Comparative Effectiveness of Biofeedback and Injectable Bulking Agents for Treatment of Fecal Incontinence: The Fecal Incontinence Treatment (FIT) Study
Phase: NA
Conditions: Fecal Incontinence, Bowel Incontinence
Sponsor: Mayo Clinic

 
 
Comparative Effectiveness of Biofeedback, 
Sacral Nerve Stimulation, and Injectable Bulking 
Agents for Treatment of Fecal Incontinence: 
The Fecal Incontinence Treatment (FIT) Study 
 
NCT#03811821 
 
11June2022 

i 
 
Comparative Effectiveness of Biofeedback and Injectable Bulking 
Agents for Treatment of Fecal Incontinence: The Fecal Incontinence 
Treatment (FIT) Study 
 
Protocol Version 10.0 
Approved: 06/11/2022 
 
 
  
 
Steering Committee: 
 
 
 
 
 
 
William E. Whitehead (PI) 
 
University of North Carolina, Chapel Hill, NC 
 
 
Adil Bharucha (Site PI)  
 
Mayo Clinic, Rochester, MN   
 
 
Ann Lowry (Site PI) 
 
 
Colon & Rectal Surgery Associates, Minneapolis, MN 
Satish Rao (Site PI)  
 
Augusta University, Augusta, GA 
Isuzu Meyer (Site PI)  
 
The University of Alabama at Birmingham, Birmingham, AL 
William Chey (Site PI) 
 
University of Michigan, Ann Arbor, MI 
Frank Hamilton (NIDDK Scientist)  
NIDDK, Bethesda, DC  
Marie Gantz (DCC PI) 
 
RTI International, Research Triangle Park, NC 
 
 
Please read and acknowledge your approval of the Version 9.0 of the Comparative Effectiveness of 
Biofeedback and Injectable Bulking Agents for Treatment of Fecal Incontinence: The Fecal 
Incontinence Treatment (FIT) Study protocol.  If you agree with the protocol in this version, as it is 
stated below, please sign and date this face page and return this face page to William Whitehead or 
Sundass Khan. This can be faxed to 
 or sent via email to 
 
 
 
 
 
 
Investigator Signature: ______________________________________  Date: _____________________ 
 
 
 
Investigator Printed Name: ______________________________________________________________ 
 
 
 
 

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iii 
 
TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS ....................................................................................................... v 
SPECIFIC AIMS ......................................................................................................................... 7 
BACKGROUND AND SIGNIFICANCE ...................................................................................... 8 
STUDY DESIGN....................................................................................................................... 12 
OUTCOME MEASURES .......................................................................................................... 17 
STUDY POPULATION ............................................................................................................. 23 
SAMPLE SIZE ......................................................................................................................... 25 
INTERVENTIONS .................................................................................................................... 29 
RANDOMIZATION AND MASKING ......................................................................................... 32 
STATISTICAL CONSIDERATIONS ......................................................................................... 34 
DATA AND SAFETY MONITORING AND INFORMED CONSENT ......................................... 36 
DATA MANAGEMENT AND DATA SHARING ........................................................................ 38 
REFERENCES ......................................................................................................................... 39 
 
 
 
 
 

iv 
 
 
 
 

v 
 
List of Abbreviations 
ABL 
Accidental Bowel Leakage 
AE 
Adverse Event 
ANOVA 
Analysis of Variance 
BM 
Bowel Movement 
BSFS 
Bristol Stool Form Scale 
CAT 
Computer Adaptive Testing 
CES-D 
Center for Epidemiological Studies Depression scale 
CEQ 
Credibility/Expectancy Questionnaire 
DCC 
Data Coordinating Center 
DSMB 
Data and Safety Monitoring Board 
EAS 
External Anal Sphincter 
EDC 
Electronic Data Capture 
EQ-5D 
EuroQol 5 item health utilities questionnaire 
EMG 
Electromyographic 
FDA 
Food and Drug Administration 
FI 
Fecal Incontinence 
FIQOL 
Fecal Incontinence Quality of Life questionnaire 
FISS 
Fecal incontinence Severity Scale 
FIT 
Fecal Incontinence Treatment study 
FU 
Follow-Up 
GI 
Gastrointestinal  
HUI-3 
Health Utilities Index Mark 3  
IAS 
Internal Anal Sphincter 
IBS 
Irritable Bowel Syndrome 
ICD-10 
International Classification of Diseases, version 10 
ITT 
Intention-to-Treat analysis 
IRB 
Institutional Review Board for protection of subjects in research 
MCID 
Minimum Clinically Important Difference 
MEP 
Motor Evoked Potential 
MRI 
Magnetic Resonance Imaging 
NIDDK 
National Institute of Diabetes and Digestion and Kidney Diseases 
PFDN 
Pelvic Floor Disorders Network 
PFE 
Pelvic Floor Exercises 
PHQ-15 
Patient Health Questionnaire (checklist of 15 most common symptoms 
seen in primary care visits; treated as a measure of somatization) 
PROMIS 
Patient Reported Outcomes Measurement Information System 
PTNS 
Posterior Tibial Nerve Stimulation 
QOL 
Quality of Life 
RCT 
Randomized Controlled Trial 

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SAE 
Serious Adverse Event 
SNS 
Sacral Nerve Electrical Stimulation 
TLMS 
Trans Rectal Magnetic Stimulation 
TSMS 
Trans Sacral Magnetic Stimulation 
UI 
Urinary incontinence 
WPAI 
Work Productivity and Activity Index 
 

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PROTOCOL VERSION: 10.0 (Approved: JUN 11, 2022). Comparative Effectiveness of Biofeedback and Injectable Bulking Agents 
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Summary of Changes from Previous Versions: 
Version 
Affected Section(s) 
Summary of Revisions Made 
Rationale 
2.0  
(December 10, 
2018) 
Throughout protocol 
All wording regarding the frequency of FI required 
for inclusion in the trial was updated to include 
staining in addition to solid and liquid episodes.  
Staining episodes are a 
relevant part of FI. 
Throughout protocol 
Clarifications and corrections of inconsistencies 
and typos. 
Changes were made to 
ensure that the protocol is 
expressed as clearly as 
possible. 
3.0  
(May 2, 2019) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Throughout protocol, 
where appropriate 
Wording was updated to include an optional 6th 
Biofeedback training session 
In instances where the 
participant needs additional 
training to fully benefit from 
the Biofeedback training, a 
6th optional training session 
may be provided at the 
discretion of the provider. 
Throughout protocol, 
where appropriate 
Wording detailing the event windows was added 
to the protocol. 
This was added to the 
protocol to provide clear 
guidance to site teams to 
ensure that the protocol is 
implemented consistently. 
Section 5.1 
Wording for two exclusion criteria was updated 
and a third exclusion criterion was deleted. 
These criteria now read as follows: 
• History of previous anorectal surgery, such as 
stapled transanal rectal resection (STARR). 
Stapled hemorrhoidectomy is not an exclusion if 
performed more than 12 months previously. 
The FENIX procedure, artificial anal sphincter or 
transposed gracilis; surgical hemorrhoidectomy 
(other than stapled), and sphincteroplasty are 
permitted if performed more than 6 months 
previously and the patient meets inclusion 
criteria. 
• Patients who have 4 or more days with 4 or 
more bowel movements classed as a 6 or 7 on 
the Bristol Stool Scale per day in either (any) 
week during the Baseline will be excluded. 
The following criterion was deleted: 
• If the participant feels urgency to have a bowel 
movement but is able to reach a toilet in time 
without leaking stool/feces. 
These changes were 
considered necessary by the 
investigators for the 
appropriate selection of 
participants. 
Throughout protocol 
but specifically in 
Wording editing to clarify time period for which 
adverse events will be documented. 
Adverse event data will be 
collected from the time that 

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PROTOCOL VERSION: 10.0 (Approved: JUN 11, 2022). Comparative Effectiveness of Biofeedback and Injectable Bulking Agents 
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Sections 4.1.2 and 
9.2 
the participant is consented 
through the 24-month 
follow-up visit. 
Throughout protocol 
but specifically in 
Section 4.3.2 
Wording edited/added to clarify the time-points 
at which the CEQ will be completed by the 
participant. 
The CEQ should be 
completed each time a study 
treatment is started, once 
the treatment has been 
initiated. 
Section 4.3.8 and 
throughout the 
protocol, as 
necessary 
It was specified that the anal ultrasound/MRI 
imaging studies need not be repeated at Baseline 
if the participant had an imaging study within the 
previous 12 months to assess the sphincters as 
long as the sphincters appeared normal and there 
has been no history of anorectal trauma, surgical 
procedures, or vaginal deliveries in the 
intervening period between the imaging exam 
and study participation. 
It was felt that it is 
unnecessary 
medically/scientifically to 
subject the participant to 
additional imaging as long as 
there is good data to indicate 
that the sphincters are 
normal. 
Throughout protocol, 
where appropriate 
Wording added to clarify the time-points at which 
the BET, ARM and MEP are performed. 
Participants who initially 
respond to EMM but are 
then randomized after they 
are identified as non-
responders at the 3-month 
follow-up visit will not have 
the BET, ARM and MEP 
repeated at their second 3-
month follow-up visit, that is, 
at the follow-up visit 3 
months after they initiated 
the randomized treatment. 
Appendices B - H 
Removed from protocol 
These appendices are 
separate Standard Operating 
Procedures (SOP) and 
questionnaires which are 
submitted to the IRB as 
separate documents, as 
appropriate.  
4.0  
 
Synopsis; Section 2 
(SCHEMA) – Item 1 
Added to protocol:  
For patients who have a variable pattern of FI and 
the investigator believes that the initial two-week 
diary data collection did not adequately capture 
the extent of the FI, then the baseline bowel diary 
may be kept by the patient for an additional two 
weeks. 
Some patients have a 
variable pattern of FI and, 
consequently, the initial two-
week diary may not reflect 
the extent of the FI they 
experience. Keeping the 
diary for an additional two 
weeks allows the 
opportunity for the team to 
better assess the extent of 
FI. If a second two-week data 
collection occurs, then only 

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PROTOCOL VERSION: 10.0 (Approved: JUN 11, 2022). Comparative Effectiveness of Biofeedback and Injectable Bulking Agents 
for Treatment of Fecal Incontinence: The Fecal Incontinence Treatment (FIT) Study 
 
the data from the last two 
weeks (second diary 
completed) will be reported 
in the study’s EDC. 
Section 5.1 
(Inclusion/Exclusion 
Criteria) 
Wording for one inclusion and four exclusion 
criteria was updated. The fourth exclusion criteria 
changed mirrors the inclusion criterion related to 
the degree of internal anal sphincter defect that is 
acceptable. 
These criteria now read as follows: 
• Inclusion criterion:  
o Meets criteria for SNS and dextranomer 
treatment except an internal anal sphincter 
defect of 180 degrees or less is acceptable. 
• Exclusion criteria: 
o Internal anal sphincter separation >180 
degrees on ultrasound or magnetic 
resonance imaging. 
o History of pelvic radiation within previous 12 
months or presence of active radiation 
proctitis. 
o Patients who have overflow diarrhea with 
rectal impaction with stool or an abnormal 
balloon expulsion test plus predominant 
symptoms of constipation. 
o Previously failed an adequate (1-2 weeks) 
trial of SNS. 
The investigators believe 
that certain eligibility criteria 
may be unnecessarily 
limiting enrollment. The 
DSMB agrees that these 
changes will not affect the 
scientific integrity of the 
protocol. 
Synopsis; Section 2 
(SCHEMA) – Item 2; 
Section 3 (Study 
Design) – Item 8 
Protocol updated to indicate that whether or not 
participants are EMM responders or not, data 
regarding ongoing adherence to the EMM 
prescriptions will be collected from participants at 
the end of the one month EMM period and then 
also at the 3-; 6-; 12-; and 24-month follow-up 
visits. 
This was requested by the 
DSMB. 
5.0 
Throughout protocol, 
as necessary 
Two additional FIT Study sites, The University of 
Alabama at Birmingham, and University of 
Michigan, have been added to the study protocol. 
In view of the current rate of 
enrollment, the Steering 
Committee has decided to 
implement the contingency 
plan for low enrollment 
(outlined in Section 5.6 of 
the protocol). The plan 
allows for additional sites to 
participate in the study if 
approved by the NIDDK 
program staff. 

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PROTOCOL VERSION: 10.0 (Approved: JUN 11, 2022). Comparative Effectiveness of Biofeedback and Injectable Bulking Agents 
for Treatment of Fecal Incontinence: The Fecal Incontinence Treatment (FIT) Study 
 
Section 4.3.7 
Specified that the two additional sites, The 
University of Alabama at Birmingham and the 
University of Michigan, will not perform the 
translumbosacral magnetic evoked potential test. 
The equipment for the 
translumbosacral magnetic 
evoked potential test is 
costly and since it is not a 
core study procedure. 
Section 4.3.8 
Specified that The University of Alabama at 
Birmingham will perform the anorectal ultrasound 
using a 2-dimensional BK probes rather than the 
3-dimensional BK probe noted in the protocol. 
The University of Alabama at 
Birmingham routinely uses 2 
dimensional BK probes when 
performing anorectal 
ultrasound and will thus not 
use a 3-dimensional BK 
probe. 
Appendix A 
Deleted Appendix A (UNC consent form) 
Although the consent forms 
are all developed from a 
template study consent and 
are very similar, each of the 
six sites has a site-specific 
consent form; thus, it is 
more appropriate to have 
the consent forms all 
submitted to the IRB as 
separate documents. 
6.0 
Section 3; 6.2; and 
6.4 
Wording updated to be consistent with the 
practice of using prophylactic antibiotics for 2 
days starting on the day of the injection (per the 
injection procedure SOP).  
Previously it was indicated in 
the injection procedure SOP 
that the first dose of the 
prophylactic antibiotic will be 
administered 4 hours prior to 
the procedure; however, the 
SOP has been updated to 
indicate that the first dose 
may be administered 4 hours 
before or immediately after 
the procedure. This is 
consistent with clinical 
practice. 
Section 5.1 
(Inclusion/Exclusion 
Criteria) 
Wording for one exclusion criteria was updated. 
Previous wording:  
o Patients who have overflow diarrhea with 
rectal impaction with stool or an abnormal 
The wording was updated for 
clarification. 

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PROTOCOL VERSION: 10.0 (Approved: JUN 11, 2022). Comparative Effectiveness of Biofeedback and Injectable Bulking Agents 
for Treatment of Fecal Incontinence: The Fecal Incontinence Treatment (FIT) Study 
 
balloon expulsion test plus predominant 
symptoms of constipation. 
Updated wording: 
o Patients who cannot expel the rectal balloon 
during the balloon expulsion test and who 
have constipation most of the time. 
Section 5.1 
(Inclusion/Exclusion 
Criteria) 
The following exclusion criterion was deleted: 
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. 
The SNS leads previously 
used were MRI-
incompatible; however, the 
new design leads are not. 
Section 6.3 (Sacral 
nerve stimulation) 
Removal of the specific model number of the lead 
used for SNS 
This model of the lead will no 
longer be supported by the 
manufacturer and will thus 
no longer be used for this 
study treatment. 
Throughout protocol 
Wording updated so that 6-, 12-, and 24-month 
follow-up events are now referred to as 
“assessments” instead of “visits”.  The 18-month 
telephonic follow-up also now referred to as an 
“assessment” so that terminology is consistent.  
6-, 12-, and 24-month follow-
up assessments (previously 
visits) which do not require 
in-person procedures may 
now be conducted remotely. 
7.0 
Throughout protocol 
Updated number of study sites to five. 
CRSA will no longer be an 
enrolling site. 
Throughout protocol 
Wording updated throughout protocol to remove 
SNS as a randomized treatment but to be retained 
as an optional treatment. 
SNS has been removed as a 
randomized treatment as 
some patients are concerned 
about being randomized to 
an invasive treatment before 
trying more conservative 
options. 
Section 5.1 
(Inclusion/Exclusion 
Criteria) 
Wording for an inclusion criterion was updated. 
Previous wording: Meets criteria for SNS and 
dextranomer treatment except an internal 
anal sphincter defect of 180 degrees or less is 
acceptable. 
Updated wording: Meets criteria for 
dextranomer treatment except an internal 
Updates made to these three 
criteria were made as SNS is 
no longer a randomized 
study treatment. 

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for Treatment of Fecal Incontinence: The Fecal Incontinence Treatment (FIT) Study 
 
anal sphincter defect of 180 degrees or less is 
acceptable. 
Wording for one exclusion criterion was updated. 
Previous wording: Anatomic limitations to 
placement of SNS or dextranomer injections. 
Updated wording: Anatomic limitations to 
placement of dextranomer injections. 
The following exclusion criterion was deleted: 
Previously failed an adequate (1-2 weeks) trial 
of SNS. 
Throughout protocol 
Wording updated to indicate that the following 
procedures may be optional at the 3-month 
assessment: 
• 
ARM 
• 
MEP 
• 
Endoanal ultrasound (INJ participants only) 
 
Throughout protocol 
Wording updated to indicate that the 3-month 
follow-up assessment may be completed in-
person or remotely. 
 
8.0 
Section 5.1 
(Inclusion/Exclusion 
Criteria) 
Language below the table of inclusion/exclusion 
criteria was updated as follows: 
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. 
 
The deleted text conflicted 
with wording in an exclusion 
criterion.  
9.0 
Section 3.1 Event 
Windows 
The following event window for initiation of the 
optional treatment was added:  
Optional additional treatment initiation should 
occur within 0 days to 4 weeks after the 3-month 
visit post randomization. 
The same window used for 
initiation of the randomized 
treatment has been applied 
to the initiation of the 
optional treatment. 0 days is 
the 3-month visit at which it 
is determined that the 
participant has not 
responded to the 
randomized treatment. 

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PROTOCOL VERSION: 10.0 (Approved: JUN 11, 2022). Comparative Effectiveness of Biofeedback and Injectable Bulking Agents 
for Treatment of Fecal Incontinence: The Fecal Incontinence Treatment (FIT) Study 
 
Section 5.1 
(Inclusion/Exclusion 
Criteria) 
Added an inclusion criterion regarding age as 
follows: 
Age >=18 years 
 
 
 
Wording for two exclusion criteria was updated. 
• First criterion change is as follows: 
Previous wording: History of previous 
anorectal surgery, such as stapled transanal 
rectal resection (STARR). Stapled 
hemorrhoidectomy is not an exclusion if 
performed more than 12 months previously. 
The FENIX procedure, artificial anal sphincter 
or transposed gracilis; surgical 
hemorrhoidectomy (other than stapled), and 
sphincteroplasty are permitted if performed 
more than 6 months previously and the 
patient meets inclusion criteria. 
Updated wording: History of previous 
anorectal surgery, such as stapled transanal 
rectal resection (STARR). Stapled 
hemorrhoidectomy is not an exclusion if 
performed more than 12 months previously. 
The FENIX procedure, artificial anal sphincter 
or transposed gracilis; surgical 
hemorrhoidectomy (other than stapled), 
sphincteroplasty, rectal reconstructions and 
ileoanal pouches are permitted if performed 
more than 6 months previously and the 
patient meets inclusion criteria. 
 
• Second criterion change is as follows: 
Previous wording: Immunotherapy or 
chemotherapy in the last 12 months. 
Updated wording: Patients currently receiving 
immunotherapy or chemotherapy. 
 
The protocol specifies that 
study participants will be 
“adults” and the eligibility 
CRF specifies 18 years or 
older, but this criterion has 
been specifically added to 
the inclusion/ exclusion 
criteria table for 
completeness. 
First criterion change: 
Wording from the paragraph 
below the inclusion/ 
exclusion table was added to 
an existing criterion to make 
its intent as an exclusion 
clearer. 
 
 
 
 
 
 
 
 
 
 
 
Second criterion change:  
The wording has been 
updated to specifically 
exclude patients who are 
currently receiving 
immunotherapy or 
chemotherapy and not those 
who previously received 
these therapies since only 
current therapy is specifically 
noted as a contra-indication 
in the Solesta package insert. 

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PROTOCOL VERSION: 10.0 (Approved: JUN 11, 2022). Comparative Effectiveness of Biofeedback and Injectable Bulking Agents 
for Treatment of Fecal Incontinence: The Fecal Incontinence Treatment (FIT) Study 
 
Section 5.1 
(Inclusion/Exclusion 
Criteria) 
Language below the table of inclusion/exclusion 
criteria was updated as follows: 
Patients with 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. 
 
The wording regarding 
obstetric injuries was deleted 
as it not required/correct in 
this instance. 
The wording regarding rectal 
reconstructions or ileoanal 
pouches was deleted as it 
was specifically incorporated 
into an exclusion criterion 
(see above).  
Section 5.6 
(Contingency Plan) 
Section deleted. 
Two additional sites have 
already been added to the 
study protocol and no 
additional sites will still be 
added. 
Section 6.2 (BIO 
training) – last 
paragraph on page 
32 
 
Language referring to audiotaping the 
Biofeedback sessions as part of the training 
program was removed. 
Therapists and investigators 
were not comfortable about 
recording the Biofeedback 
sessions and it was decided 
previously that sessions will 
not be recorded. The 
consent forms were updated 
as part of Protocol 
Modification 7.0 (approved 
4/23/2021) but this part of a 
sentence regarding various 
aspects of the training 
program was missed at that 
time. 
10.0 
Synopsis protocol 
summary (Section 3) 
and in Table 2 in 
main body of 
protocol 
Wording added to clarify that the endoanal 
ultrasound may be performed as an optional 
procedure for participants who elect to receive 
INJ as an optional treatment. If performed this 
would be done at their follow-up visit following 
completion of that treatment (likely their 6-month 
follow-up visit). 
 
This procedure is performed 
specifically when Solesta is 
administered as it is used to 
monitor migration of the 
bulking agent. 
Section 4.3.7 (Motor 
evoked potentials) 
Wording was updated to indicate that MEP data 
will not be collected at the University of North 
Carolina at Chapel Hill. 
 
The MEP data are collected 
at some but not all of the 
study sites. Previously data 
were to be collected at UNC, 
but this is no longer planned. 

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PROTOCOL VERSION: 10.0 (Approved: JUN 11, 2022). Comparative Effectiveness of Biofeedback and Injectable Bulking Agents 
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Section 5.1 
(Inclusion/Exclusion 
Criteria) 
Wording for this exclusion criterion was updated 
as follows: 
Previous wording: History of previous 
anorectal surgery, such as stapled transanal 
rectal resection (STARR). Stapled 
hemorrhoidectomy is not an exclusion if 
performed more than 12 months previously. 
The FENIX procedure, artificial anal sphincter 
or transposed gracilis; surgical 
hemorrhoidectomy (other than stapled), 
sphincteroplasty, rectal reconstructions and 
ileoanal pouches are permitted if performed 
more than 6 months previously and the 
patient meets inclusion criteria. 
 
Updated wording: 
History of ileoanal pouch; history of anal 
sphincteroplasty, rectopexy, or rectocele 
repair within the past 6 months; or history of 
pelvic surgery with synthetic graft and 
suspected graft erosion into the anus, rectum, 
or skin or if the graft ends less than 
approximately 1” above the upper limit of the 
anal canal.  
 
Wording was updated to 
more clearly define which 
surgical procedures should 
be permitted/excluded. 
Section 9.2 
(Reporting of Adverse 
Events) 
The language bolded below was added to the 
text: 
“All adverse events that occur from the time that 
the participant is consented through the 3-month 
follow up visit will be recorded on designated 
CRFs. Following the 3-month follow up 
assessment and through the 24-month follow-up 
assessment, the research coordinators will record 
only AEs of grade II or higher; however, any AE, 
regardless of severity/grade, should be reported 
through the 24-month follow-up visit if it is 
possibly related to the randomized or optional 
study treatments. Failure of the study 
interventions to adequately control fecal 
incontinence symptoms (failure of efficacy) will be 
captured by the study endpoints and will not be 
recorded as an adverse event.”  
 
This change was made to 
ensure compliance with 
safety reporting. 
 
 

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PROTOCOL VERSION: 10.0 (Approved: JUN 11, 2022). Comparative Effectiveness of Biofeedback and Injectable Bulking Agents 
for Treatment of Fecal Incontinence: The Fecal Incontinence Treatment (FIT) Study 
 
Synopsis 
STATEMENT OF COMPLIANCE 
 
The trial will be conducted in accordance with International Conference on Harmonization Good Clinical 
Practice (ICH GCP), applicable United States (US) Code of Federal Regulations (CFR), and the NIDDK Terms 
and Conditions of Award. The Principal Investigator will assure that no deviation from, or changes to the 
protocol will take place without prior agreement from the Investigational New Drug (IND) or Investigational 
Device Exemption (IDE) sponsor, funding agency and documented approval from the Institutional Review 
Board (IRB), except where necessary to eliminate an immediate hazard(s) to the trial participants. All 
personnel involved in the conduct of this study have completed Human Subjects Protection and ICH GCP 
Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be submitted to 
the IRB for review and approval.  Approval of both the protocol and the consent form must be obtained before 
any participant is enrolled.  Any amendment to the protocol will require review and approval by the IRB before 
the changes are implemented to the study.  All changes to the consent form will be IRB approved; a 
determination will be made regarding whether a new consent needs to be obtained from participants who 
provided consent, using a previously approved consent form. 
PROTOCOL SUMMARY 
1. 
SYNOPSIS  
Title: 
Comparative Effectiveness of Biofeedback and Injectable Bulking Agents for 
Treatment of Fecal Incontinence: The Fecal Incontinence Treatment (FIT) Study 
Study Description: 
Patients with severe fecal incontinence (2 or more episodes of staining, solid, or 
liquid FI per week) who meet 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 two-week daily stool diary. For patients who have a 
variable pattern of FI and the investigator believes that the initial two-week diary 
data collection did not adequately capture the extent of the FI, then the baseline 
bowel diary may be kept by the patient for an additional two weeks. All 
participants will 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 improve by at 
least 75% reduction in FI frequency will not be randomized to another treatment 
but will be followed for two years. Those not improving by 75% reduction in FI 
frequency will be randomized to BIO (5 required weekly sessions with an 
optional 6th session if needed) or INJ and they will be evaluated 3 months later. 
If they show a 75% decrease in FI at 3 months compared to baseline, they will 
be followed for two years. To assess the long-term response to treatments, 
those who improve less than 75% in FI episodes will be offered an additional 
treatment, either the randomized treatment to which they were not originally 
randomized or sacral nerve stimulation (SNS) and will also be followed for two 
years from the start of their randomized treatment. Note that participants who 
previously (prior to their participation in the study) were treated unsuccessfully 
with SNS will not be offered SNS as an optional treatment. Anorectal 
manometry and Magnetic Evoked Potentials will be used to subtype the 

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PROTOCOL VERSION: 10.0 (Approved: JUN 11, 2022). Comparative Effectiveness of Biofeedback and Injectable Bulking Agents 
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physiological basis for FI. Quality of life and psychological factors will be used to 
assess outcomes.  
 
Outcomes: 
 
Primary Outcomes:  To show that, by 3-month follow-up, the two treatments, 
biofeedback and dextranomer injection, will have different effects on (a) 
reduction in the frequency of FI compared to baseline, (b) number of people 
with abdominal events, and (c) the cost of delivering the treatment.  
 
Secondary Outcomes:  To show that by 3 months follow-up, those two 
treatments will have different effects on the severity of fecal incontinence 
(measured with the Fecal Incontinence Severity Scale), the impact of FI on 
quality of life (measured with the Fecal Incontinence Quality of Life Scale), and 
psychological symptoms (measured with the PROMIS scales for Anxiety, 
Depression, and Self-Efficacy Symptom Management). 
 
Endpoints: 
 
Primary Endpoint:  
1. The frequency of FI will be measured with a validated symptom diary. 
The definition of a responder is a reduction of 75% or greater in the 
frequency of FI from baseline, measured with the Fecal Incontinence 
Bowel Diary. 
2. The primary measure of safety is the proportion of participants with 
specified AE’s reported during treatment rated on the Common 
Terminology Criteria for Adverse Events. 
3. 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 costs.  
 
Secondary Endpoints:  
1. Fecal Incontinence Severity Scale. 
2. Fecal Incontinence Quality of Life Scale. 
3. Measures of psychological distress are the PROMIS Anxiety Scale, the 
PROMIS Depression Scale, and the PROMIS Self-Efficacy Symptom 
Management Scale.  
 
Predictions of Treatment Response: 
1. Demographic variables: sex, age, race, ethnicity, and education. 
2. Clinical history variables: FI frequency, volume, duration, association 
with urgency and loose / watery stools and hard / lumpy stools. 
3. Pelvic floor physiology:  Anal rectal pressures, squeeze pressures, 
squeeze duration, sensory threshold, structural integrity of sphincter, 
innervation of the rectum. 
 
Moderators of outcome: 
1. Patient’s expectation of benefit from the treatment they are randomized 
to. 
2. Somatization score on the Physical Healthy Questionnaire 12. 
 
 

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Study Population: 
97 adult people with FI who did not benefit from EMM will be recruited into each 
of two treatment arms. Patients will be recruited into the EMM group until there 
are 97 randomized to each treatment arm. We anticipate recruiting 
approximately 285 into the EMM condition, but this will be adjusted if necessary. 
The subjects may be referred from clinicians or may respond to posted 
advertisements about the study. The study is open to male and female patients. 
An effort will be made to recruit African American and Hispanic subjects.  
  
Phase: 
Compare BIO and INJ for the treatment of moderate or severe fecal 
incontinence, with respect to efficacy for reducing the frequency of fecal 
incontinence, safety of the interventions, and cost of providing care. 
 
Description of 
Sites/Facilities 
Enrolling 
Participants: 
Five clinical sites are enrolling patients: (1) Mayo Clinic in Rochester, 
Minnesota, headed by Adil Bharucha. (2) Augusta University in Augusta, 
Georgia, headed by Satish Rao. (3) University of North Carolina at Chapel Hill 
headed by William Whitehead. (4) The University of Alabama at Birmingham, 
headed by Isuzu Meyer. (5) University of Michigan, headed by William Chey. 
Each of these facilities is a major referral center for the treatment of fecal 
incontinence. 
 
Description of Study 
Intervention: 
Each treatment protocol will be based on previously described treatment 
algorithms. The EMM protocol will follow a protocol developed by the University 
of North Carolina group, which is similar to protocols used at the Mayo Clinic 
and Augusta University. The BIO treatment will follow the biofeedback program 
developed for the Pelvic Floor Disorders Network by Whitehead and colleagues. 
The INJ treatment will follow the Graf study.  
 
Study Duration: 
The duration of the study will be approximately 6 years from first enrollment to 
completion of the last subject. 
 
Participant Duration: 
Each participant will be studied for 24-27 months, following the completion of 
the month of EMM. 
 
 

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2. 
SCHEMA 
Study Design 
 
 
 
Study sequence is shown above for all steps following informed consent in Visit 1.  
1. Subjects who meet the inclusion criteria are first asked to keep a symptom diary for two weeks to determine 
whether they have an adequate amount of staining, solid or liquid fecal incontinence to be enrolled. The 
number of FI episodes during baseline will become the reference for judging whether they demonstrate a 75% 
reduction in the frequency of FI.  For patients who have a variable pattern of FI and the investigator believes 
that the initial two-week diary data collection did not adequately capture the extent of the FI, then the baseline 
bowel diary may be kept by the patient for an additional two weeks. 
2. Subjects who have an adequate amount of FI during baseline and who fulfill other inclusion criteria are enrolled 
in a 4-week EMM protocol to determine whether this will reduce their FI episodes by 75% or more. If it does, 
they are not included in the randomized trial but are scheduled to return at 3 months for a follow-up 
assessment. If the subject does not achieve at least a 75% reduction in FI, they are randomized to one of two 
therapies: BIO or INJ. Whether or not participants are EMM responders, data regarding ongoing adherence to 
the EMM prescriptions will be collected from participants at the end of the 1-month EMM period and then also 
at the 3-; 6-; 12-; and 24-month follow-up assessments. 
3. Each treatment intervention follows a printed protocol document. The number of treatment visits varies 
somewhat, from 2-3 visits for INJ, and 5-6 visits for BIO. 

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At 3 months, all subjects who received a randomized therapy are assessed to determine whether they meet the 
criteria for treatment success. If they fail to demonstrate a 75% decrease in FI compared to baseline, they are 
labelled as treatment failures and are offered the opportunity to try the other randomization treatment or SNS. 
Those subjects who were initial responders to EMM but who are determined at 3 months follow-up to no longer 
be responding to EMM will be eligible to be randomized to one of the two treatment therapies (BIO or INJ).  For 
all participants, follow-up assessments occur at 6, 12, 18 and 24 months. The 3-, 6-, 12 and 24-month follow-up 
assessments may be completed in-person or remotely. The more limited follow-up data collection at 18-month 
should always be collected during a telephone call.   
4. Anorectal manometry and magnetic evoked potential tests are performed at baseline and may be performed at 
the 3-month follow-up assessment. Questionnaires to assess FI severity, FIQOL, and psychological tests are given 
at the same intervals.  
3. 
SCHEDULE OF ACTIVITIES (SOA) 
 
The Table of Measures shows the assessment measures in column 1 and the part of the study during which these 
measures are made in the remaining columns.  Additionally, participants will complete the Credibility/ Expectancy 
Questionnaire (CEQ) each time that they start one of the study interventions. All study participants will complete the 
CEQ when they start EMM, all randomized participants will complete the CEQ when they start BIO or INJ as a 
randomized treatment, and participants will complete the CEQ if they select BIO, INJ or SNS when they are identified as 
non-responders to the randomized treatment at the 3-month follow-up assessment.  
 
 

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1.0   Study Overview 
Fecal incontinence (FI) is very common: 3% of US adults report that it occurs at least weekly1. It often has a 
devastating impact on quality of life and may lead to premature admission to a nursing home2. In August 2013, 
the National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK) invited leaders in the field to a 
workshop to develop a clinical research agenda for FI. Overwhelmingly, participants identified biofeedback, 
sacral nerve electrical stimulation, and perianal injection of an inert bulking agent as potentially useful 
treatments3 but felt that a critical barrier to progress is the lack of consistent evidence from well-designed, 
randomized controlled trials (RCTs) regarding their efficacy. The workshop identified trials comparing the 
effectiveness, safety, and costs of these treatments as the highest priority for research funding. Our goal is to 
address this significant gap in knowledge by conducting a multisite study comparing the effectiveness, safety, 
and costs of two treatments. In our proposed Fecal Incontinence Treatment (FIT) study, approximately 285 
people with moderate to severe FI will be enrolled in this multi-site study.  All participants will first be treated 
with 4 weeks of Enhanced Medical Management (EMM), and 194 who do not respond to EMM will be 
randomized to the two interventions, Biofeedback (BIO) or injections of Dextranomer bulking agent (INJ). 
Three months thereafter, non-responders (less than a 75% reduction in FI episodes) may choose to undergo a 
different (i.e., a second) intervention from the 3 options of BIO, INJ, or Sacral Nerve Stimulation (SNS).  
Our specific aims are as follows:  
1.1 
 Specific Aims  
A. Compare the effectiveness, safety, and cost of two treatments for moderate to severe FI in 194 male and 
female patients in a multi-center RCT; the interventions are biofeedback therapy (5 required weekly 
sessions with the option of an additional 6th visit, as needed) and perianal injection of the inert bulking 
agent dextranomer (INJ; Solesta). A >75% reduction in average weekly FI episodes compared to baseline 
will define a responder. The primary efficacy analysis will occur 3 months following the start of each 
treatment, with long-term follow-up through 2 years. Secondary outcomes will include a validated FI 
severity scale,4, 5 a disease-specific quality of life6 scale, and measures of psychological distress7.  
• Research objective 1 (primary). For the primary test of efficacy, the null hypothesis is that the 
proportion of responders in the two treatment groups will not be different. Secondary analyses will test 
for equivalence at other time points (e.g., 6, 12 and 24 months follow up) and will compare treatment 
groups on other secondary outcome measures.  
• Research objective 2 (primary). For the primary test of safety, the null hypothesis is that at 3 months 
follow up, the proportion of patients with adverse events (AEs) of pelvic pain of grade II or higher based 
on Common Terminology Criteria for AE (CTCAE) criteria, treatment site infection, or SAEs requiring 
hospitalization will not be different in the BIO or INJ groups. Secondary analyses will evaluate this 
outcome at 6, 12, 18, and 24 months follow up.  
• Research objective 3 (primary). At 3 months follow up, the estimated average cost for enhanced 
medical management non-responders will not be different for the two treatments. Secondary analyses 
will evaluate this outcome at 6, 12, 18, and 24 months.  
B. Compare efficacy in patients who complete all assigned treatment visits. Efficacy may be influenced by the 
number of BIO treatment sessions and the requirements to learn and practice new skills. Thus, in a 
secondary analysis, the primary efficacy outcome will be compared between treatment groups in the 
subset of participants who completed the treatment to which they were randomized.  
C. Identify baseline predictors of responsiveness to each intervention and the mechanistic basis for each 
treatment. Candidate predictors are (a) demographic variables (e.g., sex, age, race, ethnicity, education); 
(b) clinical history variables (e.g., FI frequency, volume, duration, and association with urgency and 
diarrhea); and (c) baseline pelvic floor physiology (e.g., anal canal resting pressure, squeeze pressure, 
duration of squeeze, rectal sensory threshold for first sensation and urgency, maximum tolerable volume, 
structural integrity of anal sphincters assessed by ultrasound, and integrity of the pelvic floor innervation by 
trans-sacral and trans-lumbar magnetic evoked potentials).  

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D. Evaluate treatment combinations. Patients who do not meet the responder criterion by 3 months follow up 
will be offered the option of choosing additional therapy. This constitutes a pragmatic clinical trial which 
mimics clinical practice and will provide preliminary data for a future study. A second reason for allowing 
patients to add an additional preferred treatment if they do not show at least a 75% improvement is to 
facilitate recruitment; in our feasibility survey, subjects told us that the opportunity to try another treatment if 
the first failed would increase their willingness to be randomized. Data analysis will estimate 95% 
confidence intervals for the percent of responders to each treatment combination and to each 
monotherapy, and differences in responder rates between groups will be assessed. 
• Research objective 4. To compare the improvement in FI after combination treatment versus 
monotherapy and compare improvement among various treatment combinations, up to 24 months after 
administration of each treatment combination, compared to monotherapy.  
• Research objective 5. To estimate differences in the magnitude of improvement in FI from baseline to 
end of treatment between the treatment combinations.   
E. Assess the efficacy and durability of enhanced medical treatment and identify patient characteristics that 
predict treatment response. 
• Research objective 6. To estimate the responder rate during the last two weeks of enhanced medical 
treatment and also during follow up at 3, 6, 12, and 24 months. 
• Research objective 7. To assess the proportion of patients reporting AEs of pelvic pain of grade II or 
higher, or SAEs requiring hospitalization, during all weeks of medical treatment. 
• Research objective 8. To estimate the cost of delivering medical treatment and compare to the cost of 
delivering any of the other two treatments.  
F. Compare the cost effectiveness of two treatments for moderate to severe FI. 
• Research objective 9: To estimate the average cost effectiveness (i.e., cost per quality adjusted life 
year gained excluding costs that are only for research purposes) among conservative medical 
management non-responders for the two treatments at 6, 12, 18 and 24 months. 
This 4-site geographically dispersed study will identify the most optimal, durable, safe, and inexpensive 
treatment for moderate to severe FI patients. In addition, this project will demonstrate the efficacy of enhanced 
medical management of FI, explore the mechanisms of action for the study treatments, and identify the factors 
that predict the response to treatment. A successful outcome may result in changes to management strategies.  
 
2.0 
Background and Significance 
2.0.1 Prevalence and epidemiology: Fecal incontinence (FI) is the involuntary passage of solid or liquid stool8. 
The age-adjusted prevalence of FI occurring in the past month in non-institutionalized U.S. adults is 9% in 
women and 8% in men, and this increases to 15% in men and women by age 701. FI occurs at least weekly in 
3% of non-institutionalized adults1. Up to one in five women in the community report one or more episodes of 
FI in the past year9. The prevalence of FI is higher in primary care clinics compared to the general population 
because poor health is a risk factor for FI; an estimated 37% of primary care patients self-report FI on 
questionnaires, although this is rarely reported to their physician or identified in their medical record10. 
2.0.2 Impact on quality of life and health care costs: FI has a major impact on quality of life11, 12 being 
associated with symptoms of anxiety and depression and with avoidance of leaving home or inviting friends to 
visit13. FI increases the likelihood of admission to a nursing home2, and the prevalence in nursing homes is 
48%14. It is associated with high health care costs for the individual13 and, partly through its impact on nursing 
home referral, also with high costs to society2.   
2.1  Rationale for conducting a comparative effectiveness trial 
Evidence-based treatments available for FI: Several treatment approaches have been described for FI 
covering a spectrum from self-management with pads through biofeedback (BIO), drugs, injections with bulking 
agents (INJ), sacral nerve electrical stimulation (SNS), up to surgical reconstruction or implanting an artificial 

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inclusion criteria, and primary outcome measures. Three assessed outcome only at the end of BIO training; 
they did not assess maintenance of improvement27, 30, 31.  
In the most methodologically robust BIO RCT 15, 168 patients with at least weekly solid or liquid FI were 
screened to eliminate those who responded to conservative medical management during a four-week 
screening period. The remaining 108 patients were randomly assigned to receive either six sessions of BIO 
with pelvic floor exercises or pelvic floor exercises alone. In the intention-to-treat analysis, 76% of the BIO 
group reported adequate relief of their FI (not otherwise defined for them) three months following the end of 
treatment (approximately six months after onset of treatment) compared to 41% of the pelvic floor exercise 
group. Considering only patients who completed at least five sessions of BIO, 85% reported adequate relief of 
FI at six months. The average number of days per week with FI decreased from 3.2 at baseline to 0.8 after 
BIO. Complete continence was achieved by 44% of BIO treated patients compared to 21% of those treated 
with pelvic floor exercises alone. In a separate long-term study33 60 patients with refractory FI were assessed 
at 12 months after completion of BIO and showed persisting clinical improvements (63% were continent), and 
improvements in sphincter strength and rectal sensation.  
The Pelvic Floor Disorders Network (PFDN) conducted a multisite study of the effects of BIO versus an 
educational handout, and oral loperamide versus placebo in a factorial design. Three hundred patients were 
enrolled across eight clinical sites. Dr. Whitehead served as a consultant on this study and Marie Gantz lead 
the PFDN Data Coordinating Center. A review of ClinicalTrials.gov identified one other ongoing RCT 
(NCT01882101) which compares BIO to percutaneous tibial nerve stimulation (PTNS), but no data have been 
reported yet. These two studies will not fill the knowledge gaps that the FIT Study is designed to address. 
Two published RCTs compared pelvic floor physical therapy with manometry-assisted BIO to physical therapy 
alone in patients with FI. The first trial demonstrated that at 3 months follow-up BIO patients had greater 
reductions in scores on the Fecal Incontinence Severity Index (pre-treatment=33 and post-treatment=22, 
estimated SD ±2) compared to Pelvic Floor Exercises (PFE) patients (F=6.82, p=0.01, ANOVA).12  Patients in 
the BIO group also tended to have fewer days/week with FI than patients in the PFE group (0.83+1.5 vs. 
1.6+2.0 days/week of FI, mean and SD, p=0.08). Complete continence (no staining) was achieved by 20/45 
(44%) of patients in the BIO group vs. 13/63 (21%) in the PFE group (χ2=7.0, p=0.008). This trial replicates the 
Heymen study15 and provides additional support for manometric BIO; however, both this and the Heymen 
study have been criticized because all the subjects were recruited and treated in a single center, so 
generalizability across centers could not be assessed. A second study found that the addition of rectal balloon 
training and pelvic floor muscle training was no more effective than pelvic muscle training alone among 
patients with FI18.  
The only adverse event reported in any RCT of BIO for the treatment of FI was “skin soreness” in one patient18, 
24, 27. Medicare reimbursement for pelvic floor rehabilitation for FI provided by a physical therapist is 
approximately $1,435 total for 6 sessions.  
While BIO has been reported to increase anal squeeze pressure15 and improve rectal sensation34, the effects 
on anorectal sensorimotor functions vary considerably among studies33, 35. Moreover, the relationship between 
improvement in symptoms and anorectal functions has not been evaluated.  
2.2.2. Perianal INJ of Dextranomer Bulking Agent: Two systematic reviews published in 201036, 37 concluded 
that there was no evidence for the efficacy of injectable bulking agents for the treatment of FI, but another 
review38 which incorporated uncontrolled studies concluded that 56% of patients were treatment responders 
including 13% who achieved continence. Subsequent to these publications, Graf and colleagues16, 39 reported 
a multisite RCT of the effects of dextranomer INJ versus sham (saline) injections in 206 patients. At six months 
follow-up, 53% of the dextranomer-INJ patients had at least a 50% decrease in FI compared to 21% of sham 
injected patients. At 12 months, the responder rate was sustained with 45% of the dextranomer INJ group 
achieving at least a 50% decrease in FI relative to baseline. Based on this multicenter RCT, dextranomer was 
approved by the FDA for treatment of FI.  
In the only other controlled study, INJ were compared to BIO18. The 62 patients in the BIO group were 
instructed to practice at home 5 days per week for 6 months with a commercially available device that could 
also provide electrical stimulation, and half of the patients used electrical stimulation as an adjunctive 

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treatment. Patients were supervised by a physical therapist five to six times during this period. However, this 
report provided few details on how BIO training was done. The treatment protocol for INJ was similar to that 
used by Graf. Results showed that FI improved in both treatment groups (St. Mark’s FI severity scores 
decreased from 12.9 to 8.3 in the INJ group and from 12.6 to 7.2 in the BIO group), but there were no 
differences between treatments.  
In the Graf multisite study16, anorectal physiology was not evaluated. In the controlled trial comparing BIO with 
INJ18, the dextranomer INJ did not increase anal resting or squeeze pressure. Hence the mechanism by which 
dextranomer improves fecal continence is unknown.  
Graf16 reported there were 128 adverse events and two serious adverse events (AEs) in the 136 patients who 
received INJ. However, many of these were minor AEs related to changes in stool consistency. The incidence 
of more significant AEs, such as pain, fever, and/or abscess, was 9.6%. Other investigators have reported 
comparable rates of AEs in uncontrolled case series40, 41. Dextranomer treatment is not consistently 
reimbursed by third party payers but is estimated to cost approximately $7,408 if two injections are given 
  
2.2.3. Sacral Nerve Stimulation:  SNS is performed in two steps: (1) During test stimulation, a temporary 
electrode is inserted with its tip near the sacral nerve and connected to an external stimulator for 1-2 weeks. 
However, screening procedures are evolving, with many surgeons now preferring to use barbed leads intended 
for permanent implant during the screening stage, reasoning that 70% to 90% of patients will improve enough 
to warrant a permanent implant, and for these patients, the permanent lead is already in place. In this study, 
we plan to use the tined lead to avoid the need for a second test if the PNE fails. (2) If FI frequency decreases 
by at least 50% during PNE, a battery-operated electrical stimulator is permanently implanted beneath the skin. 
An estimated 10% - 30% of patients fail to meet criteria for permanent implant. Publications on the 
effectiveness of SNS often report only the outcomes for patients receiving permanent implants, but this makes 
these outcomes not comparable to reports on BIO and INJ where the analysis sample includes all patients 
randomized to treatment (intent-to-treat analysis). Consequently, in the literature review below, we adjust for 
the number of patients failing test stimulation and report the intention-to-treat (ITT) outcomes for SNS. 
Although SNS is regarded as standard of care for patients with severe FI who have failed enhanced medical 
treatment and is approved by the FDA for this indication, few RCTs17, 42 have been published. Wexner25 
reported a large, uncontrolled multisite study, and this carefully done study was used for our sample size 
calculations. This study included 133 patients with at least two episodes of solid or liquid FI per week at 
baseline. After correction for patients who failed the test stimulation, the proportion achieving a 50% reduction 
by ITT analysis was 71.4% at six months and 66.2% at 12 months.  
Tjandra17 compared the effects of SNS to “optimal medical management” in 120 patients with at least weekly 
solid or liquid FI. The control intervention included pelvic floor exercises taught by digital rectal examination 
and loperamide if needed. Controls were seen approximately once per month in the first 6 months. By ITT 
analysis, 68% of SNS treated patients achieved at least a 50% reduction in FI by six months, and 42% 
achieved continence. Controls showed no improvement at all, which raises concerns about the credibility of the 
control condition for the patients randomized to control.  
Thin42 reported an underpowered RCT (described as a pilot study) which compared 19 patients treated with 
SNS to 17 treated with posterior tibial nerve stimulation (PTNS). No between-group statistical tests were 
reported but the trends favored SNS: 61% of SNS patients and 47% of PTNS patients met the responder 
criterion of a 50% reduction in FI episodes at 6 months. Leroi26 published a randomized cross-over study 
comparing simulator-on to stimulator-off periods which is often cited in support of SNS; however, the 27 
subjects in this study were likely unmasked because they could probably feel when the stimulator was on.  
Tan28 carried out a meta-analysis of available RCTs plus 32 reports on case series and concluded that SNS 
reduces incontinence episodes, improves ability to defer defecation, improves quality of life, and increases 
anal pressures. ClinicalTrials.gov identified one other ongoing cross-over study (NCT02163187) which is 
evaluating SNS in patients with FI following surgery for rectal cancer. 

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Wexner reported there were 13 treatment-related infections (AEs) including seven that required surgical 
intervention (serious adverse events, abbreviated SAE) in his series of 120 patients29. In his meta-analysis of 
34 publications, Tan28 estimated the complication rate as 15% with 3% requiring permanent explant 
(considered SAEs). Medicare reimbursement for SNS is approximately $18,450. 
With SNS, improvement in FI frequency is associated with relatively minor effects on anorectal function43. One 
study observed that SNS but not sham stimulation increased the frequency of retrograde propagated 
sequences throughout the colon, which may be anticipated to delay colonic transit44. 
2.3. Expected impact of this FI comparative effectiveness trial: The proposed project will improve scientific 
knowledge, technical capability, and clinical practice as they relate to the treatment of FI. A critical barrier to 
progress in the treatment of FI is the lack of understanding regarding comparative effectiveness of currently 
approved treatment modalities and their pathophysiological basis. Our objectives are to address this significant 
gap in our knowledge by (1) comparing the effectiveness, safety, and cost of two treatments, BIO and INJ at 3, 
6, 12, 18, and 24 months following the end of treatment; (2) identifying patient characteristics at baseline that 
predict response to each intervention; (3) investigating the mechanistic basis for treatment success by 
examining rectal sensory thresholds, rectal compliance, neurophysiological parameters, and stool consistency; 
(4) evaluating the response to treatment combinations selected by non-responders compared to the primary 
treatment assignment; and (5) assessing the rate of response to EMM, the durability of response, and patient 
characteristics that predict benefit from medical treatment. SNS will not be included as a randomized study 
treatment as it is a more invasive treatment and appears to negatively impact the willingness of patients to 
participant in the study. We will offer SNS to participants as an additional treatment choice when they are 
identified as non-responders to the randomized treatment at the 3-month follow-up assessment, thus allowing 
them the opportunity to choose as an additional treatment either SNS or the other intervention to which they 
were not initially randomized (either BIO or INJ). Participants who do not meet clinical criteria for receiving 
SNS, or who previously received and did not respond to SNS treatment will not be offered SNS as a treatment 
option at 3-month follow up. 
 
When the aims of this project are achieved, the concepts, methods, technologies and treatments or preventive 
interventions related to the management of FI will be changed as a result of (1) development of a rational basis 
for recommending treatment with BIO or INJ; (2) demonstration of comparative effectiveness of each treatment 
modality; and (3) a new understanding of the effects of each treatment on bowel symptoms, and quality of life, 
especially regarding safety, tolerability, and adherence. 
 
3.0  
Study design:  
The overall study design, shown in Figure 1, is an unmasked, multisite, randomized, parallel group study 
comparing the effectiveness of two treatments for moderate to severe FI. This study design builds on the core 
recommendations of the NIDDK Workshop for design of an ideal comparative effectiveness RCT3. It is a 
parallel group design which has the following features:  
1. Baseline: Patients will keep a daily symptom diary for two weeks prior to the Baseline visit 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. 
Adverse events and cost will be reassessed at each in-person visit and at 3-, 6-, 12-, 18- and 24-month 
follow up assessments.  
2. Enhanced medical management: All patients meeting inclusion criteria will first be treated with EMM for 4 
weeks to identify those who really need a more expensive and more invasive treatment. 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. (Section 6.1) Additional goals of the EMM protocol are (a) to ensure that patients randomized 
to INJ meet the accepted criteria by failing to respond to EMM, and (b) to document the efficacy and the 
durability of systematically applied, optimized EMM. This design is similar to the one used in the Heymen15 
RCT which provides the strongest evidence for the efficacy of BIO. We believe the exclusion of patients 

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who respond to the nonspecific treatment components that are included in the EMM protocol may make it 
easier to detect differential effects of BIO and INJ. Patients who are responders to EMM will be followed 
up 3 months later; those who remain responders will be continued on EMM and be followed for the 
remaining 24 months of the study. However, those who are no longer responders to EMM after 3 months 
will be invited to be randomized to BIO or INJ just like patients who failed EMM at the end of the initial run-
in treatment, 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. Those subjects will participate for 27 
months.  
3. Randomly assigned treatment: The window for treatment to be initiated is 0 days – 4 weeks after 
randomization. Based on a randomization scheme implemented by the Data Coordinating Center, each 
patient will be randomly assigned to BIO or INJ and treated as follows:  
• 
BIO will consist of 5 required one-hour training sessions which should, ideally, be spaced at weekly 
intervals; however, the window between visits is 2 – 10 days to accommodate participants’ schedules 
as long as no more than two visits occur in one calendar week. A 6th treatment session will be made 
available for patients if it is shown through anorectal manometry that they are having trouble 
understanding directions given during the first five sessions. These will occur in the 5-6 or so weeks 
following the initiation 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.  
• 
INJ will include a preparation for treatment and a treatment visit. Preparation will include the use of 
enemas and minimal restrictions on food intake. Prophylactic antibiotics should be started on the day 
of the procedure, per the treatment SOP.  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 either the treatment to which 
they were not randomized or SNS as an adjunctive treatment for the remaining months of the study. One 
reason for offering non-responders an opportunity to try an additional treatment is to increase the 
likelihood that patients will consent to be randomized despite possibly having a priori preferences for one 
of the two treatments. The assumption that this will increase willingness to be enrolled was confirmed in 
the pilot feasibility survey we performed in 187 patients with FI representing the clinical sites: 57% of 
patients reported that the ability to receive the treatment of their choice if the assigned treatment was not 
effective, was important to their willingness to be randomized. Moreover, the estimated 46% of patients 
who do add a second treatment after the 3 months primary assessment will enable us to collect 
exploratory data on the possible benefits of combining these treatments. (None of the two investigational 
treatments can be discontinued.) Thus, the patients  
 
 
 
 
 
 
 
 
 
 
 

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Figure 1. Study Design 
 
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). If SNS is selected as an adjunctive treatment it will be performed as follows: 
• 
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 4 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.   
5. Primary outcomes include safety and cost as well as symptom reduction: Very few studies have 
compared different treatments for FI (see Section 2.0), and these few have compared treatments based 
only on reductions in frequency of FI. Data on safety and cost as well as symptom reduction are needed 
to develop treatment algorithms and reimbursement policies. This study addresses this need by 
including number and type of adverse events and cost of care for two of the most frequently employed 
treatments for moderate to severe FI, in addition to reductions in FI. The primary outcomes will be 
assessed at 3 months following treatment initiation.  The window for the 3-month follow-up assessment 
is 1 week before and 3 weeks after the anticipated due date. 
6. 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 the treatment will be included in the analysis. These 
follow-up assessments should occur within the following windows:  
• 
6- and 12-month follow-up assessments - 1 week before and 3 weeks after the anticipated due 
date; and 
• 
24-month assessment - 3 weeks before and 3 weeks after the anticipated due date.  
All treatments will continue to be active after the training period. The bulking agents injected in the INJ 
treatment will remain in place. For BIO, patients will be encouraged to continue to practice pelvic floor 

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• But, all requirements for randomization eligibility must be completed before 
randomization in Medidata. 
Treatment 
initiation (Time 0) 
for first 
randomized 
intervention (BIO, 
INJ) 
Randomized treatment should start 0 days to 4 weeks after randomization in 
Medidata. 
Note:  
• If treatment is initiated on the same day as the Randomization Visit, all 
randomization requirements (questionnaires and procedures) should be 
completed before treatment initiation. 
• The Time 0 date used to determine subsequent events dates in the Medidata 
EDC will be determined as follows: 
o Time 0 for BIO = Date of Train Session 1 
o Time 0 for INJ = Date of the first injection 
o Time 0 for EMM responders = Date the randomization eligibility CFR is 
completed in Medidata (that is, date when participant is deemed to be 
ineligible for a randomized intervention as considered a responder to 
EMM). 
o For any participant who does not respond to EMM but who is also not 
randomized for any other reason, the Time 0 used to determine the 
schedule for the follow-up assessments will also be the date on which the 
randomization eligibility CRF is completed in Medidata.  
Biofeedback (BIO) 
therapy (5 x 1-
hour visits, with an 
optional 6th) 
Each Biofeedback Train session should be spaced with a minimum interval of 2 
days and a maximum interval of 10 days from the previous session, with no 
more than two sessions in a calendar week. Preferred is one training session 
per week. 
Injection (INJ) – 6-
week follow-up 
1 week before – 2 weeks after the target date determined from Time 0 
3-month follow-up 
1 week before – 3 weeks after the target date determined from Time 0 
6-month follow-up 
assessment 
1 week before – 3 weeks after the target date determined from Time 0 
12-month follow-
up assessment 
1 week before – 3 weeks after the target date determined from Time 0 
18-month follow-
up assessment 
1 week before – 3 weeks after the target date determined from Time 0 
24-month follow-
up assessment 
3 weeks before – 3 weeks after the target date determined from Time 0 
Optional treatment 
- initiation 
Optional additional treatment initiation should occur within 0 days to 4 weeks 
after the 3-month visit post randomization.  
Note: 
• Event windows for follow-up assessments will continue to be determined from treatment initiation (Time 0) of 
the randomized intervention even when participants who fail that treatment select a second intervention. 
• The timeline for those participants who initially respond to EMM but are then randomized after they are 
determined to be treatment failures at the 3-month follow-up assessment will reset when they begin the 
randomized intervention. For these participants, the timeline for subsequent events will reset based on the 
Time 0 of their randomized intervention. These participants will be active in the trial for an additional 3 
months so that they are able to complete the 24 months of follow-up following the start of the randomized 
treatment. 

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4.0 
Outcome Measures 
4.1 Primary Outcomes:  There are three primary outcomes: efficacy, safety, and cost. 
4.1.1 Efficacy: The primary efficacy analysis will be based on the proportion of responders in each treatment 
arm. A responder will be defined as an individual whose symptom diaries demonstrate at least a 75% reduction 
in the average weekly frequency of FI from baseline (prior to the EMM to the last two weeks of the treatment 
period preceding the 3-month post intervention follow up. The rationale for choosing a 75% reduction in the 
frequency of staining, solid and liquid stool incontinence as the primary outcome measure is that, both in focus 
groups and surveys we conducted, half of patients with FI reported that they did not consider a 50% reduction 
in FI episodes to be a satisfactory measure of treatment success; rather, they believed an improvement of 70-
80% was necessary for a treatment to be considered successful47.  
The frequency of FI will be recorded on a paper diary. Patients will be asked to record (1) the time of each 
accidental bowel leakage (ABL), (2) the amount of leakage that occurred, (3) the rectal sensation that occurred 
prior to the event (no awareness, normal warning, or strong urge), and (4) the consistency of the leaked stool. 
Patients will also be asked to record (5) the time of any BM that occurred in the toilet even if this starts as an 
ABL and is finished by passing stool in the toilet, (6) the consistency of the BM using the Bristol Stool Form 
Scale, and (7) medications or other treatments employed.  The primary outcome is based only on the number 
of FI events; however, the amount of stool lost and the type of sensation experienced before the leakage are 
needed to guide the BIO intervention, and the number and consistency of BMs and use of fiber or medications 
is used to guide the EMM intervention. Rather than use different diaries for each of these purposes, we will ask 
all subjects to use this paper diary throughout the intervention period and for two-week periods preceding all 
follow up assessments.  
Previous studies have identified a number of limitations to paper diaries: (1) Missing data if subjects forget to 
complete the diary or if it is illegible. (2) Inaccurate data that may result if subjects forget to record events when 
they occur and then try to remember what happened at the end of the day or several days later. In previous 
studies48, we provided patients with a pocket-sized paper diary to take with them throughout the day and asked 
them to transfer their symptom ratings from the paper diary to a website at the end of the day. If they failed to 
submit a report to the website within 12 hours, they were sent an email reminder or were telephoned. They 
were also reminded the next time they attempted to enter data, if the data for the previous day was missing, 
and they were given an opportunity to report on the previous day; however, they were not permitted to go back 
further than the previous 24 hours. They were also provided with bonus payments for not missing any diary 
reports. With this combination of techniques, we were able to obtain an average of 73 consecutive days of 
symptom diaries without interruption from 185 IBS patients varying in age from 18 to 84. However, there is 
concern that since advancing age is a risk factor for FI, the patients who enroll in this study will be older and 
less comfortable than young or middle-aged subjects with transferring data to the internet. Therefore, to avoid 
biasing enrollment against these older subjects, we decided to use paper diaries for this study. To ameliorate 
potential problems with missing or untimely data reporting we will (1) thoroughly train subjects in recording their 
diary information at enrollment, and (2) telephone subjects during the first two weeks that they keep the diary 
to ensure that they are able to record events on this paper diary when they occur.  
To protect against experimenter bias, patients will be classified as responders or non-responders based on 
diary data entered into the electronic data capture (EDC) system at the end of EMM and at 3-, 6-, 12-, and 24- 
month follow-up. Once the diary data are entered, a calculation performed within the EDC system will 
determine which patients are non-responders eligible for randomization, and the same process will determine 
which patients are non-responders at 3 months so they can be offered alternative treatment. 
4.1.2 Safety: Adverse events will be collected by participant interview and medical records review, as 
appropriate, at all clinic and follow-up assessments. Adverse events occurring in the period from the time that 
the participant is consented through the end of the participant’s study involvement at the 24-month follow-up 
assessment should be documented (See Section 9.2). Adverse events will be classified as Serious Adverse 
Events (SAEs) if conventional criteria are met 
 or simply as adverse events (AEs). AE 

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severity will be graded based on common terminology criteria for adverse events (CTCAE). Relationship to 
treatment will be assessed by the treating clinician and reviewed by the Medical Safety Monitor for the purpose 
of determining which events need to be reported to the IRB, DSMB and NIDDK in an expedited manner. At the 
end of the study, relationship to treatment will be evaluated by comparing the incidence of specific AEs 
between treatment groups.  AEs will not be collected on the bowel diary, but patients will be encouraged to 
contact the study coordinator any time they notice a new symptom or side-effect.  
4.1.3 Cost of care: A primary endpoint is cost for each treatment from the payer, patient, and societal 
perspectives. For the payer perspective, we will tabulate the numbers and types of treatment visits and multiply 
these by Medicare authorized reimbursement rates. Patient costs will be obtained from an Out-of-Pocket Cost 
Questionnaire developed to collect information on amounts patients pay for non-prescription medications and 
absorbent pads. Estimated costs from the societal perspective will be the sum of payer costs, patient costs, 
and patients’ productivity losses associated with FI as evaluated by the Work Productivity and Impairment 
questionnaire (WPAI)49. The WPAI is a widely used measure of work absenteeism, impairment while at work, 
and interference with daily activities.  
A secondary endpoint is an analysis of the cost-effectiveness of the two treatments. The metric used for 
comparing cost-effectiveness is the quality adjusted life years. This calculation requires a health-related quality 
of life index, i.e., a generic health related quality of life scale that may be used to compare the morbidity-related 
impact of different disease states. Harvie and colleagues50 compared three of these health-related quality of 
life indices in a group of 200 women with fecal incontinence, urinary incontinence, and/or pelvic organ 
prolapse. The utility indices compared were the Health Utilities Index Mark 3 (HUI-3)51, the Euro-Qol (EQ-
5D)52, and the Short Form 12 (SF-6)53. The HUI-3 and the EQ-5D were comparable in terms of their correlation 
with FI severity scales and their ability to discriminate between women with FI and those without. However, the 
EQ-5D is the only one that has previously been used to estimate cost-effectiveness for treatment of FI, and it 
was shown to be able to discriminate between SNS and another surgical treatment for FI54.   
4.1.3.1 EuroQol 5D (EQ-5D): The EQ-5D consists of 5 domains – mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression – with three possible responses indicative of severity of impact for 
each of the 5 single question corresponding to these 5 domains55. It shows good convergent validity with other 
standard measures of health utility such as the HUI-350, and is able to discriminate between different 
treatments for FI54. The EQ-5D is the most widely used health utilities instrument for assessing cost-
effectiveness. This generic QoL measure will complement the disease-specific Fecal Incontinence Quality of 
Life Scale. 
4.1.3.2 Work Productivity and Impairment (WPAI)56. The WPAI will be used to measure cost from a societal 
perspective. It is a widely used measure of work absenteeism, impairment while at work, and interference with 
daily activities. The WPAI can be given in two forms: one of which measures the impact of general health 
problems and a second which measures the impact of a specific health condition. The WPAI has been shown 
to have good convergent validity with other measures of work and activity impairment as well as test-retest 
reliability and discrimination between health states49, 56. It has not been used to measure the impact of FI on 
work productivity but has been used in studies of overactive bladder and urinary incontinence57, and it is 
sensitive to the benefits of a drug on absenteeism and activity impairment in patients with irritable bowel 
syndrome58.  
 
 

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scale is strongly correlated with the impact of FI on quality of life63. It will be given at baseline, end of EMM, 3, 
6, 12, and 24 months (Table 2).  
4.2.2 Fifty percent responder. To facilitate comparisons with previously published studies that have used a 
50% responder definition16, 25, we will also calculate the proportion of patients who have at least a 50% 
reduction in FI episodes. This will be calculated from diary data entered in the EDC system at the end of EMM 
and at 3-, 6-, 12-, and 24-month follow-up. 
 4.2.3 Continence rating. The proportion of patients in each treatment arm who are continent at each follow up 
will be reported as an additional secondary outcome of treatment efficacy. This will be calculated from diary 
data entered in the EDC system at the end of EMM, and at 3, 6, 12, and 24 months. Continence will be defined 
by three criteria: (1) Absence of FI episodes on the two-week bowel diary, (2) self-report by the patient using a 
questionnaire that they have had no ABLs for the last month, and (3) self-report that they “no longer have this 
problem” (question 1 below).  
1. 
Have you had any ABLs in the last 30 days? Yes/No. 
2. 
“How would you rate your response to this treatment? Please choose from the following:  
(a) Worse than before treatment. (b) About the same as before treatment. (c) Somewhat 
improved. (d) Much improved. (e) I no longer have this problem.”  
4.2.4 FI Quality of Life (FIQOL) scale6. This is a validated disease-specific quality of life scale which is 
commonly used in FI treatment trials. It will be given at baseline, end of EMM, and 3, 6, 12, and 24 months 
follow up (Table 2). The FIQOL contains 29 items and is scored for four subscales: Lifestyle, Coping/Behavior, 
Depression/Self-Perception, and Embarrassment6. It has good convergent validity with generic measures of 
health-related quality of life, good test-retest reliability, and ability to discriminate patients with FI from those 
with IBS.  
4.2.5 PROMIS Anxiety Scale. PROMIS refers to the Patient Reported Outcomes Measurement Information 
System, which is a large collection of publicly available outcome measures available to clinical researchers. 
This library of validated patient reported outcome scales resulted from a collaboration between academic 
investigators and the National Institutes of Health. A team of PROMIS investigators consisting of experts in 
each domain (including anxiety) identified candidate items from existing questionnaires and wrote new items 
when necessary. This large item bank was then reviewed and revised if necessary, tested in focus groups of 
patients and non-patients to ensure domain coverage, and tested for understandability by cognitive interviews 
with individual items. Final edits were then made prior to field testing in large samples drawn from the 
population and from clinical samples. For each domain, a large bank of items was developed to be used as a 
pool of items for future test development, and subsets of items were selected for the development of computer 
adaptive testing (CAT) based on item response theory, and short paper forms of (typically) 4-8 items. Although 
there are no publications listed in PubMed for the use of the PROMIS Anxiety Scale in patients with FI, there 
are data on the psychometric properties of the scales in population samples and clinical samples with other 
disorders such as cancer and knee osteoarthritis. These sources show that the 7-item PROMIS anxiety scale 
correlated .97 with the 29 items in the full bank of anxiety items, showed an alpha reliability coefficient of .98 
throughout most of the range for the scale, and a correlation of .96 with legacy measures of anxiety64. In 
clinical samples of patients with knee osteoarthritis65 and multiple sclerosis66, the correlations with legacy 
measures of anxiety were .71 and .95 respectively.   
4.2.6 PROMIS Depression Scale. This scale was developed by the same process as the PROMIS Anxiety 
scale above. The 8-item short form PROMIS Depression scale correlates .96 with the whole bank of 28 
depression items, has a reliability coefficient of .99 through most of the range of scores, and is correlated .83 
with the CES-D depression scale64. In clinic samples with knee osteoarthritis65 and multiple sclerosis66, the 
correlations are .70 and .80 respectively.  
4.2.7 PROMIS Self-Efficacy for Managing Symptoms Scale. This questionnaire was developed to assess the 
participant’s willingness to engage in self-management skills, which is relevant to how patients perceive and 
react to the obligation to learn new skills and practice them when managing a symptom as compared to 

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accepting a treatment applied by a physician that does not require any responsibility for self-management. 
Although no validity data has been reported for the self-efficacy scale, this scale was selected because the 
items have face validity for FI (example: “I can keep my symptoms from interfering with relationships with 
friends and family.” 49)  
4.3 Moderator variables  
4.3.1 PHQ12 (Somatization). This scale is derived from the Prime MD structured interview. It consists of the 15 
most commonly reported symptoms in primary care practice. The subject is asked to rate how much they were 
bothered by each symptom in the last 1 months on a scale from 0=”not bothered at all” to 2=“bothered a lot”. 
Total scores are 0-30, with cut-off points of 5, 10, and 15 dividing the responders into mild, medium, and high 
severity. The PHQ-15 is highly correlated with other measures of somatization67, and it is a strong predictor of 
disability days, clinic visits, and scores on all subscales of the SF-20 health related quality of life scale67, 68. 
Cronbach’s alpha is .80. The PHQ-15 includes 3 gastrointestinal symptoms, which could confound the 
interpretation of the impact of somatization in gastrointestinal (GI) disorders if the GI symptoms on the PHQ-15 
are part of the diagnostic criteria for the GI disorder. Spiller has recommended eliminating these three items for 
GI studies, and he refers to this derived scale as the PHQ-1269. The cut-points dividing mild, medium, and high 
severity will be adjusted to 4, 8, and 12. We are using the PHQ-12 as a moderator variable because we have 
found somatization (measured by a different scale) to be a strong predictor of fecal incontinence severity. This 
is included as a moderator variable because recent unpublished studies show that somatization is a strong 
predictor of FI-specific quality of life. 
4.3.2 Credibility/expectancy questionnaire (CEQ)45. A potential bias in trials where the treatment conditions 
cannot be masked is the patient’s perception of the credibility and expectation of benefit associated with the 
treatments; these have been shown to influence the outcome of clinical trials. It is possible to assess the extent 
of this bias by asking patients to rate the intervention to which they are randomized for credibility and 
expectancy after their first exposure to the treatments. The CEQ consists of 6 items which are scored for two 
subscales: credibility and expectancy. This questionnaire has high internal consistency and good test-retest 
reliability45. It is recommended to be used in clinical trials of behavioral and surgical interventions where it is 
not possible to mask which treatment subjects are receiving and where a priori differences in credibility and 
expectancy could confound the interpretation of the trial results70. 
This questionnaire will be completed each time the participant starts one of the study interventions (EMM, BIO, 
INJ), as well as the optional treatment, SNS. So, all participants should complete the CEQ at least once – 
when they begin EMM. Randomized participants will complete it once or twice more – when they begin the 
randomized treatment (BIO, INJ) and then possibly again if they are identified as non-responders to the 
randomized treatment at the 3-month follow-up assessment and select the other treatment to which they were 
not originally randomized or SNS. The CEQ should always be administered at the treatment initiation visit but 
after the treatment has been initiated as follows: 
• 
EMM – after the participant has completed the EMM treatment initiation session; 
• 
BIO – after the participant has completed the TRAIN 1 session; 
• 
INJ – after the participant has received the injection of bulking agent; 
• 
SNS – after the participant has undergone the procedure to implant the temporary leads. 
4.3.3 Sex. Because there are different risk-factors for FI in females vs. males1, it is possible that the females 
and males will respond differently to these treatments. Randomization will be stratified by sex. 
4.3.4 Subtype of FI: Passive vs. urge-related FI. Passive FI is defined as FI that occurs without any warning 
sensation, while urge FI is said to occur when the patient feels a warning sensation of rectal fullness or 
urgency prior to stool leakage but is unable to reach the toilet before leakage occurs. It has been suggested 
that dextranomer may be more effective in patients with passive FI as compared to urge FI71. Patients will be 
classified at baseline as passive FI if their symptom diary shows >50% of FI episodes occurring without 
warning and as urge FI if <50% occur without warning.  
4.3.5 Bristol Stool Form Scale (BSFS) rating of stool consistency72. This is imbedded in the bowel diary. 
Measured at baseline, end of EMM, and at 3-, 6-, 12-, and 24-month follow-up (Table 2). The bowel diary form 

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includes validated pictures and descriptors of 7 different stool consistencies. For each 14-day bowel diary, we 
will compute the proportion of all BMs (including both continent and incontinent BMs) that are rated as BSFS 
types 1 or 2, and the proportion rated as BSFS types 6 or 7. The BSFS is a valid measure of stool form which 
correlates more strongly with whole gut transit time measured by the radio-opaque marker technique (r=.54) 
than with stool frequency (r=.35) or total stool output (r=.41). BSFS rating are also responsive to treatment with 
laxatives or antidiarrheal medications72. Another study73 showed a significant correlation of r=.49 between the 
BSFS ratings of healthy volunteers and stool water content, and a stronger correlation of r=.70 between BSFS 
ratings made by GI experts and stool water. As might be expected from the classification of a continuous 
measure into discrete categories, there is moderate variability between raters in the discrimination of type 2 
from type 3 and the discrimination of type 5 from type 6, but there is excellent discrimination overall between 
the three functional categories: hard stools of types 1-2, normal stools of types 3-5, and loose stools of types 6-
7.  
4.3.6 Anorectal manometry. Determine anal resting and anal squeeze pressures, sphincter squeeze 
endurance, rectal sensory thresholds (bag volume and intra-bag pressure at the first report of sensation, desire 
to defecate, urgency to defecate, and maximum tolerable volume), and rectal compliance. These parameters 
will be measured at baseline (but can be measured prior to randomization if not measured at Baseline) and 
may also be done at 3 months following initial treatment using the portable Medspira Anorectal manometry 
equipment, which can be used in the office and does not require a dedicated laboratory. This system includes 
a catheter, with 4 radially-oriented equidistant anal balloons and 1 rectal balloon, a wireless manometer, and a 
computer. The catheter is connected to the manometer that has pressure transducers and communicates 
wirelessly to the computer. The acquisition module display provides instructions that guide users conducting 
the study. The maneuvers used during portable manometry are identical to those in high-resolution manometry 
(HRM). Anorectal pressures and rectal sensation measured with portable manometry are significantly 
correlated with high-resolution manometry74. Participants who initially respond to EMM but are then 
randomized after they are identified as non-responders at the 3-month follow-up visit may have the ARM 
performed at the initial 3-month assessment but it should not be repeated at their second 3-month follow-up 
assessment if they are then randomized to BIO or INJ. 
4.3.7 Motor evoked potentials (MEP) will be tested at the Baseline visit (but can be tested at any time before 
randomization). It may also be tested at 3-month follow-up in all treatment groups. However, participants who 
initially respond to EMM but are then randomized after they are identified as non-responders at the 3-month 
follow-up assessment will not have the MEP repeated at their second 3-month follow-up assessment, that is, at 
the follow-up 3 months after they initiated the randomized treatment. The MEP data will be collected at the 
Mayo Clinic and Augusta University. MEP data will not be collected at the University of North Carolina at 
Chapel Hill, the University of Alabama at Birmingham, and the University of Michigan. 
This test uses a specially designed rectal probe with 2 pairs of bipolar steel ring electrodes, each 2 cm apart, 
mounted on a catheter (Gaeltec Ltd, Isle of Skye). The proximal pair will be located 8-10 cm from anus and the 
distal pair at 1-2 cm from anus. The electrodes are used to record the motor evoked potentials after magnetic 
stimulation. Magnetic stimulation of the lumbar (TLMS) and sacral (TSMS) nerve roots will be performed using 
a commercially available 90 mm coil magnetic stimulator (Magstim 2002; MAGSTIM, Whitland, UK). The 
subject will lie prone. For the TLMS study, the coil will be placed on each side of the midline approximately 3-5 
cm laterally and between L2 and L3 vertebra. The coil will be discharged with increasing frequency starting at 
50% and up to a maximum output of 85% of the scale range for magnetic stimulation intensity. For the TSMS 
test, the sacrum will be palpated to identify the S2 and S3 vertebra. The coil will be placed on each side of the 
midline over the sacrum (S2-S3) and discharged up to a maximum of 85% magnetic stimulation intensity. The 
EMG responses from anterior tibialis muscle of one leg will also be recorded (as a control) using Ag/AgCl disc 
electrodes The MEP responses will be recorded into a 4-channel amplifier with a built in AD interface (Nihon 
Kohden, Japan) with filter settings of 5-2000 Hz and at a sampling rate of 4-8 kHz, fed into a computer for 
display and analysis. Figure 3 shows the whole system. An optimal response will be defined as an anal and 
rectal MEPs of >10µV and tibialis response of 100µV on at least 3/6 consecutive trials. A rest period of 5 
minutes will be allowed between stimulations on each side. Five MEP responses will be obtained on each side 
and the average of the best three responses will be used to measure MEP response. 

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Measurements and Analysis: The latencies of wave forms (Figure 2) on both the TLMS and TSMS-induced 
MEP responses will be analyzed on both the right and left sides. The first and most prominent negative or 
positive deflection will be designated as the MEP response. We will measure the average latency for the left 
lumbo-rectal and lumbo-anal and the right lumbo-rectal and lumbo-anal MEPs. Similarly, the average latency 
for the left sacro-rectal and left sacro-anal and the right sacro-rectal and right sacro-anal MEP responses will 
be measured for a total of 8 measures. Each averaged response latency will be classified as abnormal if it is 
greater than the upper confidence interval reported previously for healthy controls; otherwise normal. Patients 
will be classified as having a neuropathy if >1 of 8 average latencies are abnormal. The validity of this test as a 
measure of pelvic nerve neuropathies was demonstrated in previous studies showing that these latencies 
differentiate patients with FI as a group from healthy controls (abnormally delayed latencies in 80% of patients 
with FI)75, and abnormally delayed latencies are also found in patients with spinal cord injury (known 
neuropathy)76  
Figure 2. Typical motor response to magnetic stimulation of the lumbar spine 
                                                     
 
                                                                        
4.3.8 Anorectal ultrasound or pelvic floor MRI. Measured at baseline (but if not done at Baseline, can still be 
measured up to and including at the time of the Randomization visit) in all subjects and may also be done at 3 
months in dextranomer treated patients. Sites will report who performs and interprets the test, whether an 
anorectal ultrasound or a pelvic floor MRI was performed, the person performing the test and the person 
interpreting the study, the width of any defects in the internal and external anal sphincters and puborectalis 
muscles, and the minimum thickness of these muscles. For sites using anorectal ultrasound, BK probes that 
are 3 dimensional will be used, except for The University of Alabama at Birmingham where 2 dimensional BK 
probes will be used. Please see the Anorectal ultrasound/pelvic floor operating procedure manuals. If this was 
performed in the previous 12 months to assess the sphincters, then this need not be repeated at Baseline if the 
sphincters appeared normal and there has been no history of anorectal trauma, surgical procedures, or vaginal 
deliveries in the intervening period between the imaging exam and study participation. 
 
4.3.9 Treatment Burden Scale. This questionnaire was developed to assist in understanding the burden of 
treatment, concerning time needed to complete the treatment, risk of new symptoms, adverse events or side 
effects, personal responsibility, and financial burden of the treatment.  
 
5.0 Study population  
The target study population are males and females aged 18 or older who have moderate to severe FI, defined 
as a minimum average frequency of staining, solid or liquid FI events at least 2/week using the baseline bowel 
diary. Patients will be recruited by a variety of methods: Direct referrals from clinicians, patients with a 
diagnosis of FI in their medical record (ICD 10 diagnosis code R15), registries of research participants with FI 
who have participated in previous studies of FI treatment, and advertisements in newsletters, newspapers, on 
websites, or flyers posted in medical or surgical clinics. Information on how the patient learned about the study 
will be collected at their screening visit.  
 

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15% attrition during this treatment phase and also assume that 20% (n=57) will be responders to EMM and 
therefore not eligible for randomization. This will leave 194 to be randomized (97 per group).  
 
Figure 3 shows that we expect 78 from the BIO group to complete the 3-month assessment after allowing for 
attrition of 20% and we expect 92 from the INJ group to complete the 3-month assessment. (We assume 
attrition will be no greater than 5% for the INJ group because this is a low-burden treatment and also because 
patients will want to be screened for AEs related to INJ.) However, the statistical analysis will be by intent to 
treat (ITT) and will include all 194 randomized to treatment; patients who are lost to follow up prior to 3 months 
will be considered treatment failures. The number of patients we expect to be responders to each of the 
treatments at the 3-month assessment is based on the pivotal trials shown in Table 1. We separated them in 
this way in Figure 3 to be able to estimate the numbers of non-responders who are likely to choose an 
additional treatment option after 3 months. The expected number of non-responders eligible for an additional 
therapy at 3 months is 63 for the INJ arm16 and 17 for the biofeedback arm15. Assuming equal probability of 
choosing either of the 2 available options as an added or alternative treatment, we could expect 40 patients to 
choose the SNS treatment, 32 to choose BIO, and 9 to choose INJ. For the primary analyses of follow up at 6, 
12 and 24 months, these non-responders will be retained in the ITT analysis as non-responders to their 
primary assignment at randomization. However, when we perform exploratory analyses of treatment 
combinations, these subjects will be treated as distinct groups and compared to patients who received 
monotherapy for the duration of the study. These comparisons (Aim D) are exploratory because there is 
insufficient power to test for significance. The left column of boxes in Figure 3 shows how we intend to follow 
up the responders to EMM.   
 
5.5 Feasibility Survey 
In Year 1 of the U34 planning grant, we conducted two feasibility surveys to inform us whether sufficient 
numbers of subjects would be willing to be randomized to a 3-arm treatment study. In the first survey, we 
recruited 164 individuals through an internet registry who reported experiencing FI at least twice each month. 
The anonymous internet survey gave brief descriptions of BIO, SNS, and INJ including published reports of 
their effectiveness, safety, and cost. These subjects were then asked to rate the effectiveness and safety of 
each treatment on a 0-10 scale from “definitely not” to “yes, definitely”. They rated their willingness to undergo 
each treatment on a 0-10 scale from “definitely not” to “yes, definitely”. The 164 respondents to this survey 
included 112 females (68% of total sample), average age was 43 years, and average FISS severity score was 
8 with 119 (73%) scoring in the moderate to severe range of FI severity. When asked to rate their willingness 
to enroll in a study in which they would be randomly assigned to one of these three treatments, 32% rated their 
willingness as 8 or greater on the 0-10 scale. When asked about each treatment separately they were 
significantly more willing to try BIO than INJ, and significantly more willing to try INJ than SNS. They rated 
these three treatments as equally effective but BIO was perceived as significantly safer than INJ, and INJ was 
perceived as significantly safer than SNS.  Concerns expressed about the safety of SNS included infection 
risk, use of electricity, and possible nerve damage.  
 

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The second feasibility survey was 
carried out in the 4 clinical settings 
where this study would take place. 
From 40 to 51 patients with 
established diagnoses of FI 
participated at each site (total 
n=187). The proportion who would 
be willing to be randomized with a 
confidence rating of at least 8/10 
was 40%. Patients who were 
unwilling to be randomized to this 
three-arm study most commonly 
listed safety concerns (62%) or 
unequal costs as reasons for their 
reluctance to be randomized. 
The data from these two surveys 
suggest that approximately 32% to 
40% of eligible patients would be 
willing to be randomized. This is 
consistent with our assumption 
(see Figure 3) that 1 in 3 patients 
screened will be eligible and 
willing to be randomized. 
 
6.0  
Details of Interventions 
Detailed procedure manuals were 
developed for each intervention 
(including the conservative run-in 
treatment) by separate protocol 
committees and are given below in 
subsequent Appendices. 
Adherence to these treatment 
protocols will be monitored as 
detailed in the procedure manuals.  
6.1 Enhanced medical 
management 
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. This treatment will be tailored to the underlying bowel disturbance as evaluated by a 2-week 
baseline bowel diary and described Manual of Procedures.  
We have previous experience with the design and testing of EMM. In an RCT of BIO15, we developed a 
protocol for a conservative run-in prior to implementation of the BIO or pelvic floor exercise protocol. This 
conservative treatment protocol included educating patients about the basic physiology of continence and 
defecation by showing them videos of defecography examinations, teaching them to normalize stool 
consistency by adding fiber to their diet or taking antidiarrheal or laxative medications if needed, and teaching 
 
Figure 3: Expected Patient Flow 
 
 

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them to use a daily symptom diary to chart their progress. By the end of this 4-week intervention, there was an 
average 60% reduction in frequency of FI, and 22% of patients reported adequate relief.  
Subsequently, with the support of grant R01 HS018695 we enhanced the EMM protocol by giving it to a series 
of small groups of patients with FI and asking them for feedback on what they found helpful or difficult, and 
what suggestions they had for improvement. Then with the assistance of two consultants who were nurses with 
expertise on FI (Christine Norton and Diane Newman), we developed a pamphlet for explaining each step in 
the program to patients and a series of training videos to teach nurses how to provide this intervention. These 
data were adapted by Dr. Bharucha into a Standard Operating Procedure for EMM.   
 
6.2 BIO training 
 
The BIO protocol developed for the PFDN by Whitehead and other experts on BIO for FI80 provided the 
foundation for the Biofeedback Manual of Procedures. An important feature of this BIO protocol is its ability to 
adapt to the individual patient’s needs: The most common physiological deficits that cause FI are (1) weakness 
of the external anal sphincter, (2) loss of the ability to sense weak distentions of the rectum caused by the 
movement of stool into the rectum, and (3) strong urges associated with rectal contractions that overwhelm the 
patient’s ability to retain stool in the rectum long enough to reach the toilet. We developed separate BIO 
procedures specific to each of these deficits: (1) strength training for sphincter weakness, (2) sensory 
discrimination training to improve the ability to detect weak rectal distentions, and (3) urge resistance training. 
Each component is described briefly below: 
a. Strength training: The patient is provided with visual feedback of anal canal pressure and rectal pressure, 
shown as two line tracings on a graph. The interventionist explains that the sphincter should be able to 
squeeze with enough strength to increase anal canal pressure to at least 100 mmHg. Then over a series of 
20-second trials, the interventionist sets intermediate goals that are beyond the patient’s average ability but 
which can be achieved at least 25% of the time. The interventionist sets a target line on the screen for the 
patient to aim for, and as performance improves, this target is moved up. Once the patient demonstrates 
improvement in the maximum anal canal squeeze pressure, the interventionist asks the patient to focus on 
the rectal balloon pressure and to avoid increases in rectal pressure when squeezing the external 
sphincter. Rectal pressure is caused by contraction of the abdominal wall muscles, which many patients 
are in the habit of doing although this actually increases the likelihood of FI. Lastly, when the patient is 
making progress on strengthening the sphincter squeeze and isolating it from inappropriate abdominal wall 
contractions, the interventionist will ask them to practice increasing the duration of their anal squeeze 
response by keeping the anal pressure tracing above the target pressure for progressively longer periods.  
b. Sensory training: No visual feedback is provided to the patient during sensory training; instead they are 
asked to focus on internal sensations to learn to recognize weaker distentions. The interventionist rapidly 
inflates the rectal balloon using a hand-held syringe and holds the air in the balloon for 5-seconds before 
withdrawing it. The patient is asked to squeeze when they feel any sensation in their rectum and to also 
report their perception verbally to the interventionist. The first distention is with 50 ml of air which most 
patients can detect. If the patient detected and responded to the 50 ml distention, the next distention is 10 
ml less. This is repeated until the patient begins to make errors; the last distention to which they responded 
correctly is the sensory threshold. At this point the interventionist switches to a discrimination training 
protocol in which some distentions are at the sensory threshold and some 5 ml less than this with the 
sequence being made unpredictable to the patient. The interventionist provides verbal encouragement 
during training to help the patient gradually improve their sensory threshold. 
c. Urge resistance training: Some patients with FI have strong urge sensations associated with rectal 
contractions, and they are unable to make it to the toilet. These urge sensations may be precipitated by 
anxiety about the possibility of having an accident (commonly experienced when they are trying to open the 
door of their house after returning from a shopping trip). Urge resistance training is based on the principles 
of systematic desensitization of a feared situation. The interventionist first inflates the rectal balloon to 

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identify the threshold for a strong urge. She (or he) then deflates the rectal balloon by 30 ml to reduce the 
intensity of the urge sensation and has the patient use deep breathing to relax. She then re-inflates the 
rectal balloon slowly while encouraging the patient to use relaxation to inhibit the urge sensation. Three to 
four such ramp distentions are used in the training session. It is usually possible to see an improvement in 
the tolerance for rectal distention within a session.    
Which of these three BIO protocols are used, alone or in combination, depends on the patient’s deficits. To 
guide the BIO therapist, a brief anorectal manometry test to assess sphincter squeeze responses and sensory 
thresholds is performed at the beginning of each BIO session. The patient’s symptom diary is also used to 
determine what type of training to focus on during BIO: the occurrence of FI without awareness suggests the 
need for sensory discrimination training while the occurrence of strong urges before FI suggests a need for 
urge resistance training. Strength training is provided in every BIO training session, but the interventionist may 
place greater emphasis on maximum squeeze, squeeze duration, or avoidance of abdominal wall contractions 
based on the initial anorectal manometry assessment.  
BIO training and anorectal manometric testing will use the Medspira Anorectal Manometry system and 
MCompass software (Minneapolis, MN). The PFDN worked closely with software engineers at Medspira to 
tailor the software to the needs of BIO therapy and to incorporate on-screen prompts to assist the BIO 
interventionist in following the protocol. 
We have also developed a program for training the BIO interventionists and monitoring their adherence to 
protocol. The key elements are these: (1) we recruit physical therapists or nurses with prior experience in 
muscle retraining, (2) these candidates are asked to review a series of training slides and videos and to pass 
built-in quizzes, and (3) they are trained one-on-one with a live patient surrogate and then evaluated (certified) 
with a live patient surrogate by Dr. Whitehead. 
6.3 INJ of dextranomer: This protocol is a modified version of the protocol used by Graf to ensure consistency 
across sites and safety of patients16. Patients are treated prophylactically with oral antibiotics to minimize 
injection site infections. One ml of NASHA dextranomer is injected through an anoscope into each quadrant of 
the submucosa (4 ml total) approximately 5 mm above the dentate line. After each INJ, the needle is left in 
place for 10 seconds to avoid backward leakage of contrast through the injection channel. Following the INJ 
patients are counselled to use stool softeners (docusate sodium) until the first bowel movement and to use 
paracetamol as needed for INJ site discomfort. Prophylactic antibiotics will be administered for 2 days starting 
on the day of injection. Six weeks after initial INJ, patients return for evaluation, and if the patient has achieved 
less than 75% reduction in FI, a second INJ is given.  
 
 

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6.4 Comparison of elements of BIO and INJ: 
Table 9 shows the elements of the two treatments compared to each other.  
 
Enhanced Medical 
Management 
Biofeedback 
Injection 
Preparation 
None 
None 
Diet restrictions; enemas; and 
antibiotics per the procedure SOP 
Number of 
visits 
2 visit + 2 phone calls 
5-6 visits 
2 visits 
Visit duration 
60 min 1st visit; 15 min phone 
calls (Day 3; Day 14); 30 min 
last visit 
60 min 
45 min 
Visit frequency 
1st and last visits 
(start of treatment and after 
treatment program has 
ended) 
Up to 2 visits per 
week, spaced 2-10 
days apart for first 5-6 
weeks or so 
0 and 6 weeks 
Procedure 
Daily sphincter exercises, 
meds to normalize bowel 
habits  
Learn how to improve 
strength and rectal 
sensation 
Bulking agent injected into 
rectal wall to narrow opening 
Expected 
Adverse 
Events 
None 
None 
Pain at injection site, bleeding, 
infection 
 
7.0 
Randomization and Masking 
7.1  Randomization  
Enrollment in the study will be defined as satisfying all eligibility criteria and signing informed consent (see 
Section 9.4). Randomization to the two interventions being compared BIO and INJ) will not occur until patients 
have completed EMM and been classified as a non-responder based on showing a less than 75% reduction in 
the average frequency of solid, liquid, and/or staining FI events compared to the two-week baseline. See 
Figure 4 for Decision Tree governing patient flow through the study.  
Randomization will occur in a ratio of 1:1 with an equal chance of being randomized to each treatment group. 
Randomization will be performed using randomly permuted blocks, with block sizes known only to the DCC, 
and will be stratified by clinical site and sex (male and female). For each participant, the web-based electronic 
data capture system will determine the treatment allocation from a static randomization table. Personnel at the 
clinical sites will not have access to the randomization table in order to minimize the risk of selection bias. 
 
 
 

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Figure 4: Decision Tree 
 
 
 
7.2 Masking  
7.2.1 Masking of patients to treatment assignment. Patients will be aware of the treatment to which they are 
assigned and the nature of alternative treatment to which they were not assigned. Should subjects have 
an a priori preference for one of the treatments, their expectation of benefit could be biased based on 
whether they were randomized to their preferred treatment. However, random assignment to the two 
treatments should balance the number of people with a positive expectancy in each treatment group. 
Moreover, we will assess individual differences in expectation of benefit by administering the 
Credibility/Expectancy Questionnaire at baseline and immediately after randomization. The expectancy 
scores will be entered into the analysis as a covariate to see if treatment group differences in efficacy 
are explained by expectancy, and to correct for this bias in the outcome assessment if present. 
7.2.2 Masking of investigators and study staff to treatment assignment. The investigators and study staff will 
be unmasked with respect to the treatment assignment at randomization, raising the possibility of 
investigator bias. However, this investigator bias will be reduced or eliminated by (1) having separate 
protocol committees develop each protocol and separate study teams administer the intervention; and 
(2) masking the assessment of outcome measures to the investigators and study staff as explained 
below. 
7.2.3 Masking of outcome assessment. Please refer to Table 2 for a list of measures and when they are 
assessed. Treatment response will be calculated from patient bowel diary data entered in the EDC 
system. The research assistant who enters the data into the electronic data capture system on the study 
website will be responsible for checking the diaries for completeness and interpretability to be sure the 
data can be entered into the EDC system and may contact subjects to clarify data entries if necessary. 
Patient reported outcome questionnaires will be completed by participants in the clinic using tablet 
computers or at home via links sent by email. For the small minority of patients who are unable or 
unwilling to complete these questionnaires electronically, paper versions of these questionnaires will be 

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available. 
 
  
8.0 
Statistical Considerations 
8.1 Analysis of Primary Endpoints 
Assessment of Randomized Treatment Response at 3 Months (Primary Efficacy Analysis). To test  
the efficacy of randomized treatment assignment, a generalized linear model with a logit link will be 
constructed to predict treatment response at 3 months post-randomization. Treatment group and the 
stratification factors of clinical site and sex will be included in the model as categorical independent variables. 
An ITT approach will be used in which participants will be analyzed based on their assigned treatment group 
regardless of actual treatment received. Participants without a valid bowel diary at 3 months due to drop out or 
other reasons will be classified as non-responders.  Using this model, we will test the null hypothesis that the 
proportion of responders is the same in the two treatment groups at 3 months following randomization using an 
alpha of 0.05. Sensitivity analyses will be conducted to assess the impact of classifying participants with 
missing data as non-responders. 
 
Assessment of Safety. The primary safety outcome is the percentage of participants in each randomized 
treatment group who experience an adverse event (AE) of pelvic pain of grade II or greater severity, treatment 
site infection, or a serious adverse event (SAE) requiring hospitalization between randomization and the 3 
month assessment. Because the proportion of participants with one of these events is expected to be small, 
Fisher’s exact tests will be used to compare the percentage of participants with a qualifying adverse event. The 
difference between the two treatment groups will be evaluated for significance using an alpha of 0.05. 
Participants who are missing safety data due to drop out or other reasons will be excluded from this analysis.  
 
Cost of Care Analysis. Mean and median costs per participant will be estimated for each of the two treatment 
groups and from the perspectives of payers, patients, and society. We will analyze whether differences in costs 
through 3-month follow up across the intervention arms and perspectives are statistically significant using 
parametric t-tests or using non-parametric bootstrapping methods. We will evaluate differences between the 
two treatment groups using an alpha of <0.05. 
8.2 Analysis of Secondary Efficacy Endpoints 
Assessment of Efficacy through 24 months. Treatment response (≥75% reduction in weekly FI episodes) at 
time points through 24 months will be analyzed using a longitudinal extension of the model used for the 
primary efficacy analysis. Month of assessment, and interaction between month and other predictors, will be 
included in the model, and the correlation between measures assessed on the same participant over time will 
be modeled using an appropriate covariance structure. Participants classified as non-responders at 3 months 
will continue to be considered non-responders at subsequent time points. Participants with missing responses 
will be classified as non-responders, but sensitivity analyses will be conducted to assess the impact of this 
assumption. 
Assessment of Safety through 24 months. The percentage of participants reporting AEs of pelvic pain of grade 
II or greater severity, treatment site infection, or an SAE requiring hospitalization by 6, 12, 18, and 24 months 
will be estimated with 95% confidence intervals using the Wilson Score interval method. Separate estimates 
will be produced for the groups of participants treated with each of the two therapies alone, and for participants 
in each of the treatment-order combinations. Confidence intervals will be compared descriptively.  
Assessment of Cost of Care through 24 months. The median costs per participant from the perspectives of 
payers, patients, and society through 24 months will be estimated for each of the treatment groups, including 
the treatment combinations, using methods described for the primary cost of care endpoint. No formal 
hypothesis testing will be done, and p-values will be presented for informational purposes only. 

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Assessment of FI Severity. General linear modeling will be used to analyze change from baseline to 3 months 
in FI severity as assessed by the Fecal Incontinence Severity Scale (FISS). Independent variables in the 
model will include randomized treatment group, clinical site, and sex. Missing outcomes will be assumed 
missing at random for the purpose of this analysis, but sensitivity analyses will be conducted to test the 
robustness of the results to this assumption. The model will be used to estimate 95% confidence intervals for 
the change from baseline to 3 months in FISS score in each of the randomized treatment groups. In addition, 
longitudinal general linear modeling will be used to analyze change from baseline to 6, 12, and 24 months in 
FISS score. In addition to the independent variables used in the 3-month analysis, the model will include fixed 
effects for time and the interaction between treatment and time. The model will account for the lack of 
independence between multiple measures assessed over time on the same study participant by modeling the 
within-participant covariance structure. For the 6- to 24-month time points, 95% confidence intervals for change 
from baseline in FISS score will be estimated for responders in each randomized treatment group, as 
determined at 3 months, and separate estimates will be produced for groups of non-responders who select into 
each treatment combination. In this analysis, no formal hypothesis testing will be done, and confidence 
intervals will be compared descriptively.  
Fifty Percent Responder Rate. The proportion of participants who have at least a 50% reduction in FI episodes 
will be modeled using the same methods described for the primary efficacy outcome. However, no formal 
hypothesis testing will be done, and p-values will be presented for informational purposes only. This will be 
analyzed for each follow-up assessment through 24 months. 
Continence Rate. The proportion of participants who are continent at each follow up time point will be modeled 
using the same methods described for the primary efficacy outcome. No formal hypothesis testing will be done, 
and p-values will be presented for informational purposes only. This will be analyzed for each follow-up 
assessment through 24 months. 
Assessment of Disease-Specific Quality of Life. Change from baseline to 3 months, and to 6 through 24 
months in the FI Quality of Life (FIQOL) scale will be analyzed using methods described for the analysis of FI 
severity.  
Assessment of Anxiety, Depression, and Self-Efficacy for Managing Symptoms. Change from baseline to 3 
months, and to 6 through 24 months in these Patient Reported Outcomes Measurement Information System 
(PROMIS) scales will be analyzed using methods described for assessment of FI severity.  
8.3 
Analysis of Secondary Aims 
Identify predictors of treatment response to each intervention. Generalized linear modeling will be used to 
identify baseline variables which are significant independent predictors of responder status at 3 months. 
Candidate independent variables in these models include (a) demographic variables (e.g., sex, age, race, 
ethnicity, education); (b) clinical history variables (e.g., FI frequency, volume, duration, and association with 
urgency and diarrhea); and (c) baseline pelvic floor physiology (e.g., anal canal resting pressure, squeeze 
pressure, duration of squeeze, rectal sensory threshold for first sensation and urgency, maximum tolerable 
volume, structural integrity of anal sphincters assessed by ultrasound, and integrity of the pelvic floor 
innervation by trans-sacral and trans-lumbar magnetic evoked potentials) and other moderator variables 
described in the protocol. Differences in predictors of response among the treatment groups will be assessed 
by evaluating interaction terms for the predictors and treatment group. Secondary analyses evaluating 
predictors of treatment response at other time points and predictors of other secondary outcomes will be 
conducted using similar methods.  
Investigate the mechanistic basis for treatment success for each intervention. General linear modeling will be 
used to identify measures associated with change from baseline to 3 months in FI frequency. The independent 
variables to be tested are anal squeeze pressures, rectal sensory thresholds, rectal maximum tolerable 
volume, trans-lumbar and trans-anal magnetic evoked potential, stool consistency measure by the Bristol Stool 
Form Scale, and adherence to protocol. Differences in predictors among the treatment groups will be assessed 
by evaluating interaction terms for the predictors and treatment group.  

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Evaluate treatment combinations. To assess the effectiveness of allowing non-responders to choose an 
additional treatment at 3 months, we will estimate 95% confidence intervals for the number of responders in 
each treatment-order combination at 6, 12, and 24 months using a Wilson Score interval79. Confidence 
intervals will be compared descriptively.  
Assess the efficacy and durability of enhanced medical treatment and identify patient characteristics that 
predict treatment response. The proportion of responders will be calculated at the end of EMM and at 3-, 6-, 
12-, and 24-month follow-up. A longitudinal generalized linear model will be constructed to predict treatment 
response based on time and clinical site; the model will account for the lack of independence between multiple 
measures assessed over time on the same study participant by modeling the within-participant covariance 
structure.  Participants who are non-responders to EMM at 3 months will continue to be classified as non-
responders at 6, 12, and 24 months. Participants without a valid bowel diary will be classified as non-
responders at that time point, and those who initiate off-study treatment for FI after EMM will be classified as 
non-responders at each subsequent visit/assessment. Using this model, we will compare response rates at the 
end of EMM to response rates at 3, 6, 12, and 24 months. We will also calculate 95% confidence intervals for 
the percentage of participants reporting AEs during EMM. Costs of EMM will be estimated and compared to 
costs of the other study interventions using methods described for cost of care analysis. The predictors of 
response to EMM at baseline, 3, 6, 12, and 24 months will be explored using generalized linear modeling.  
Cost- Effectiveness Analysis. We will estimate the impact of each intervention on quality-adjusted life-years 
(QALYs). QALYs are summary measures of morbidity and mortality that typically range from 0 to 1 over a full 
year, where 1 represents perfect health. QALY estimates will be obtained from the EQ-5D; annual QALY 
measures will be calculated. We will assess the average cost per QALY gained for each intervention and the 
incremental cost per QALY gained by comparing the interventions ordered from lowest to highest QALY gains 
(i.e., comparing the intervention with medium effectiveness to the intervention with lowest effectiveness and 
the intervention with highest effectiveness to the intervention with medium effectiveness). 
8.4 Interim Analysis 
Interim analyses for safety will take place at regular intervals corresponding to the timing of Data and Safety 
Monitoring Board (DSMB) meetings. For each meeting, the DCC will prepare confidential reports for the DSMB 
summarizing AEs and SAEs, with statistical comparisons of event rates between treatment groups. Based on 
the data presented, the DSMB may recommend stopping the study for safety concerns, but there are no formal 
stopping guidelines for safety for this study. 
The percent of treatment responders in each randomized treatment group will also be presented to the DSMB, 
but no formal interim analyses for efficacy are planned. The primary reason for this is that an interim analysis 
would be very unlikely to reveal an adequately strong signal in favor of one of the treatment groups for all three 
of the primary outcomes, and in that case, stopping the study early would prevent some of the primary study 
questions from being answered. In addition, if the study was stopped early, the smaller sample size that would 
result would reduce the precision with which we could estimate efficacy among participants who add a 
supplemental treatment.  
 
9.0 
Data and Safety Monitoring and Informed Consent 
9.1  Data and Safety Monitoring Board 
The protocol will be approved by the DSMB prior to initiation of participant recruitment. The DSMB will also 
review study data at regularly scheduled meetings either in person or by teleconference. Reports prepared by 
the DCC for these meetings will include AE and SAE summaries by treatment group and individual SAE 
narratives. They will also include data on participant recruitment, visit/assessment completion, and adherence 
to protocol. The DSMB will provide recommendations to NIDDK regarding continuing the study or stopping the 
study for safety or futility.  

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9.2  Reporting of Adverse Events 
All adverse events that occur from the time that the participant is consented through the 3-month follow up visit 
will be recorded on designated CRFs. Following the 3-month follow up assessment and through the 24-month 
follow-up assessment, the research coordinators will record only AEs of grade II or higher; however, any AE, 
regardless of severity/grade, should be reported through the 24-month follow-up visit if it is possibly related to 
the randomized or optional study treatments. Failure of the study interventions to adequately control fecal 
incontinence symptoms (failure of efficacy) will be captured by the study endpoints and will not be recorded as 
an adverse event.  
9.3  Reporting of Serious Adverse Events 
Each clinical investigator is responsible for reporting serious adverse events (SAEs) to the IRB at their 
institution per local IRB requirements, and to the DCC within 24 hours of when the clinical site is notified of the 
event. In accordance with GCP, an adverse event is considered "serious" if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes: death, a life-threatening adverse event, 
inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or 
substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require hospitalization may be 
considered serious when, based upon appropriate medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition.  
An adverse event is considered "life-threatening" if, in the view of either the investigator or sponsor, its 
occurrence places the patient or subject at immediate risk of death. It does not include an adverse event that, 
had it occurred in a more severe form, might have caused death. 
Reporting of Unanticipated Adverse Device Effect 
 
Unanticipated adverse device effect means any serious adverse effect on health or safety or any life-
threatening problem or death caused by, or associated with, a device, if that effect, problem, or death was not 
previously identified in nature, severity, or degree of incidence in the investigational plan or application 
(including a supplementary plan or application), or any other unanticipated serious problem associated with a 
device that relates to the rights, safety, or welfare of subjects. 
 
An investigator shall submit to the sponsor and to the reviewing IRB a report of any unanticipated adverse 
device effect occurring during an investigation as soon as possible, but in no event later than 10 working days 
after the investigator first learns of the effect. A sponsor who conducts an evaluation of an unanticipated 
adverse device effect shall report the results of such evaluation to all reviewing IRB's and participating 
investigators within 10 working days after the sponsor first receives notice of the effect.    
 
Additionally, 21CFR803.1 requires reporting of any required intervention to prevent permanent impairment or 
damage (applies to devices).  This should be reported if the investigator suspects that the use of a medical 
product may have resulted in a condition which required medical or surgical intervention to preclude permanent 
impairment or damage to a patient. 
Once the SAE is reported to the DCC, it is reviewed by the medical safety monitor (MSM). An SAE summary 
report is sent to the DSMB and NIDDK (the sponsor). The SAE review process will be documented by the 
DCC. 
Any serious adverse events (SAEs) that are deemed related and unexpected will be submitted in a safety 
report to the DSMB, NIDDK, and all participating investigators.  Clinical sites will follow local IRB guidelines for 
submission of any unexpected and related SAEs that occur at either their own site or at other study sites. 
9.4  
Informed Consent 

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PROTOCOL VERSION: 10.0 (Approved: JUN 11, 2022). Comparative Effectiveness of Biofeedback and Injectable Bulking Agents 
for Treatment of Fecal Incontinence: The Fecal Incontinence Treatment (FIT) Study 
 
Patients who are candidates for study participation will be approached for enrollment. Written informed consent 
will be obtained in accordance with IRB Guidelines. A common template for informed consent will be used by 
all clinical sites, with modifications allowed to meet the necessary requirements of their institutional human 
subjects committees.  
 
A participant may be prematurely withdrawn from the trial and/or discontinue study treatment as a 
result of the following: 
• At their own request or at the request of their legally acceptable representative. 
• If in the investigator’s opinion, continuation in the trial would be detrimental to the well-being of 
the participant. 
• If the patient is diagnosed with a condition which is excluded per protocol. 
• At the specific request of the sponsor or termination of the study by the sponsor. 
• Participant becomes pregnant. 
 
In the event that a participant withdraws consent before completing the study per protocol, attempts will be 
made to collect the most recently applicable information and follow AEs/SAEs to resolution. If a participant 
discontinues treatment but does not withdraw consent, all attempts will be made to continue follow up of the 
participant per protocol. 
 
10.0 
Data Management and Data Sharing 
 
10.1  Data Sharing 
Study data will be provided to the Repository so that it can be shared in accordance with NIDDK data sharing 
policies. Publicly released data will satisfy HIPAA and other applicable requirements for protecting participant 
identity. The informed consent form will include language regarding data sharing.  
 
 
 

39 
 
PROTOCOL VERSION: 10.0 (Approved: JUN 11, 2022). Comparative Effectiveness of Biofeedback and Injectable Bulking Agents 
for Treatment of Fecal Incontinence: The Fecal Incontinence Treatment (FIT) Study 
 
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