points on the St. Mark’s
92
(Vaizey) scale between baseline and 24 weeks. Intent-to-treat analysis was performed using a
93
longitudinal mixed model, controlling for baseline scores, to estimate changes in PAC-SYM
94
scores from baseline through 24 weeks.
95
Results: At 24 weeks, there were small changes in PAC-SYM global scores in all four groups: oral
96
placebo plus education (-0.3; 95% CI -0.5, -0.1), loperamide plus education (-0.1, 95% CI -0.3,
97
0.0), oral placebo plus biofeedback (-0.3, 95% CI -0.4, -0.2), and loperamide plus biofeedback (-
98
0.3, 95% CI -0.4, -0.2). No differences were observed in change in PAC-SYM scores between
99
women randomized to placebo plus education and those randomized to loperamide plus
100
education (p=0.17) or placebo plus biofeedback (p=0.82). Change in PAC-SYM scores in women
101
randomized to combination loperamide plus biofeedback therapy was not different from that
102
of women randomized to treatment with loperamide or biofeedback alone. Responders had
103
greater improvement in PAC-SYM scores than non-responders (-0.4; 95% CI -0.5, -0.3 vs. -0.2;
104
95% CI -0.3, -0.0, p<0.01, mean difference 0.2, 95% CI 0.1, 0.4).
105
Conclusion: Change in constipation symptoms following treatment of FI in women are small and
106
are not significantly different between groups. Loperamide treatment for FI does not worsen
107
constipation symptoms among women with normal consistency stool. Women with clinically
108
significant improvement in FI symptoms report greater improvement in constipation
109
symptoms.
110
111
112
Introduction Defecatory symptoms, especially those associated with constipation, are paradoxically
113
common in women with fecal incontinence. In a series of 262 subjects, 36% of patients
114
presenting primarily with constipation reported fecal incontinence while 34% of subjects
115
presenting primarily with fecal incontinence reported symptoms of constipation (1). The
116
quality of life of subjects with coexisting constipation and fecal incontinence is also significantly
117
worse than either symptom alone (2). The presence of defecatory symptoms such as straining
118
to defecate, feeling of incomplete bowel evacuation, digitation, sensation of blockage, and
119
constipation indicate the presence of an underlying defecation dysfunction. Manometry studies
120
have shown that potential markers of defecation dysfunction, such as poor rectal compliance,
121
are common in women with FI (3). Thus, it is important that providers treating FI understand
122
potential implications of therapies on commonly-coexisting defecatory symptoms.
123
First line treatments for FI include constipating medications, such as loperamide, and
124
pelvic floor physical therapy, with or without anorectal biofeedback. Loperamide has been
125
shown to reduce incontinence episodes and improve symptoms and quality of life but can
126
exacerbate constipation symptoms (4, 5). Pelvic floor physical therapy and anorectal
127
biofeedback have been shown to improve defecatory symptoms such as such as straining and
128
splinting for bowel movements (6). Despite the common coexistence of FI and defecatory
129
symptoms and the potential impact of treatments of FI on defecatory symptoms, well-designed
130
prospective studies exploring the relationship between defecatory symptoms and response to
131
treatment for FI are lacking.
132
We conducted a planned secondary analysis to the Controlling Anal incontinence by Performing
133
Anal Exercises with Biofeedback or Loperamide (CAPABLe) trial (7) to determine the impact of
134
first-line treatments for FI on constipation symptoms. Our primary aim was to compare the
135
changes in constipation symptoms in women randomized to treatment for FI with education
136
only, loperamide, anal muscle exercises with biofeedback, or both loperamide and biofeedback.
137
Our secondary aim was to compare changes in constipation symptoms among women who
138
reported improved FI symptoms and those who did not report improvement in FI symptoms
139
following treatment.
140 141 142
Materials and Methods The CAPABLe trial is a randomized controlled factorial trial conducted between April
143
2014 and April 2016 at 8 sites participating in the Pelvic Floor Disorders Network, sponsored by
144
Eunice Kennedy Shriver National Institute of Child Health and Human Development. The study
145
design has been previously published (8). Women with bothersome FI occurring at least
146
monthly over the preceding 3 months were invited to participate. Women who reported Type 1
147
(hard) or Type 7 (watery) stool consistency over the last 3 months using the Bristol Stool Form
148
were excluded. All sites received IRB approval and all participants gave written informed
149
consent (Clinicaltrials.gov NCT02008565).
150
Enrolled participants underwent a single randomization using a 0.5:1:1:1 allocation to
151
one of four treatment combinations: 1) oral placebo plus education only, 2) oral loperamide
152
plus education only, 3) oral placebo plus anal sphincter exercise training using manometry-
153
assisted biofeedback, and 4) oral loperamide plus anal sphincter exercise training using
154
manometry-assisted biofeedback. All participants were provided education consisting of the
155
publicly available pamphlet from the National Institute of Diabetes and Digestive and Kidney
156
Diseases (NIDDK) with deletion of a single reference to the drug loperamide. The pamphlet
157
discusses symptoms, causes, diagnosis, and treatments including dietary treatment for bowel
158
control problems.
159
Participants not randomized to biofeedback had baseline, 12 and 24 week visits.
160
Participants randomized to biofeedback had visits at baseline, 2, 4, 6, 9, 12 and 24 weeks.
161
Participants randomized to the biofeedback group received an individualized program that
162
included diagnostic anorectal manometry (ARM) evaluation, biofeedback strength training and
163
sensory or urge resistance training (mcompass, Medspira, Minneapolis, MN). Biofeedback
164
participants were prescribed a home exercise program based on their individual performance
165
during the intervention visits. All study interventionists underwent standardized training (9).
166
Participants initially received placebo or 2 mg of oral loperamide (1 capsule) per day
167
with the option of dose escalation up to a maximum of 4 capsules daily and the option of dose
168
reduction due to adverse effects to 1 capsule every other day. Dose escalation, maintenance or
169
reduction was based on balancing efficacy and side effects of treatment using two Likert scales:
170
the Patient Global Symptom Control rating scale (PGSC), “My current treatment is giving me
171
adequate control of my stool leakage” and the Patient Global Tolerability rating Scale (PGTS),
172
“My current medication is giving me bothersome side effects.” Responses on both scales ranged
173
from 1, ‘disagree strongly’ to 5, ‘agree strongly.’ Those women reporting inadequate control of
174
stool leakage and bothersome side effects were instructed to discontinue the study medication
175
but were requested to remain in the study follow-up for the duration. Participants reporting
176
deterioration in FI symptoms after discontinuing the study drug due to side effects were
177
allowed to re-start study drug after an assessment by the site investigator.
178
The primary outcome for CAPABLe was the change from baseline to 24 weeks in the St.
179
Mark’s (Vaizey) FI severity scale. The primary outcome for this secondary study was change
180
from baseline to 24 weeks in the Patient Assessment of Constipation Symptoms (PAC-SYM)
181
global score (10). The PAC-SYM consists of 12 items that contribute to a global score and 3
182
subscales: stool characteristics/ symptoms (hardness of stool, size of stool, straining, inability to
183
pass stool), rectal symptoms (burning, pain, bleeding, incomplete bowel movement), and
184
abdominal symptoms (discomfort, pain, bloating, cramps). Subscales and global scores range
185
from 0 (no symptoms) to 4 (maximum score), with decreasing scores representing
186
improvement in defecatory symptoms. The minimal important difference (MID) for the PAC-
187
SYM questionnaire is -0.6 (21). Secondary outcomes included change from baseline to 24
188
weeks in the PAC-SYM subscale scores. Throughout the study, outcome evaluators were
189
masked to the treatment assignment for the biofeedback intervention. Participants and all
190
study staff other than the research pharmacist were masked to the medication assignment.
191
A responder-to-treatment was defined as any subject that showed the minimally
192
important clinical difference, at least a 5-point decrease, in the St. Mark’s (Vaizey) score at 24
193
weeks (11).
194
Statistical Analysis
195
Women who had constipation symptom outcome data at 12 or 24 weeks were included
196
in analysis. The change from baseline in PAC-SYM global scores at 24 weeks was analyzed using
197
a general linear mixed model. Independent variables included baseline PAC-SYM global score,
198
treatment assignments, interactions between drug and exercise, week 12 or 24, interactions
199
between week and treatment, and clinical site. The model accounted for the dependence
200
between repeated measurements on the same subject by modeling the within-participant
201
covariance structure. Combination treatment (oral loperamide plus anal sphincter exercise
202
training using manometry-assisted biofeedback) was compared to oral loperamide plus
203
education only or oral placebo plus biofeedback alone. Oral loperamide plus education only
204
was compared to oral placebo plus education only, and oral placebo plus biofeedback was
205
compared to oral placebo plus education only. Each comparison was evaluated at a type I error
206
level of 0.05. Box plots were used to explore the relationship between baseline stool
207
consistency (Bristol stool type) and change in PAC-SYM scores from baseline for each treatment
208
group.
209
The change from baseline in PAC-SYM global score at 24 weeks was also compared
210
between responders-to-treatment and non-responders. The baseline PAC-SYM global score was
211
first compared between responders and non-responders using a general linear model with
212
responder status and clinical site as independent variables. The change from baseline in PAC-
213
SYM global scores at 24 weeks was compared for responders and non-responders using a
214
general linear mixed model with responder status, treatment assignments, week 12 or 24,
215
clinical site, and interactions between drug and exercise, week and treatment, and responder
216
status and week as independent variables. The model accounted for the dependence between
217
repeated measurements on the same subject by modeling the within-participant covariance
218
structure. Responders were compared to non-responders at a type I error level of 0.05.
219
Subjects without 24-week data available for the St. Mark’s (Vaizey) score were excluded from
220
the analysis comparing responders and non-responders. The other secondary outcomes, changes in PAC-SYM subscales, were evaluated similarly
221 222
for both comparisons between treatments and between responders and non-responders.
223
Primary and secondary outcomes were analyzed using a modified intent-to-treat principle, with
224
the limitation that only observed outcomes at 12 and 24 weeks were included in analysis. No
225
adjustments were made for performing multiple statistical tests.
226 227
Results In the CAPABLe trial, 296 eligible women were randomized to the following groups: oral
228 229
placebo plus education (n=42), loperamide plus education (n=86), oral placebo plus
230
biofeedback (n=83) and the combined intervention of loperamide plus biofeedback (n=85).
231
Over 83% of participants had defecatory symptom outcome data at 12 or 24 weeks and were
232
included in analysis: oral placebo plus education 35/42 (83%), loperamide plus education 71/86
233
(83%), oral placebo plus biofeedback 69/83 (83%), and loperamide plus biofeedback, 72/85
234
(85%).
235
Baseline demographic and clinical characteristics of participants included in this analysis
236
are presented in Table 1. As expected in a randomized trial, women randomized to placebo plus
237
education did not differ significantly from women randomized to loperamide plus education or
238
oral placebo plus biofeedback. Similarly, baseline characteristics of women who received both
239
active treatments (loperamide plus biofeedback) were not different from women who received
240
one active treatment (loperamide plus education or placebo plus biofeedback) only. Baseline
241
PAC-SYM scores were similar in all groups.
242
All groups demonstrated small improvements in global PAC-SYM scores at 24 weeks:
243
oral placebo plus education (-0.3, 95% CI -0.5, -0.1), loperamide plus education (-0.1, 95% CI -
244
0.3, 0.0), oral placebo plus biofeedback (-0.3, 95% CI -0.4, -0.2) and loperamide plus
245
biofeedback (-0.3, 95% CI -0.4, -0.2). No differences in improvement in PAC-SYM global scores
246
between women randomized to placebo plus education and women randomized to loperamide
247
plus education or oral placebo plus biofeedback were observed (Table 2). Improvement in PAC-
248
SYM global scores in women randomized to combination loperamide plus biofeedback therapy
249
was also not significantly different from improvement in women randomized to loperamide or
250
biofeedback alone (Table 3). Likewise, no differences between groups were noted in the
251
subscales of the PAC-SYM with the exception of the rectal subscale when comparing
252
loperamide plus biofeedback to loperamide plus education. No associations or patterns that
253
might support an association between baseline stool consistency and improvement or
254
worsening of PAC-SYM scores for any of the treatment groups were observed in visual box plots
255
(data not shown).
256
Of the women with FI symptom outcome data at 24 weeks, 137 had clinically significant
257
improvement in Vaizey score (responders) and 129 did not (non-responders). Of these women,
258
124/137 (91%) of responders and 119/129 (92%) of non-responders had PAC-SYM defecatory
259
symptom outcomes available at either 12 or 24 weeks. Responders had greater improvement in
260
global PAC-SYM scores at 24 weeks than non-responders (-0.4; 95% CI -0.5, -0.3 vs. -0.2; 95% CI
261
-0.3, -0.0, mean difference 0.2, 95% CI 0.1, 0.4) despite similar scores at baseline (Tables 4 and
262
5). Responders had greater improvement in the all subscales of the PAC-SYM (Table 5).
263 264
Comments
265
Principal Findings
266
We did not find differences in change in constipation symptoms among women with at
267
least monthly FI and normal stool consistency randomized to loperamide and/or biofeedback
268
compared to placebo plus education. Women who reported improvement in FI symptoms had
269
greater improvement in constipation symptoms as measured by the PAC-SYM compared to
270
those with no improvement in FI symptoms. These findings are useful in understanding the
271
relationship between defecatory symptoms and FI treatments, and provide clinical reassurance
272
that the use of loperamide in women with FI with normal stool consistency does not worsen
273
constipation symptoms as all groups had small improvements in constipation symptoms.
274
Results, Clinical and Research Implications
275
Defecatory symptoms commonly co-exist in women with FI. Several retrospective or
276
cross-sectional community-based studies and surveys in urogynecology clinics demonstrate a
277
significant association between constipation that includes defecatory symptoms and FI (12-15).
278
Studies have also demonstrated that coexisting constipation can modify the response to
279
treatment for fecal incontinence. In a retrospective study of 145 patients treated for FI using
280
biofeedback, symptoms such as straining with bowel movements, use of splinting, and
281
abnormal rectal compliance on anorectal manometry were significantly more common in
282
women who had poor response to treatment (6). Despite lack of controlled studies, clinical
283
guidelines recommend treating women with co-existing FI and underlying evacuation disorders
284
with interventions such as biofeedback to train patients to relax their pelvic floor (16).
285
Unfortunately, these studies and recommendations have not been prospectively studied to
286
assess treatment effect and did not use valid and reliable defecatory symptom-severity scales.
287
In contrast, our study demonstrated that defecatory symptoms do not worsen with
288
treatment with either loperamide or anal muscles exercises with biofeedback and suggest there
289
may be marginal improvement. The biofeedback training protocol in this study included
290
instruction on recto-anal coordination which may have improved evacuation of the rectum.
291
However, it is unclear why women randomized to loperamide did not report higher defecatory
292
symptom severity after treatment compared to women not taking loperamide. One possibility
293
is that loperamide improved stool consistency and this improved efficiency of evacuation.
294
However, we did not notice any association between baseline stool consistency and change in
295
PAC-SYM score in women who received loperamide. Another possible explanation is that
296
loperamide, which in addition to established effects on improving stool consistency, has been
297
shown to affect rectal perception and increase anal sphincter resting and squeeze pressure
298
impacts defecatory symptoms through these mechanisms.(17,18) When anal sphincter
299
pressures are low, stool in the anorectum is sensed at lower volumes (18); thus our findings
300
suggest that loperamide’s effect on increasing sphincter pressure may result in changes in
301
visceral sensitivity leading to improvement in symptoms such as sense of incomplete emptying.
302
Greater improvement in defecatory symptoms in responders compared to non-
303
responders may suggest shared underlying mechanisms between FI and defecatory
304
dysfunction. Women with FI have been shown to have poor rectal compliance indicating the
305
presence of co-existing defecatory dysfunction (3). Additionally, women with symptoms of
306
defecatory dysfunction such as straining for bowel movements and sense of incomplete
307
evacuation, have weaker axial forces not only during expulsion but also during contraction of
308
the pelvic floor muscles, suggesting an increased risk for FI (19). In women where treatments
309
affect these underlying mechanisms, both FI and defecatory symptoms may improve.
310
Alternatively, our finding may reflect the significant impact of functional anorectal disorders on
311
quality of life. In a prior study examining the risk factors for constipation and FI, poor self-rated
312
health and depression were found to be common risk factors for both conditions (20). Thus,
313
women who had improvement in FI severity may have perceived overall subjective
314
improvement in quality of life including defecatory symptoms.
315
Strengths and Limitations
316
The strengths of this study include the prospective study design of women randomly
317
assigned to the two common conservative treatments for FI. Defecatory symptoms were
318
evaluated using a valid, reliable and responsive questionnaire that has been used in other
319
clinical trials to assess patient-reported defecatory dysfunction. Despite the large sample size
320
adequately powered for the primary study (7), there was limited power to detect marginal
321
differences between the combined versus individual treatments and single treatment versus
322
control groups. The study findings are generalizable to women with normal stool consistency
323
who are seeking treatment for FI rather than constipation symptoms and the study did not
324
collect additional objective measures of defecatory dysfunction such as transit studies or
325
balloon testing. Additionally, we excluded women with large rectoceles and we did not assess
326
for high tone dysfunction, two conditions that could impact constipations symptoms and as
327
such our data may not be generalizable to women with those conditions. Further, although all
328
intervention groups as well as the responder group had defecatory symptom improvements
329
compared to baseline, the change in scores did not meet the minimal important difference
330
(MID, -0.6) for the PAC-SYM questionnaire (21). The concept of MID, the smallest difference in
331
score associated with a clinically meaningful improvement, is frequently used in clinical trials to
332
determine whether the difference observed is not only statistically significant but also clinically
333
relevant. The proposed MID of 0.6 for the PAC-SYM was derived from trials evaluating the
334
treatment efficacy of a medication for chronic constipation. Therefore, the improvement in
335
defecatory symptoms observed in the current study may not have the same magnitude of
336
change in symptoms compared to the clinical trials evaluating the treatment of constipation.
337
Conclusion
338
In summary, women seeking treatment for FI had modest improvements in defecatory
339
symptoms, regardless of treatment group. These improvements were more marked in women
340
who reported improvement in FI. In contrast to other studies, the addition of loperamide did
341
not have a negative impact on defecatory symptoms.
342
343 344
Acknowledgements
345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384
We thank the Pelvic Floor Disorders Network Contributors who made this study possible: Cleveland Clinic Mathew D. Barber, Co-Investigator Marie Fidela R. Paraiso, Co-Investigator Mark D. Walters, Co-Investigator Beri Ridgeway, Co-Investigator Brooke Gurland, Co-Investigator Massarat Zutshi, Co-Investigator Geetha Krishnan, Research Nurse Ly Pung, Research Nurse Annette Graham, Research Nurse Alpert Medical School of Brown University-Women & Infant’s Hospital of Rhode Island Vivian W. Sung, Principal Investigator Deborah L. Myers, Co-Investigator Charles R. Rardin, Co-Investigator Cassandra Carberry, Co-Investigator B. Star Hampton, Co-Investigator Kyle Wohlrab, Co-Investigator Ann S. Meers, RN, Research Nurse Duke University Anthony Visco, Principal Investigator Cindy Amundsen, Co-Investigator Alison Weidner, Co-Investigator Nazema Siddiqui, Co-Investigator Amie Kawasaski, Co-Investigator Shantae McLean, Clinical Site Coordinator Nicole Longoria, Clinical Research Coordinator Jessica Carrington, Clinical Research Coordinator Niti Mehta, Clinical Research Specialist Ingrid Harm-Ernandes, Interventionist Jennifer Maddocks, Interventionist Amy Pannullo, Interventionist University of Alabama at Birmingham Alayne Markland, Primary Investigator Holly E. Richter, Co- investigator R. Edward Varner, Co-Investigator Robert Holley, Co-Investigator
385 386 387 388 389 390 391 392 393 394 395 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428
L. Keith Lloyd, Co-Investigator Tracy S. Wilson, Co-Investigator Alicia Ballard, Co-Investigator Jeannine McCormick, Interventionist Velria Willis, Research Nurse Nancy Saxon, Research Nurse Kathy Carter, Research Nurse Julie Burge, Research Coordinator Northwest Physician Group, Amarillo, TX Susan Meikle, Co-Investigator University of California, San Diego Charles Nager, Principal Investigator Michael Albo, Co-Investigator Emily Lukacz, Co-Investigator Cindy Furey, Interventionist Patricia Riley, Interventionist JoAnn Columbo, Research Coordinator Sherella Johnson, Research Coordinator Kaiser Permanente – San Diego Shawn Menefee, Co-Investigator Karl Luber, Co-Investigator Gouri Diwadkar, Co-Investigator Jasmine Tan-Kim, Co-Investigator University of New Mexico Yuko Komesu, Co-Investigator Gena Dunivan, Co-Investigator Peter Jeppson, Co-Investigator Sara Cichowski, Co-Investigator Christy Miller, Interventionist Erin Yane, Interventionist Julia Middendorf, Research Nurse Risela Nava, Research Coordinator RTI International Dennis Wallace, Alternate Principal Investigator Amanda Shaffer, Research Operations Manager Poonam Pande, Chemistry, Manufacturing, and Controls Project Leader Kelly Roney, Regulatory Project Leader Ryan E. Whitworth, Statistician Lauren Klein Warren, Statistician
429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472
Kevin A. Wilson, Clinical Research Informatics Project Leader Brenda Hair, Clinical Research Informatics Manager Kendra Glass, Data Manager Daryl Matthews, Data Manager James W. Pickett, II, Programmer Yan Tang, Programmer Tamara L. Terry, Research Services Manager Lynda Tatum, Research Services Supervisor Barbara Bibb, Programmer Jutta Thornberry, Program Manager Kristin Zaterka-Baxter, Clinical Study Specialist Lindsay Morris, Research Coordinator University of Pennsylvania Lily Arya, Principal Investigator Ariana Smith, Co-Investigator Heidi Harve, Co-Investigator Pamela Levin, Co-Investigator Diane K. Newman, Co-Investigator Mary Wang, Interventionist Donna Thompson, Interventionist Teresa Carney, Interventionist Michelle Kinglee, Research Coordinator Lorraine Flick, Research Nurse University of Pittsburgh Halina M. Zyczynski MD, Principle Investigator Pam Moalli PhD, MD, Co-Investigator Gary Sutkin MD, Co-Investigator Jonathan Shepherd MD, Co-Investigator Michael Bonidie MD, Co-Investigator Steven Abo, MD Co-Investigator Janet Harrison MD, Co-Investigator Christopher Chermansky MD, Co-Investigator Lori Geraci, Research Coordinator Judy Gruss, Research Coordinator Karen Mislanovich, Research Coordinator Ellen Eline, Interventionist Beth Klump, Interventionist Susan E. George DPT, Interventionist University of North Carolina at Chapel Hill William E. Whitehead Ph.D., Co-Investigator
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10. Frank L, Kleinman L, Farup C, Taylor L, Miner P,Jr. Psychometric validation of a constipation symptom assessment questionnaire. Scand J Gastroenterol. 1999 Sep;34(9):870-7. 11. Bols EM, Hendriks EJ, Deutekom M, et al. Inconclusive psychometric properties of the Vaizey score in fecally incontinent patients: A prospective cohort study. Neurourol Urodyn 2010;29:370–7.
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12. Damon H, Guye O, Seigneurin A, Long F, Sonko A, Faucheron JL, et al. Prevalence of anal incontinence in adults and impact on quality-of-life. Gastroenterol Clin Biol 2006 Jan;30(1):37-43. 13. Bharucha AE, Seide BM, Zinsmeister AR, Melton LJ, 3rd. Relation of bowel habits to fecal incontinence in women. Am J Gastroenterol 2008 Jun;103(6):1470-5.
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14. Bharucha AE, Zinsmeister AR, Schleck CD, Melton LJ, 3rd. Bowel disturbances are the most important risk factors for late onset fecal incontinence: a population-based case-control study in women. Gastroenterology 2010 Nov;139(5):1559-66.
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15. Boreham MK, Richter HE, Kenton KS, Nager CW, Gregory WT, Aronson MP, et al. Anal incontinence in women presenting for gynecologic care: prevalence, risk factors, and impact upon quality of life. Am J Obstet Gynecol 2005 May;192(5):1637-42.
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21. Yiannakou Y. et al. The PAC-SYM questionnaire for chronic constipation: defining the minimal important difference. Aliment Pharmacol Ther. 2017 Dec; 46(11-12): 1103–1111.
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Table 1. Demographics: Baseline clinical and demographic characteristics of participants in placebo, individual treatment, and combined treatment groups. Placebo - Education Only (N=35)
Loperamide Education Only (N=71)
Placebo - Exercise plus Biofeedback (N=69)
Loperamide Exercise plus Biofeedback (N=72)
Baseline Characteristic
Baseline Characteristic
Baseline Characteristic
Baseline Characteristic
62.5 (10.5) [40.2, 83.3]
62.5 (10.7) [38.1, 83.3]
65.5 (10.3) [39.7, 93.4]
63.6 (12.4) [27.5, 87.6]
American Indian/Alaskan Native
2 (5.7)
0 (0.0)
1 (1.4)
0 (0.0)
Black/African American
6 (17.1)
10 (14.1)
10 (13.9)
9 (13.0)
More than one race
0 (0.0)
0 (0.0)
4 (5.6)
1 (1.4)
Other
2 (5.7)
2 (2.8)
1 (1.4)
2 (2.9)
White
25 (71.4)
59 (83.1)
56 (77.8)
57 (82.6)
2 (5.7)
7 (9.9)
7 (9.7)
7 (10.1)
32 (91.4)
63 (88.7)
64 (88.9)
61 (88.4)
1 (2.9)
1 (1.4)
1 (1.4)
1 (1.4)
Prior accidental bowel leakage surgery, No(%)
0 (0.0)
4 (5.6)
3 (4.2)
5 (7.2)
Prior rectal or anal surgery, No. (%)
7 (20.6)
6 (8.6)
12 (17.1)
8 (11.6)
BMI, mean (SD) [min, max]
30.5 (9.0) [20.2, 62.1]
31.0 (6.7) [20.2, 48.5]
29.9 (6.7) [19.5, 55.0]
28.8 (6.6) [17.1, 43.2]
Dietary Fiber Score, mean (SD) [min, max]
15.1 (7.3) [2.0, 33.0]
15.3 (6.3) [4.0, 31.0]
16.5 (6.4) [4.0, 41.0]
16.1 (5.8) [5.0, 29.0]
Daily fiber intake, mean (SD) [min, max]
14.6 (5.4) [4.9, 27.8]
14.7 (4.7) [6.4, 26.3]
15.6 (4.7) [6.4, 33.7]
15.3 (4.3) [7.1, 24.9]
Type 2. Sausage shaped but lumpy
6 (17.1)
6 (8.5)
16 (22.2)
5 (7.2)
Type 3. Like a sausage or snake but with cracks on
2 (5.7)
14 (19.7)
9 (12.5)
10 (14.5)
Type 4. Like a sausage or snake, smooth and soft
14 (40.0)
24 (33.8)
20 (27.8)
25 (36.2)
Type 5. Soft blobs with clear cut edges
5 (14.3)
13 (18.3)
12 (16.7)
15 (21.7)
Type 6. Fluffy pieces with ragged edges, a mushy s
8 (22.9)
14 (19.7)
15 (20.8)
14 (20.3)
5 (14.3)
14 (19.7)
14 (19.4)
15 (21.7)
Endpoint
Category
Age, mean (SD) [min, max], y Race, No. (%)
Ethnicity, No. (%)
Hispanic/Latina Not Hispanic/Not Latina Unknown/Not Reported
Bristol Stool Index, No. (%)
Rome III IBS Clinical Status, No. (%)
Endpoint PAC-SYM Scores, mean (SD) [min, max]
542 543
Placebo - Education Only (N=35)
Loperamide Education Only (N=71)
Placebo - Exercise plus Biofeedback (N=69)
Loperamide Exercise plus Biofeedback (N=72)
Baseline Characteristic
Baseline Characteristic
Baseline Characteristic
Baseline Characteristic
Stool Score
1.1 (0.8) [0.0, 2.6]
1.2 (0.8) [0.0, 2.8]
0.9 (0.9) [0.0, 3.8]
1.1 (0.8) [0.0, 2.8]
Rectal Score
0.8 (0.8) [0.0, 2.7]
0.7 (0.7) [0.0, 2.7]
0.9 (0.7) [0.0, 3.3]
0.7 (0.7) [0.0, 2.3]
Abdominal Score
1.0 (1.1) [0.0, 3.5]
1.1 (0.9) [0.0, 3.3]
1.1 (0.8) [0.0, 3.4]
0.9 (0.8) [0.0, 3.0]
Global Score
1.0 (0.7) [0.0, 2.7]
1.1 (0.7) [0.0, 2.6]
0.7 (0.8) [0.0, 3.0]
0.9 (0.6) [0.0, 2.5]
Category
544 545
Table 2. Change in PAC-SYM at 24 weeks for Placebo versus Loperamide and Placebo versus Biofeedback Placebo- Education (N=35)
Loperamide - Education (N=71)
Placebo - Biofeedback (N=69)
Change in PAC-SYM Score
Mean Change from Baseline(95% CI)
Mean Change from Baseline(95% CI)
P-value for Comparison
Mean Change from Baseline(95% CI)
P-value for Comparison
Change in PAC-SYM Abdominal Score
-0.4 (-0.7, -0.2)
-0.2 (-0.3, 0.0)
0.052
-0.3 (-0.5, -0.2)
0.537
Change in PAC-SYM Rectal Score
-0.3 (-0.5, -0.1)
-0.1 (-0.2, 0.0)
0.125
-0.3 (-0.5, -0.2)
0.677
Change in PAC-SYM Stool Score
-0.2 (-0.4, 0.0)
-0.2 (-0.3, 0.0)
0.878
-0.3 (-0.4, -0.1)
0.379
Change in PAC-SYM Global Score
-0.3 (-0.5, -0.1)
-0.1 (-0.3, 0.0)
0.169
-0.3 (-0.4, -0.2)
0.819
546 547 548 549
Table 3: Change in PAC-SYM at 24 weeks for Combined Loperamide and Biofeedback versus Loperamide only and Biofeedback only Loperamide Biofeedback (N=72)
550 551 552 553 554 555
Loperamide - Education (N=71)
Placebo - Biofeedback (N=69)
Change in PAC-SYM Score
Mean Change from Baseline(95% CI)
Mean Change from Baseline(95% CI)
P-value for Compa rison
Mean Change from Baseline(95% CI)
P-value for Compa rison
Change in PAC-SYM Abdominal Score
-0.3 (-0.5, -0.1)
-0.2 (-0.3, 0.0)
0.257
-0.3 (-0.5, -0.2)
0.616
Change in PAC-SYM Rectal Score
-0.4 (-0.5, -0.1)
-0.1 (-0.2, 0.0)
0.010
-0.3 (-0.5, -0.2)
0.862
Change in PAC-SYM Stool Score
-0.2 (-0.4, 0.0)
-0.2 (-0.3, 0.0)
0.549
-0.3 (-0.4, -0.1)
0.499
Change in PAC-SYM Global Score
-0.3 (-0.4, -0.2)
-0.1 (-0.3, 0.0)
0.147
-0.3 (-0.4, -0.2)
0.600
556
Table 4. Baseline PAC-SYM scores in responders and non-responders to treatment for FI Responders
Non-Responders
(N=124)
(N=119)
Baseline PAC-SYM Score
Mean (95% CI)
Mean(95% CI)
PAC-SYM Abdominal Score
1.06 (0.89, 1.23)
0.88 (0.70, 1.06)
0.127
PAC-SYM Rectal Score
0.67 (0.52, 0.81)
0.67 (0.52, 0.81)
0.992
PAC-SYM Stool Score
1.10 (0.95, 1.25)
1.14 (0.99, 1.30)
0.675
PAC-SYM Global Score
0.98 (0.85, 1.11)
0.94 (0.80, 1.07)
0.641
P-value for Comparison
557 558 559 560
Table 5. Change in PAC-SYM scores at 24 weeks in responders and non-responders to treatment for FI Responders
Non-Responders
(N=124)
(N=119)
Mean Change from Baseline (95% CI)
Mean Change from Baseline (95% CI)
Change in PAC-SYM Abdominal Score
-0.48 (-0.63, -0.32)
-0.17 (-0.33, -0.01)
0.005
Change in PAC-SYM Rectal Score
-0.37 (-0.50, -0.24)
-0.16 (-0.29, -0.03)
0.020
Change in PAC-SYM Stool Score
-0.34 (-0.47, -0.20)
-0.13 (-0.26, 0.01)
0.022
Change in PAC-SYM Global Score
-0.39 (-0.50, -0.28)
-0.15 (-0.26, -0.03)
0.002
Change in PAC-SYM Score
561 562 563 564 565 566
P-value for Comparison