<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03811821</url>
  </required_header>
  <id_info>
    <org_study_id>17-0525</org_study_id>
    <secondary_id>1U01DK115575-01</secondary_id>
    <nct_id>NCT03811821</nct_id>
  </id_info>
  <brief_title>Fecal Incontinence Treatment (FIT) Study</brief_title>
  <official_title>Comparative Effectiveness of Biofeedback and Injectable Bulking Agents for Treatment of Fecal Incontinence: The Fecal Incontinence Treatment (FIT) Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of North Carolina, Chapel Hill</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
    <collaborator>
      <agency>Mayo Clinic</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Colon and Rectal Surgery Associates, Ltd.</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Augusta University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>RTI International</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of North Carolina, Chapel Hill</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>Yes</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Patients with severe fecal incontinence (FI), defined as two or more episodes of staining,&#xD;
      solid or liquid FI per week, and who meet the inclusion criteria for Injection of Solesta&#xD;
      (INJ; an inert bulking agent), or Biofeedback (BIO) will be enrolled. The baseline rate of FI&#xD;
      will be assessed using a 2-week daily stool diary. All participants will initially be&#xD;
      enrolled into a 4-week trial of Enhanced Medical Management (EMM; education, pelvic floor&#xD;
      exercises, and use of non-prescription drugs to normalize stool consistency). Those who&#xD;
      demonstrate at least a 75% reduction in FI frequency will not be randomized to one of the two&#xD;
      treatment groups but will be followed-up for two years. Those not showing a 75% reduction in&#xD;
      FI frequency will be randomized to BIO or INJ and will be evaluated three months later with&#xD;
      respect to efficacy for reducing the frequency of fecal incontinence, safety of the&#xD;
      interventions, and cost of providing care. All participants who experience a 75% decrease in&#xD;
      FI after three months of treatment, compared to baseline, will be followed-up for a further&#xD;
      21 months, for a total of 24 months from the time of treatment initiation. To assess the&#xD;
      long-term response to treatment, those who improve less than 75% in FI episodes will be&#xD;
      offered an additional treatment with either the treatment to which they were not randomized&#xD;
      or sacral nerve stimulation (SNS). Anorectal manometry and Magnetic Evoked Potentials will be&#xD;
      used to subtype the physiological basis for FI. Quality of life and psychological factors&#xD;
      will be used to assess outcomes.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is an unmasked, multisite, randomized, parallel group study comparing the effectiveness&#xD;
      of two treatments [BIO and INJ] for moderate to severe FI:&#xD;
&#xD;
        1. Baseline: Participants will keep a daily symptom diary for two weeks to (a) document&#xD;
           that they meet the minimum frequency required for inclusion in the study and (b) provide&#xD;
           a reference value for assessing treatment response at the end of EMM and at 3, 6, 12,&#xD;
           and 24 months follow-up points.&#xD;
&#xD;
        2. EMM: All participants meeting inclusion criteria will first be treated with EMM for 4&#xD;
           weeks. The key components of treatment are patient education about the basic&#xD;
           physiological mechanisms for defecation, diet and medication to normalize stool&#xD;
           consistency, and pelvic floor exercises taught by printed instructions. Additional goals&#xD;
           of the EMM protocol are (a) to ensure that participants randomized to BIO or INJ meet&#xD;
           the accepted criteria for these treatments by failing to respond to EMM, and (b) to&#xD;
           document the efficacy and the durability of systematically applied, optimized EMM.&#xD;
           Patients who are responders to EMM will be followed up 3 months later; those who remain&#xD;
           responders will be continued on EMM and followed for the remaining 24 months of the&#xD;
           study. However, those who are no longer responders to this conservative treatment after&#xD;
           3 months will be invited to be randomized to BIO or INJ and all outcome measures will be&#xD;
           assessed at 3 months from initiation of the treatment arm to which they are randomized.&#xD;
           They will be pooled with other patients randomly assigned to the same treatment for the&#xD;
           primary analyses and will be assessed at 6 months.&#xD;
&#xD;
        3. Randomly assigned treatment: Each participant who fails the EMM will be randomly&#xD;
           assigned to BIO or INJ and treated as follows:&#xD;
&#xD;
             -  BIO will consist of 5-6 one-hour training sessions spaced at weekly intervals.&#xD;
                These will occur in the first 5-6 weeks of treatment. Treatment approaches will&#xD;
                include strength training in all participants, sensory training for participants&#xD;
                with hyposensitivity, and/or urge-resistance training for participants with&#xD;
                hypersensitivity to the sensations caused by rectal distention. Home exercises will&#xD;
                be assigned to participants to practice these skills, and these will be guided by a&#xD;
                brochure.&#xD;
&#xD;
             -  INJ will include a preparation for treatment and a treatment visit. The preparation&#xD;
                will involve prophylactic antibiotics for the day of the procedure and minimal&#xD;
                restrictions on food intake. On the day of the procedure, a physician will inject 1&#xD;
                ml of dextranomer into each of 4 quadrants of the rectum proximal to the dentate&#xD;
                line. Ten seconds will be allowed to pass before the injection needle is withdrawn&#xD;
                to minimize drainage of the dextranomer. The participant will be scheduled to&#xD;
                return in 6 weeks for possible repeat injection of a second 4 ml of dextranomer. At&#xD;
                this second appointment, if FI has improved by 75% or more compared to baseline,&#xD;
                the participant will be continued without a second injection. However, if the rate&#xD;
                of FI is greater than 75% of baseline, the participant will be offered a second&#xD;
                injection of dextranomer.&#xD;
&#xD;
        4. Combination therapy: The primary assessment of efficacy is at 3 months following the&#xD;
           first treatment visit completed, and participants who have not achieved at least a 75%&#xD;
           reduction in FI frequency compared to baseline will be classified as treatment failures;&#xD;
           they will be invited to choose the treatment to which they were not randomized or SNS as&#xD;
           an adjunctive treatment for the remaining months of the study. One reason for this is to&#xD;
           increase the likelihood that participant will consent to be randomized despite possibly&#xD;
           having a priori preferences for one of the two treatments. Thus, the participants who&#xD;
           add a second treatment and continue to be monitored up to 24 months will constitute a&#xD;
           pragmatic clinical trial (i.e., the study design for these participants going forward&#xD;
           emulates the clinical situation in which patients who have an unsatisfactory response to&#xD;
           a treatment are offered a new treatment or an ancillary treatment).&#xD;
&#xD;
        5. Long-term follow-up: An intention-to-treat analysis of efficacy will be carried out at&#xD;
           6, 12 and 24 months. For these analyses, all participants randomized to treatment will&#xD;
           be included in the analysis. All treatments will continue to be active. The bulking&#xD;
           agents injected in the INJ treatment will remain in place. For BIO, participants will be&#xD;
           encouraged to continue to practice pelvic floor exercises and enhanced awareness of&#xD;
           rectal sensations following the initial training period. Participants who withdraw from&#xD;
           the study or who fail treatment at 3 months will be evaluated as treatment failures in&#xD;
           follow-up analyses of efficacy. Data will be collected from participants who add an&#xD;
           alternative treatment at 3 months, but these data will not be considered in this&#xD;
           analysis. Safety data will be collected at every visit. Participants who are responders&#xD;
           at 3 months will continue to monitor symptoms for an additional 21 months (2 years&#xD;
           total) whereas participants who are non-responders at 3 months will be retained as&#xD;
           treatment failures in the long-term analysis of the comparative effectiveness of the BIO&#xD;
           and INJ treatments. For longitudinal assessments of safety, cost, and secondary outcomes&#xD;
           such as quality of life and FI severity scales, statistical models will include data&#xD;
           from follow up time points through 24 months.&#xD;
&#xD;
        6. Adjust for Expectation of Benefit: In a trial comparing behavioral and medical therapy,&#xD;
           participants cannot be masked. The validated Credibility/Expectancy Questionnaire was&#xD;
           developed to assess the patient's expectation of benefit after initial exposure to&#xD;
           treatment and was used in previous studies to determine whether there is equipoise&#xD;
           between the active and control conditions in behavioral treatment trials.&#xD;
&#xD;
        7. Characterization of Enhanced Medical Treatment - Durability of improvement and&#xD;
           predictors of response: The primary purpose of treating all participants with an EMM&#xD;
           run-in is to be able to exclude participants who do not require more costly&#xD;
           interventions. However, the investigators will take advantage of the opportunity&#xD;
           provided by this run-in study to identify predictors of response to EMM and to assess&#xD;
           the durability of improvements. EMM will not be &quot;usual care&quot; but will follow a written&#xD;
           protocol that is intended to optimize EMM, which is why this is labelled enhanced&#xD;
           medical management. Participants who are treatment responders at the end of the EMM&#xD;
           run-in will be scheduled for 3-month follow-up, and those who are no longer treatment&#xD;
           responders at 3 months follow-up will be offered an opportunity to be randomized to one&#xD;
           of the 3 treatments at this point. However, those who remain responders to EMM at 3&#xD;
           months follow-up will continue to be followed for an additional 21 months. All&#xD;
           participants, regardless of their outcomes at the end of EMM, will be encouraged to&#xD;
           continue using the treatment approaches learned during the EMM phase.&#xD;
&#xD;
      Each participant will be studied for 24-27 months after completing the month of EMM and the&#xD;
      anticipated duration of the study is 4.5 years from first enrollment to completion of the&#xD;
      last participant. Approximately 285 adult participants, both male and female, will be&#xD;
      recruited for EMM to ensure that 194 participants who did not benefit from EMM will be&#xD;
      available for randomization to the two treatment arms (97 per treatment arm). The&#xD;
      participants may be referred by clinicians or may respond to posted advertisements about the&#xD;
      study.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">February 1, 2019</start_date>
  <completion_date type="Anticipated">December 31, 2025</completion_date>
  <primary_completion_date type="Anticipated">March 31, 2024</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>Participants who do not demonstrate at least a 75% reduction in FI following a 4-week trial of EMM will be randomized to one of two treatments (INJ or BIO) and assessed after three months. All participants who experience a 75% decrease in FI after three months of treatment, compared to baseline, will then be followed-up for two years. To assess the long-term response to treatment, those who demonstrate an improvement of less than 75% in FI episodes will be offered an additional treatment with either the treatment to which they were not initially randomized or SNS.&#xD;
An anticipated 285 participants will be enrolled in the EMM to ensure a sample size of 97 in each of the two treatments arms.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Treatment Response Defined as a 75% or Greater Change in Number of Average Weekly FI Episodes at Month 3 Follow-Up Compared to Baseline</measure>
    <time_frame>3-month follow-up</time_frame>
    <description>FI episodes will be assessed using a validated symptom diary at Baseline and at three months follow-up.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Proportion of Participants with Specified Adverse Events at Month 3 Follow-Up</measure>
    <time_frame>3-month follow-up</time_frame>
    <description>Adverse events of pelvic pain of grade II or higher based on Common Terminology Criteria for AE (CTCAE) criteria, treatment site infection, or serious adverse events (SAEs) requiring hospitalization.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Treatment Costs at Month 3 Follow-Up</measure>
    <time_frame>3-month follow-up</time_frame>
    <description>Costs will be measured from three sources: (a) Number of treatment visits multiplied by the Medicare reimbursement rates. (b) An Out-of-Pocket Treatment Cost Questionnaire. (c) A Work Productivity and Impairment Questionnaire for direct and indirect costs. These costs will be combined to establish overall costs.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in the Severity of FI as Assessed Using the Fecal Incontinence Severity Scale</measure>
    <time_frame>up to 24 months</time_frame>
    <description>Treatment effect on the severity of FI at 3-month follow-up, compared to baseline, will be assessed using the Fecal Incontinence Severity Scale, a validated FI severity scale which incorporates the frequency of different types of stool loss (solid, liquid, staining and a combination), the circumstances surrounding FI (urgency, passive, combined, or neither), and volume of leakage. Higher scores indicate more severe fecal incontinence. Assessed at Baseline, Months 6, 12, and 24.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Quality of Life as Assessed Using the Fecal Incontinence Quality of Life Scale</measure>
    <time_frame>up to 24 months</time_frame>
    <description>Treatment effect on the impact of FI on quality of life will be assessed using the Fecal Incontinence Quality of Life Scale which contains 29 items and is scored for four subscales: Lifestyle, Coping/Behavior, Depression/Self-Perception, and Embarrassment. Scores for each item range from 1 - 4 with 1 indicating a lower functional status of quality of life. Scale scores are the average (mean) response to all items after adjusting for missing and not applicable items. Assessed at Baseline, Months 6, 12, and 24.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Psychological Distress as Assessed Using the 7-item Patient-Reported Outcomes Measurement Information System (PROMIS) Anxiety Scale</measure>
    <time_frame>up to 24 months</time_frame>
    <description>One of the measures of psychological distress is the 7-item PROMIS Anxiety Scale for which higher scores indicate higher levels of anxiety. The Anxiety Scale (SF 7a) has a score range of 5 - 35. Assessed at Baseline, Months 6, 12, and 24.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Psychological Distress as Assessed Using the 8-item PROMIS Depression Scale</measure>
    <time_frame>up to 24 months</time_frame>
    <description>One of the measures of psychological distress is the 8-item PROMIS Depression Scale for which higher scores indicate higher levels of depression. The Depression Scale (SF 8a) has a score range of 5 - 40. Assessed at Baseline, Months 6, 12, and 24.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Psychological Distress as Assessed Using the 8-item PROMIS Self-Efficacy Symptom Management Scale</measure>
    <time_frame>up to 24 months</time_frame>
    <description>One of the measures of psychological distress is the 8-item PROMIS Self-Efficacy Symptom Management Scale for which higher scores indicate higher levels of self-efficacy. The Self-Efficacy for Managing Symptoms Scale (SF 8a) has a score range of 5 - 40. Assessed at Baseline, Months 6, 12, and 24.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants with Reduction of 50% or More in Average Weekly FI Episodes</measure>
    <time_frame>up to 24 months</time_frame>
    <description>Assessed at Baseline, Months 6, 12, and 24.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of Participants Who are Continent</measure>
    <time_frame>up to 24 months</time_frame>
    <description>Assessed at Baseline, Months 6, 12, and 24.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">285</enrollment>
  <condition>Fecal Incontinence</condition>
  <condition>Bowel Incontinence</condition>
  <arm_group>
    <arm_group_label>Biofeedback (BIO)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Participants will receive biofeedback intervention during five (5) required weekly 1-hour sessions. A 6th treatment session will be made available for participants if it is shown through anorectal manometry that they are having trouble understanding directions given during the first five sessions.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Injection (INJ)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Bulking agent injected into rectal wall to narrow opening. Two visits each lasting 45 minutes at weeks 0 and 6 respectively.</description>
  </arm_group>
  <intervention>
    <intervention_type>Behavioral</intervention_type>
    <intervention_name>Biofeedback</intervention_name>
    <description>The participant will learn how to improve strength and rectal sensation during five (5) - six (6) visits each lasting 60 minutes.</description>
    <arm_group_label>Biofeedback (BIO)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Injection</intervention_name>
    <description>The participant will have a bulking agent injected into rectal wall to narrow opening. Two visits each lasting 45 minutes at weeks 0 and 6 respectively.</description>
    <arm_group_label>Injection (INJ)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Physician diagnosis of FI (R15) for the past 6 months or longer.&#xD;
&#xD;
          -  Able to ambulate independently on level surfaces. Patient may use assistive devices&#xD;
             other than parallel bars.&#xD;
&#xD;
          -  Average &gt;2 staining, solid or liquid FI episodes per week by self-report and during&#xD;
             the two-week baseline&#xD;
&#xD;
          -  Meets criteria for dextranomer treatment except an internal anal sphincter defect of&#xD;
             180 degrees or less is acceptable.&#xD;
&#xD;
          -  Less than 75% reduction in the number of FI episodes after 4 weeks of conservative&#xD;
             treatment.&#xD;
&#xD;
          -  Age &gt;=18 years&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Dementia, assessed using the Six-Item Screener to Identify Cognitive Impairment.&#xD;
&#xD;
          -  Obstetrical injuries including third and fourth degree tears in the anal sphincter&#xD;
             within the past 6 months.&#xD;
&#xD;
          -  Pregnant or planning pregnancy in next 2 years&#xD;
&#xD;
          -  Internal anal sphincter separation &gt;180 degrees on ultrasound or magnetic resonance&#xD;
             imaging&#xD;
&#xD;
          -  Spinal cord injury or spina bifida&#xD;
&#xD;
          -  Congenital malformation of anus or rectum&#xD;
&#xD;
          -  Complete rectal prolapse or grade III/IV hemorrhoids&#xD;
&#xD;
          -  History of ileoanal pouch; history of anal sphincteroplasty, rectopexy, or rectocele&#xD;
             repair within the past 6 months; or history of pelvic surgery with synthetic graft and&#xD;
             suspected graft erosion into the anus, rectum, or skin or if the graft ends less than&#xD;
             approximately 1&quot; above the upper limit of the anal canal.&#xD;
&#xD;
          -  Established diagnosis of inflammatory bowel disease&#xD;
&#xD;
          -  Intestinal stoma present&#xD;
&#xD;
          -  History of pelvic radiation within previous 12 months or presence of active radiation&#xD;
             proctitis.&#xD;
&#xD;
          -  Patients who cannot expel the rectal balloon during the balloon expulsion test and who&#xD;
             have constipation most of the time.&#xD;
&#xD;
          -  Anatomic limitations to placement of dextranomer injections.&#xD;
&#xD;
          -  Presence of existing implant in the anal or rectal region&#xD;
&#xD;
          -  Allergy to hyaluronic acid-based products&#xD;
&#xD;
          -  Active anal or rectal conditions in the last 6 months including abscess, fissures,&#xD;
             sepsis, significant bleeding, proctitis, colovaginal and rectovaginal fistulas, anal&#xD;
             or rectal tumors, or other infections.&#xD;
&#xD;
          -  The patient's physician believes it is unsafe for the patient to temporarily stop&#xD;
             anticoagulants for any test procedures and treatments associated with the study.&#xD;
&#xD;
          -  Patients who have 4 or more days with 4 or more bowel movements classed as a 6 or 7 on&#xD;
             the Bristol Stool Scale per day in either (any) week bowel movements classed as a 6 or&#xD;
             7 during the Baseline will be excluded.&#xD;
&#xD;
          -  Patients with Parkinson's disease, multiple sclerosis, severe diabetic neuropathy&#xD;
             documented by electromyography (EMG), and neurodegenerative disorder.&#xD;
&#xD;
          -  Patients currently receiving immunotherapy or chemotherapy.&#xD;
&#xD;
          -  Significant anal pain in the last 6 months.&#xD;
&#xD;
          -  Unwillingness of participant to stop using over-the-counter medications, herbal&#xD;
             supplements, or prescribed medications for the purpose of modifying stool consistency,&#xD;
             that are not included in the approved medications list (loperamide, laxatives, fiber&#xD;
             supplements, and Questran are approved medications), for the duration of the research&#xD;
             study.&#xD;
&#xD;
        Medical history will be documented to test for predictors of response.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Adil Bharucha, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Mayo Clinic</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Adil Bharucha, MD</last_name>
    <phone>507-284-2511</phone>
    <email>bharucha.adil@mayo.edu</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Marie Gantz, PhD</last_name>
    <phone>919-597-5110</phone>
    <email>mgantz@rti.org</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>University of Alabama at Birmingham</name>
      <address>
        <city>Birmingham</city>
        <state>Alabama</state>
        <zip>35801</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Isuzu Meyer, MD, MSPH</last_name>
      <phone>205-934-1704</phone>
      <email>imeyer@uabmc.edu</email>
    </contact>
    <investigator>
      <last_name>Isuzu Meyer, MD, MSPH</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Augusta University Medical College of Georgia</name>
      <address>
        <city>Augusta</city>
        <state>Georgia</state>
        <zip>30912</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Satish Rao, MD, PhD</last_name>
      <phone>706-721-0207</phone>
      <email>SRAO@augusta.edu</email>
    </contact>
    <investigator>
      <last_name>Satish Rao, MD, PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>University of Michigan</name>
      <address>
        <city>Ann Arbor</city>
        <state>Michigan</state>
        <zip>48109</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>William Chey, MD</last_name>
      <phone>734-763-9337</phone>
      <email>wchey@med.umich.edu</email>
    </contact>
    <investigator>
      <last_name>William Chey, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Mayo Clinic</name>
      <address>
        <city>Rochester</city>
        <state>Minnesota</state>
        <zip>55905</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Adil Bharucha, MBBS, MD</last_name>
      <phone>507-284-2511</phone>
      <email>bharucha.adil@mayo.edu</email>
    </contact>
    <investigator>
      <last_name>Adil Bharucha, MBBS, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Colon and Rectal Surgery Associates, Ltd.</name>
      <address>
        <city>Saint Paul</city>
        <state>Minnesota</state>
        <zip>55114</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Terminated</status>
  </location>
  <location>
    <facility>
      <name>The University of North Carolina at Chapel Hill</name>
      <address>
        <city>Chapel Hill</city>
        <state>North Carolina</state>
        <zip>27599</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Active, not recruiting</status>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>September 2023</verification_date>
  <study_first_submitted>January 17, 2019</study_first_submitted>
  <study_first_submitted_qc>January 18, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 22, 2019</study_first_posted>
  <last_update_submitted>September 11, 2023</last_update_submitted>
  <last_update_submitted_qc>September 11, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">September 13, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Accidental Bowel Leakage</keyword>
  <keyword>Fecal Incontinence</keyword>
  <keyword>Biofeedback</keyword>
  <keyword>Sacral Nerve Stimulation</keyword>
  <keyword>Injectable Bulking Agents</keyword>
  <keyword>Enhanced Medical Management</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Fecal Incontinence</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>Deidentified individual data that supports the results will be shared beginning 9 to 36 months following publication provided the investigator who proposes to use the data has approval from an Institutional Review Board (IRB), Independent Ethics Committee (IEC), or Research Ethics Board (REB), as applicable, and executes a data use/sharing agreement with the University of North Carolina (UNC).</ipd_description>
    <ipd_time_frame>9 to 36 months following publication</ipd_time_frame>
    <ipd_access_criteria>Following approval from an appropriate review board as described above and execution of a data use/sharing agreement with UNC-Chapel Hill.</ipd_access_criteria>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03811821
org study id: 17-0525
secondary id: 1U01DK115575-01
nct id: NCT03811821
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: Yes
is us export: No
Patients with severe fecal incontinence (FI), defined as two or more episodes of staining,
      solid or liquid FI per week, and who meet the inclusion criteria for Injection of Solesta
      (INJ; an inert bulking agent), or Biofeedback (BIO) will be enrolled. The baseline rate of FI
      will be assessed using a 2-week daily stool diary. All participants will initially be
      enrolled into a 4-week trial of Enhanced Medical Management (EMM; education, pelvic floor
      exercises, and use of non-prescription drugs to normalize stool consistency). Those who
      demonstrate at least a 75% reduction in FI frequency will not be randomized to one of the two
      treatment groups but will be followed-up for two years. Those not showing a 75% reduction in
      FI frequency will be randomized to BIO or INJ and will be evaluated three months later with
      respect to efficacy for reducing the frequency of fecal incontinence, safety of the
      interventions, and cost of providing care. All participants who experience a 75% decrease in
      FI after three months of treatment, compared to baseline, will be followed-up for a further
      21 months, for a total of 24 months from the time of treatment initiation. To assess the
      long-term response to treatment, those who improve less than 75% in FI episodes will be
      offered an additional treatment with either the treatment to which they were not randomized
      or sacral nerve stimulation (SNS). Anorectal manometry and Magnetic Evoked Potentials will be
      used to subtype the physiological basis for FI. Quality of life and psychological factors
      will be used to assess outcomes.
This is an unmasked, multisite, randomized, parallel group study comparing the effectiveness
      of two treatments [BIO and INJ] for moderate to severe FI:

        1. Baseline: Participants will keep a daily symptom diary for two weeks to (a) document
           that they meet the minimum frequency required for inclusion in the study and (b) provide
           a reference value for assessing treatment response at the end of EMM and at 3, 6, 12,
           and 24 months follow-up points.

        2. EMM: All participants meeting inclusion criteria will first be treated with EMM for 4
           weeks. The key components of treatment are patient education about the basic
           physiological mechanisms for defecation, diet and medication to normalize stool
           consistency, and pelvic floor exercises taught by printed instructions. Additional goals
           of the EMM protocol are (a) to ensure that participants randomized to BIO or INJ meet
           the accepted criteria for these treatments by failing to respond to EMM, and (b) to
           document the efficacy and the durability of systematically applied, optimized EMM.
           Patients who are responders to EMM will be followed up 3 months later; those who remain
           responders will be continued on EMM and followed for the remaining 24 months of the
           study. However, those who are no longer responders to this conservative treatment after
           3 months will be invited to be randomized to BIO or INJ and all outcome measures will be
           assessed at 3 months from initiation of the treatment arm to which they are randomized.
           They will be pooled with other patients randomly assigned to the same treatment for the
           primary analyses and will be assessed at 6 months.

        3. Randomly assigned treatment: Each participant who fails the EMM will be randomly
           assigned to BIO or INJ and treated as follows:

             -  BIO will consist of 5-6 one-hour training sessions spaced at weekly intervals.
                These will occur in the first 5-6 weeks of treatment. Treatment approaches will
                include strength training in all participants, sensory training for participants
                with hyposensitivity, and/or urge-resistance training for participants with
                hypersensitivity to the sensations caused by rectal distention. Home exercises will
                be assigned to participants to practice these skills, and these will be guided by a
                brochure.

             -  INJ will include a preparation for treatment and a treatment visit. The preparation
                will involve prophylactic antibiotics for the day of the procedure and minimal
                restrictions on food intake. On the day of the procedure, a physician will inject 1
                ml of dextranomer into each of 4 quadrants of the rectum proximal to the dentate
                line. Ten seconds will be allowed to pass before the injection needle is withdrawn
                to minimize drainage of the dextranomer. The participant will be scheduled to
                return in 6 weeks for possible repeat injection of a second 4 ml of dextranomer. At
                this second appointment, if FI has improved by 75% or more compared to baseline,
                the participant will be continued without a second injection. However, if the rate
                of FI is greater than 75% of baseline, the participant will be offered a second
                injection of dextranomer.

        4. Combination therapy: The primary assessment of efficacy is at 3 months following the
           first treatment visit completed, and participants who have not achieved at least a 75%
           reduction in FI frequency compared to baseline will be classified as treatment failures;
           they will be invited to choose the treatment to which they were not randomized or SNS as
           an adjunctive treatment for the remaining months of the study. One reason for this is to
           increase the likelihood that participant will consent to be randomized despite possibly
           having a priori preferences for one of the two treatments. Thus, the participants who
           add a second treatment and continue to be monitored up to 24 months will constitute a
           pragmatic clinical trial (i.e., the study design for these participants going forward
           emulates the clinical situation in which patients who have an unsatisfactory response to
           a treatment are offered a new treatment or an ancillary treatment).

        5. Long-term follow-up: An intention-to-treat analysis of efficacy will be carried out at
           6, 12 and 24 months. For these analyses, all participants randomized to treatment will
           be included in the analysis. All treatments will continue to be active. The bulking
           agents injected in the INJ treatment will remain in place. For BIO, participants will be
           encouraged to continue to practice pelvic floor exercises and enhanced awareness of
           rectal sensations following the initial training period. Participants who withdraw from
           the study or who fail treatment at 3 months will be evaluated as treatment failures in
           follow-up analyses of efficacy. Data will be collected from participants who add an
           alternative treatment at 3 months, but these data will not be considered in this
           analysis. Safety data will be collected at every visit. Participants who are responders
           at 3 months will continue to monitor symptoms for an additional 21 months (2 years
           total) whereas participants who are non-responders at 3 months will be retained as
           treatment failures in the long-term analysis of the comparative effectiveness of the BIO
           and INJ treatments. For longitudinal assessments of safety, cost, and secondary outcomes
           such as quality of life and FI severity scales, statistical models will include data
           from follow up time points through 24 months.

        6. Adjust for Expectation of Benefit: In a trial comparing behavioral and medical therapy,
           participants cannot be masked. The validated Credibility/Expectancy Questionnaire was
           developed to assess the patient's expectation of benefit after initial exposure to
           treatment and was used in previous studies to determine whether there is equipoise
           between the active and control conditions in behavioral treatment trials.

        7. Characterization of Enhanced Medical Treatment - Durability of improvement and
           predictors of response: The primary purpose of treating all participants with an EMM
           run-in is to be able to exclude participants who do not require more costly
           interventions. However, the investigators will take advantage of the opportunity
           provided by this run-in study to identify predictors of response to EMM and to assess
           the durability of improvements. EMM will not be "usual care" but will follow a written
           protocol that is intended to optimize EMM, which is why this is labelled enhanced
           medical management. Participants who are treatment responders at the end of the EMM
           run-in will be scheduled for 3-month follow-up, and those who are no longer treatment
           responders at 3 months follow-up will be offered an opportunity to be randomized to one
           of the 3 treatments at this point. However, those who remain responders to EMM at 3
           months follow-up will continue to be followed for an additional 21 months. All
           participants, regardless of their outcomes at the end of EMM, will be encouraged to
           continue using the treatment approaches learned during the EMM phase.

      Each participant will be studied for 24-27 months after completing the month of EMM and the
      anticipated duration of the study is 4.5 years from first enrollment to completion of the
      last participant. Approximately 285 adult participants, both male and female, will be
      recruited for EMM to ensure that 194 participants who did not benefit from EMM will be
      available for randomization to the two treatment arms (97 per treatment arm). The
      participants may be referred by clinicians or may respond to posted advertisements about the
      study.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Participants who do not demonstrate at least a 75% reduction in FI following a 4-week trial of EMM will be randomized to one of two treatments (INJ or BIO) and assessed after three months. All participants who experience a 75% decrease in FI after three months of treatment, compared to baseline, will then be followed-up for two years. To assess the long-term response to treatment, those who demonstrate an improvement of less than 75% in FI episodes will be offered an additional treatment with either the treatment to which they were not initially randomized or SNS.
An anticipated 285 participants will be enrolled in the EMM to ensure a sample size of 97 in each of the two treatments arms.
primary purpose: Treatment
masking: None (Open Label)
measure: Treatment Response Defined as a 75% or Greater Change in Number of Average Weekly FI Episodes at Month 3 Follow-Up Compared to Baseline
time frame: 3-month follow-up
description: FI episodes will be assessed using a validated symptom diary at Baseline and at three months follow-up.
measure: Proportion of Participants with Specified Adverse Events at Month 3 Follow-Up
time frame: 3-month follow-up
description: Adverse events of pelvic pain of grade II or higher based on Common Terminology Criteria for AE (CTCAE) criteria, treatment site infection, or serious adverse events (SAEs) requiring hospitalization.
measure: Treatment Costs at Month 3 Follow-Up
time frame: 3-month follow-up
description: Costs will be measured from three sources: (a) Number of treatment visits multiplied by the Medicare reimbursement rates. (b) An Out-of-Pocket Treatment Cost Questionnaire. (c) A Work Productivity and Impairment Questionnaire for direct and indirect costs. These costs will be combined to establish overall costs.
measure: Change in the Severity of FI as Assessed Using the Fecal Incontinence Severity Scale
time frame: up to 24 months
description: Treatment effect on the severity of FI at 3-month follow-up, compared to baseline, will be assessed using the Fecal Incontinence Severity Scale, a validated FI severity scale which incorporates the frequency of different types of stool loss (solid, liquid, staining and a combination), the circumstances surrounding FI (urgency, passive, combined, or neither), and volume of leakage. Higher scores indicate more severe fecal incontinence. Assessed at Baseline, Months 6, 12, and 24.
measure: Change in Quality of Life as Assessed Using the Fecal Incontinence Quality of Life Scale
time frame: up to 24 months
description: Treatment effect on the impact of FI on quality of life will be assessed using the Fecal Incontinence Quality of Life Scale which contains 29 items and is scored for four subscales: Lifestyle, Coping/Behavior, Depression/Self-Perception, and Embarrassment. Scores for each item range from 1 - 4 with 1 indicating a lower functional status of quality of life. Scale scores are the average (mean) response to all items after adjusting for missing and not applicable items. Assessed at Baseline, Months 6, 12, and 24.
measure: Change in Psychological Distress as Assessed Using the 7-item Patient-Reported Outcomes Measurement Information System (PROMIS) Anxiety Scale
time frame: up to 24 months
description: One of the measures of psychological distress is the 7-item PROMIS Anxiety Scale for which higher scores indicate higher levels of anxiety. The Anxiety Scale (SF 7a) has a score range of 5 - 35. Assessed at Baseline, Months 6, 12, and 24.
measure: Change in Psychological Distress as Assessed Using the 8-item PROMIS Depression Scale
time frame: up to 24 months
description: One of the measures of psychological distress is the 8-item PROMIS Depression Scale for which higher scores indicate higher levels of depression. The Depression Scale (SF 8a) has a score range of 5 - 40. Assessed at Baseline, Months 6, 12, and 24.
measure: Change in Psychological Distress as Assessed Using the 8-item PROMIS Self-Efficacy Symptom Management Scale
time frame: up to 24 months
description: One of the measures of psychological distress is the 8-item PROMIS Self-Efficacy Symptom Management Scale for which higher scores indicate higher levels of self-efficacy. The Self-Efficacy for Managing Symptoms Scale (SF 8a) has a score range of 5 - 40. Assessed at Baseline, Months 6, 12, and 24.
measure: Number of Participants with Reduction of 50% or More in Average Weekly FI Episodes
time frame: up to 24 months
description: Assessed at Baseline, Months 6, 12, and 24.
measure: Proportion of Participants Who are Continent
time frame: up to 24 months
description: Assessed at Baseline, Months 6, 12, and 24.
arm group label: Biofeedback (BIO)
arm group type: Active Comparator
description: Participants will receive biofeedback intervention during five (5) required weekly 1-hour sessions. A 6th treatment session will be made available for participants if it is shown through anorectal manometry that they are having trouble understanding directions given during the first five sessions.
arm group label: Injection (INJ)
arm group type: Active Comparator
description: Bulking agent injected into rectal wall to narrow opening. Two visits each lasting 45 minutes at weeks 0 and 6 respectively.
intervention type: Behavioral
intervention name: Biofeedback
description: The participant will learn how to improve strength and rectal sensation during five (5) - six (6) visits each lasting 60 minutes.
arm group label: Biofeedback (BIO)
intervention type: Device
intervention name: Injection
description: The participant will have a bulking agent injected into rectal wall to narrow opening. Two visits each lasting 45 minutes at weeks 0 and 6 respectively.
arm group label: Injection (INJ)
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Adil Bharucha, MD
role: Principal Investigator
affiliation: Mayo Clinic
last name: Adil Bharucha, MD
phone: 507-284-2511
email: bharucha.adil@mayo.edu
last name: Marie Gantz, PhD
phone: 919-597-5110
email: mgantz@rti.org
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Terminated
facility: 
status: Active, not recruiting
country: United States
responsible party type: Sponsor
mesh term: Fecal Incontinence
sharing ipd: Yes
ipd description: Deidentified individual data that supports the results will be shared beginning 9 to 36 months following publication provided the investigator who proposes to use the data has approval from an Institutional Review Board (IRB), Independent Ethics Committee (IEC), or Research Ethics Board (REB), as applicable, and executes a data use/sharing agreement with the University of North Carolina (UNC).
ipd time frame: 9 to 36 months following publication
ipd access criteria: Following approval from an appropriate review board as described above and execution of a data use/sharing agreement with UNC-Chapel Hill.