Fecal Incontinence Treatment (FIT) Study

This is an unmasked, multisite, randomized, parallel group study comparing the effectiveness
of three treatments [BIO; SNS; and INJ] for moderate to severe FI:

1. Baseline: Patients 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 patients 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 patients randomized to INJ or SNS meet the accepted
criteria for those 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 conservative treatment after 3 months will be
invited to be randomized to BIO, SNS, 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 patient who fails the EMM will be randomly assigned to
BIO, SNS, or INJ and treated as follows:

- BIO will consist of 5 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 patients, sensory training for patients with
hyposensitivity, and/or urge-resistance training for patients with hypersensitivity
to the sensations caused by rectal distention. Home exercises will be assigned to
patients to practice these skills, and these will be guided by a brochure.

- SNS will include insertion of a barbed stimulating electrode into the region of the
S3-S4 nerve and connection to an external, battery operated electrical stimulator
for 10-14 days to test for reductions in FI. If the rate of FI decreases to at
least 50% of the baseline rate, a permanent stimulator will be implanted beneath
the skin. The patient will be scheduled to return in 2 weeks for an evaluation of
the stimulator settings with adjustment if needed. If the initial 2-week test
stimulation shows less than a 50% reduction in FI compared to baseline, SNS will be
judged ineffective. The stimulator electrode may be removed at the patient's
request or left in place.

- 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 patient 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
patient will be continued without a second injection. However, if the rate of FI is
greater than 75% of baseline, the patient 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 patients 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 one of the other two treatments as adjunctive treatment
for the remaining months of the study. One reason for this is to increase the likelihood
that patients will consent to be randomized despite possibly having a priori preferences
for one of the three treatments. Thus, the patients 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 patients 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 patients randomized to treatment will be
included in the analysis. All treatments will continue to be active after the training
period: the SNS stimulator will continue to operate and the bulking agents injected in
the INJ treatment will remain in place. For BIO, patients will be encouraged to continue
to practice pelvic floor exercises and enhanced awareness of rectal sensations following
the initial training period. Patients 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 patients who switch to an alternative treatment at 3 months,
but these data will not be considered in this analysis. Safety data will be collected at
every visit. Patients who are responders at 3 months will continue to monitor symptoms
for an additional 21 months (2 years total) whereas patients who are non-responders at 3
months will be retained as treatment failures in the long-term analysis of the
comparative effectiveness of these three 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, surgical, and
medical therapy, patients 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 patients with an EMM run-in
is to be able to exclude patients 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. Patients 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 patients, 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 569 adult participants, both male and female, will be
recruited for EMM to ensure that 387 participants who did not benefit from EMM will be
available for randomization to the three treatment arms (129 per treatment arm). The
participants may be referred by clinicians or may respond to posted advertisements about the
study.

Inclusion Criteria:

- Physician diagnosis of FI (R15) for the past 6 months or longer.

- Able to ambulate independently on level surfaces. Patient may use assistive devices
other than parallel bars.

- Average >2 staining, solid or liquid FI episodes per week not including staining by
self-report and during the two-week baseline

- Meets criteria for SNS and dextranomer treatment except an internal anal sphincter
defect of 120 degrees or less is acceptable.

- Less than 75% reduction in the number of FI episodes after 4 weeks of conservative
treatment.

Exclusion Criteria:

- Dementia, assessed using the Six-Item Screener to Identify Cognitive Impairment.

- Obstetrical injuries including third and fourth degree tears in the anal sphincter
within the past 6 months.

- Pregnant or planning pregnancy in next 2 years

- Internal anal sphincter separation >120 degrees on ultrasound or magnetic resonance
imaging

- Spinal cord injury or spina bifida

- Congenital malformation of anus or rectum

- Complete rectal prolapse or grade III/IV hemorrhoids

- History of previous anorectal surgery, such as stapled transanal rectal resection
(STARR) or stapled hemorrhoidectomy. The FENIX procedure, artificial anal sphincter or
transposed gracilis; surgical hemorrhoidectomy, and sphincteroplasty are permitted if
performed more than 6 months previously and the patient meets inclusion criteria.

- Established diagnosis of inflammatory bowel disease

- Intestinal stoma present

- History of pelvic radiation

- FI is secondary to an evacuation disorder

- Anatomic limitations to placement of SNS or dextranomer injections.

- Previously failed an adequate (1-2 weeks) trial of SNS or dextranomer injections

- Presence or history of any medical disorder likely to require follow-up with MRI of
the body (not head or neck), diathermy, microwave, or RF energy therapy.

- Presence of existing implant in the anal or rectal region

- Allergy to hyaluronic acid-based products

- Active anal or rectal conditions in the last 6 months including abscess, fissures,
sepsis, significant bleeding, proctitis, colovaginal and rectovaginal fistulas, anal
or rectal tumors, or other infections.

- The patient's physician believes it is unsafe for the patient to temporarily stop
anticoagulants for any test procedures and treatments associated with the study.

- Watery diarrhea that is not managed by diet or drugs is an exclusion. Patients who
have 4 or more days of Bristol Stool Scale bowel movements classed as a 6 or 7 during
the Baseline will be excluded.

- Patients with Parkinson's disease, multiple sclerosis, severe diabetic neuropathy
documented by EMG, and neurodegenerative disorder.

- Immunotherapy or chemotherapy in the last 12 months.

- Significant anal pain in the last 6 months.

- Unwillingness of participant to stop using over-the-counter medications, herbal
supplements, or prescribed medications for the purpose of modifying stool consistency,
that are not included in the approved medications list (loperamide, laxatives, fiber
supplements, and Questran are approved medications), for the duration of the research
study.

- Participant feels urgency to have a bowel movement, but is able to reach a toilet in
time without leaking stool/feces.

Patients with clinically evident diabetic neuropathy, Parkinson's disease, multiple
sclerosis, other neurological disorders, and obstetric injuries with or without previous
sphincter repair who have less than 1/3 external anal sphincter (EAS) separation, and
patients with rectal reconstructions or ileoanal pouches, will be permitted. Medical
history will be documented to test for predictors of response.