Fecal Microbial Transplantation (FMT) For the Treatment of Fecal Incontinence in Women
Phase: PHASE1
Conditions: Fecal Incontinence
Sponsor: University of Pennsylvania

 
FMT for FI 
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CLINICAL RESEARCH PROTOCOL 
INVESTIGATIONAL 
PRODUCT(S): 
Penn Microbiome Therapy – 002 (Suspension) for Fecal 
Microbial Transplantation (FMT) 
STUDY NUMBER: 
IRB#: 834196 
NCT04201821 
PROTOCOL(S) TITLE: 
Fecal Microbial Transplantation (FMT) For the Treatment 
of Fecal Incontinence in Women 
IND NUMBER: 
19405 
REGULATORY SPONSOR: 
University of Pennsylvania 
FUNDING SPONSOR: 
Harrison Grant - Department of OB GYN University of 
Pennsylvania 
MEDICAL DIRECTOR: 
Brendan Kelly, MD 
Division of Infectious Diseases, Department of Medicine 
VERSION NUMBER & 
DATE: 
V1.0, 03 Sep 2019 
V2.0, 05 Nov 2019 
V3.0, 19 Feb 2020 
V4.0, 14 Jun 2021 
V5.0, 12 May 2022  
V6.0, 19 Sep 2022 
 

 
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TABLE OF CONTENTS 
1 
Study Summary ..........................................................................................................5 
1.1 
Synopsis ...................................................................................................................5 
1.2 
Schema ....................................................................................................................6 
1.3 
Schedule of Activities (SoA) ..................................................................................7 
2 
Introduction and Rational .........................................................................................9 
2.1 
Study Rationale ......................................................................................................9 
2.2 
Background ............................................................................................................9 
2.2.1 
Assessment for Potential Study Products Drug-Drug Interactions ..........10 
2.2.2 
Clinical Adverse Event Profile ......................................................................10 
2.2.3 
Dosing Rationale ............................................................................................10 
2.3 
Risk/Benefit Assessment ......................................................................................12 
2.3.1 
Known Potential Risks ..................................................................................12 
2.3.2 
Known Potential Benefits ..............................................................................12 
2.3.3 
Assessment of Potential Risks and Benefits .................................................12 
3 
Study Objectives and Endpoints .............................................................................13 
4 
Study Plan..................................................................................................................14 
4.1 
Study Design .........................................................................................................14 
4.2 
Scientific Rationale for Study Design .................................................................14 
4.3 
Justification for Dose and Route of Administration .........................................14 
4.4 
End of Study Definition .......................................................................................14 
5 
Study Population .......................................................................................................15 
5.1 
Inclusion Criteria .................................................................................................15 
5.2 
Exclusion Criteria ................................................................................................15 
5.3 
Lifestyle Considerations ......................................................................................16 
5.4 
Screen Failures .....................................................................................................16 
5.5 
Strategies for Recruitment and Retention .........................................................17 
6 
Study Intervention ....................................................................................................18 
6.1 
Study Intervention Administration ....................................................................18 
6.1.1 
Study Intervention Description ....................................................................18 
6.1.2 
Dosing and Administration ...........................................................................18 
6.2 
Preparation/Handling/Storage/Accountability .................................................18 
6.2.1 
Acquisition and accountability .....................................................................18 
6.2.2 
Formulation, Appearance, Packaging, and Labeling .................................19 
6.2.3 
Product Storage and Stability .......................................................................19 
6.2.4 
Preparation .....................................................................................................19 
6.3 
Measures to Minimize Bias: Randomization and Blinding..............................20 
7 
Study Intervention Discontinuation and Participant 
Discontinuation/Withdrawal ...................................................................................20 
7.1 
Participant Discontinuation/Withdrawal from the Study ...............................20 
7.2 
Lost To Follow-Up ...............................................................................................20 
8 
Study Assessment and Procedures ..........................................................................21 
8.1 
Efficacy Assessments ...........................................................................................21 

 
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8.1.1 
Screening Visit ................................................................................................21 
8.1.2 
Visit 1: Treatment ..........................................................................................22 
8.1.3 
Phone Contact 1 (1 week post treatment) ....................................................23 
8.1.4 
Visit 2 (4 weeks post treatment) ....................................................................23 
8.1.5 
Visit 3 (12 weeks post treatment) ..................................................................24 
8.1.6 
Phone Contact 2 (End-of-study at 180 days) ...............................................25 
8.1.7 
Early Termination Visits ...............................................................................25 
8.1.8 
Unscheduled Visits .........................................................................................25 
8.2 
Safety and Other Assessments ............................................................................25 
8.3 
Adverse Events and Serious Adverse Events ....................................................25 
8.3.1 
Definition of Adverse Events (AE) ...............................................................25 
8.3.2 
Definition of Serious Adverse Events (SAE) ...............................................26 
8.3.3 
Classification of an Adverse Event ...............................................................26 
8.3.4 
Adverse Events of Special Interest ...............................................................28 
8.3.5 
Time Period and Frequency for Event Assessment and Follow-Up .........28 
8.3.6 
Adverse Event Reporting ..............................................................................30 
8.3.7 
Serious Adverse Event (SAE) Reporting .....................................................30 
8.3.8 
Stopping/Halting Rules ..................................................................................31 
8.3.9 
Unanticipated Problems ................................................................................31 
9 
Statistical Considerations .........................................................................................32 
9.1 
Statistical Hypotheses ..........................................................................................32 
9.3 
Sample Size Determination .................................................................................32 
9.4 
Statistical Analyses...............................................................................................33 
9.4.1 
General Approach ..........................................................................................33 
9.4.2 
Analysis of Stool Samples ..............................................................................33 
10 Supporting Documentation and Operational Considerations ..............................34 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ..............................34 
10.1.1 
Informed Consent Process ............................................................................34 
10.1.2 
Study Discontinuation and Closure ..............................................................34 
10.1.3 
Confidentiality and Privacy ..........................................................................35 
10.1.4 
Future Use of Stored Specimens and Data ..................................................36 
10.1.5 
Safety Oversight .............................................................................................36 
10.1.6 
Clinical Monitoring ........................................................................................36 
10.1.7 
Quality Assurance and Quality Control ......................................................36 
10.1.8 
Data Handling and Record Keeping ............................................................36 
10.1.9 
Protocol Exceptions and Deviations .............................................................37 
10.1.10 
Conflict of Interest Policy ..............................................................................39 
11 References ..................................................................................................................39 
TABLE OF TABLES 
Table 1: FMT dosing and associated risks. ...................................................................11 
 

 
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LIST OF ABBREVIATIONS 
ABL: accidental bowel leakage 
AE: adverse event 
BM: bowel movement 
CDI: Clostridium difficile infection 
CRF: case report form 
CTCAE: common terminology criteria for adverse events 
DSMB: Data Safety Monitoring Board 
FDA: Food and Drug Administration 
FDI-20: Pelvic Floor Disability Index 
FI: fecal incontinence 
FIQL: Fecal Incontinence quality of life 
FMT: Fecal Microbiota Transplantation 
GCP: good clinical practices 
HIPPA: Health Insurance Portability and Accountability Act of 1996 
IBS: irritable bowel syndrome 
ICH: International Conference on Harmonisation 
IRB: Institutional Review Board 
MDRO: multi-drug resistant organism 
NG: nasogastric 
NGT: nasogastric tube 
NIH: National Institutes of Health 
OCR: Office of Clinical Research 
OHRP: Office for Human Research Protection 
PGSC: Patient Global Symptom Control 
PHI: protected health information 
PI: principal investigator 
PMT: Penn Microbiome Therapy 
QOL: quality of life 
RCT: randomized clinical trial 
R-CDI: recurrent Clostridium dificile infection 
SAE: serious adverse event 
SoA: schedule of activities 
SUSAR: suspected unexpected serious adverse reaction 
UP: unanticipated problems 

 
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1 STUDY SUMMARY 
1.1 
Synopsis 
Title: 
Fecal Microbial Transplantation (FMT) For the Treatment of Fecal 
Incontinence in Women 
Short Title: 
FMT for FI 
Study 
Description: 
Open label pilot study assessing FMT to treat fecal incontinence in 
women > 50 years of age. 
Objectives: 
The primary objective is to determine if fecal microbial transplantation 
leads to clinical improvement in fecal incontinence. 
Primary 
Endpoint: 
Change in the St. Mark’s Vaizey score, a measure of fecal incontinence 
severity, 4 weeks after FMT. 
Secondary 
Endpoints: 
Determine whether the effectiveness of microbial engraftment following 
fecal microbial transplantation is associated with the degree of clinical 
improvement. 
Determine whether the baseline microbiota configuration affects 
engraftment in fecal microbial transplantation for fecal incontinence. Our 
working hypothesis is that the transplant will be more effective in 
baseline samples with lower microbial diversity. 
Study 
Population: 
15 evaluable women, > 50 years of age, who have been diagnosed with 
fecal incontinence and have failed standard treatment. 
Phase: 
1/2 
Description of 
Sites/Facilities 
Penn Medicine - University of Pennsylvania Health System 
Enrolling 
Participants: 
Participants will be enrolled form the Urogynecology clinics at the 
University of Pennsylvania. 
Description of 
Study 
Intervention: 
Participants will undergo fecal microbial transplantation (FMT) using the 
Penn Microbiome Therapy – 002 (PMT-002): no more than 152 mL 
suspension for intragastric or intraduodenal administration from 40g 
human stool, comprising 1x108 – 1x1012 anaerobic bacterial CFUs/dose. 
Study Duration: 
24 months 
Participant 
Duration: 
Approximately 8 months 

 
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1.2 
Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
-One-week BM diary 
-Stool kit 
FMT Tx 
4 weeks 
Week 4 Visit 
-Temperature log 
-One-week BM diary #2 
-Stool kit 
Week 12 Visit 
8 weeks 
-One-week BM diary #3 
-Stool kit 
14 weeks 
180 Day Phone 
Call 
Consent / Screening 

 
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1.3 
Schedule of Activities (SoA) 
Procedures 
Screening/Enrollment 
Treatment Visit 1 
(within 30 days of 
screening *) 
Follow-Up: 30 & 60 
minutes 
Phone Contact # 1 
(within 7 days of 
treatment) 
Study Visit 2 
Week 4 (+/- 7 days) 
Study Visit 3  
Week 12 (+/- 7 days) 
Phone Contact # 2 
180 days (+/- 7 days) 
Informed Consent 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
Concomitant Medication 
Review 
X 
X 
 
X 
X 
X 
X 
Abbreviated Physical 
X 
 
 
 
 
 
 
Stool Collection 
 
X** 
 
 
X** 
X** 
 
PFIQ-7 
X 
 
 
 
X 
X 
 
Adaption Index 
X 
 
 
 
X 
X 
 
Dietary Screener 
X 
 
 
 
 
 
 
SF-12 
X 
 
 
 
X 
X 
 
PFDI-20 
X 
 
 
 
X 
X 
 
Pregnancy Test (women of 
childbearing potential) 
X 
X 
 
 
X 
X 
 
ABLe Questionnaire 
X 
 
 
 
X 
X 
 
Radiologic/Imaging 
Assessment 
 
X 
 
 
 
 
 
FIQL 
X 
 
 
 
X 
X 
 
Bristol Stool Index 
Questionnaire 
X 
 
 
 
X 
X 
 
St. Mark’s Score 
X* 
 
 
 
X 
X 
 
PMT Administration 
 
X 
 
 
 
 
 
Vital Signs Review 
 
 
X 
 
 
 
 
Symptom Review 
 
 
X 
 
 
 
 
PGI-I 
 
 
 
 
X 
X 
X 
PGSC 
 
 
 
 
X 
X 
X 
AE/SAE Review 
 
X 
X 
X 
X 
X 
X 
Protocol Deviation Review 
X 
X 
 
X 
X 
X 
X 

 
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Procedures 
Screening/Enrollment 
Treatment Visit 1 
(within 30 days of 
screening *) 
Follow-Up: 30 & 60 
minutes 
Phone Contact # 1 
(within 7 days of 
treatment) 
Study Visit 2 
Week 4 (+/- 7 days) 
Study Visit 3  
Week 12 (+/- 7 days) 
Phone Contact # 2 
180 days (+/- 7 days) 
PAC-SYM 
X 
 
 
 
X 
X 
 
Temperature Log 
Completion 
 
 
 
 
X 
 
 
One Week BM Diary 
 
X 
 
X 
X 
 
 
* If time between screening and visit one is greater than 30 days, this test must be repeated prior to 
administration of FMT. 
** Stool Collection will be performed by self-collection procedures and brought by the patient on day of 
study visit or mailed. 
 

 
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2 INTRODUCTION AND RATIONAL 
2.1 
Study Rationale 
Fecal incontinence, also known as accidental bowel leakage, is a common condition that is an 
immense burden to older women, caregivers, and the health care system. Traditionally, fecal 
incontinence has been ascribed to obstetric neuromuscular injury, but preliminary results of a 
Penn led translational study in the Pelvic Floor Disorders Network show that gut microbiota may 
be a significant contributor (Arya et al., Neuro Uro, 2018). The overall goal of this study is to 
gather pilot data in order to conduct a future randomized controlled trial (RCT) for a novel 
treatment for fecal incontinence in older women utilizing fecal microbial transplantation (FMT). 
Our hypothesis is that infusion of intestinal microbiota from healthy donors to older women with 
fecal incontinence will increase microbial diversity, reduce symptom severity, and improve 
quality of life. We plan to conduct a single arm open label clinical trial of FMT for the treatment 
of fecal incontinence refractory to conservative management. We will measure the impact of 
FMT on change in symptom severity and quality of life and stool microbial diversity at 4 and 12 
weeks after FMT. 
2.2 
Background 
Childbirth and its associated neuromuscular injury to the anal sphincter muscles have 
traditionally been considered as the cause of fecal incontinence in women. However, the onset of 
fecal incontinence is usually after age 50 which is remote from delivery (Robinson, FPMRS, 
2013; Rey, Am J Gastro, 2019). Recent large epidemiologic studies suggest that gut motility 
(diarrhea) and stool consistency (liquid stool) are significant contributing factors that are more 
important than obstetric factors in the pathogenesis of fecal incontinence (Robinson, FPMRS, 
2013; Rey, Am J Gastro, 2019; Bharucha, Gastroenterology, 2010). Since gut motility and stool 
consistency are modulated by gut microbes, Penn investigators are currently performing a large 
multi-center translational study using 16S rRNA gene sequencing to investigate stool microbiota 
and metabolites in women with fecal incontinence and controls. The hypothesis of this study is 
that fecal incontinence is caused by abnormalities of gut microbial pathways that synthesize 
butyrate, a metabolite known to modulate gut motility and consistency. 
The Penn led study has yielded promising results. Fecalibacterium prausnitzii, an important 
producer of gut butyrate, is lower in women with fecal incontinence than controls. Additionally, 
functional profiling of the microbial metagenome has revealed that at least four additional 
pathways may be involved in fecal incontinence (Arya, Neuro Uro, 2018; unpublished data). 
Thus, gut dysbiosis, involving a variety of microbiota and metabolites, may be important 
contributors to fecal incontinence and restoring normal fecal microbiota could be a potential 
novel way of treating fecal incontinence. 
Possible options for treating gut dysbiosis include dietary manipulation, probiotics, prebiotics, 
and FMT. Human feces from healthy donors is diverse and contains many more types of 

 
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microbiota than pro- or prebiotics. FMT is also emerging as a promising treatment for 
inflammatory bowel disease and irritable bowel syndrome (Parfenov, Ter Arkh, 2018; Narula, 
Inflamm Bowel Dis, 2017; Shi Y, PLoS One, 2016; Holleran, Drugs Today, 2018; Halkjaer, Gut, 
2018; Arya, Neuro Uro, 2018). The principal of restoration of dysbiotic gut microbiota through 
FMT could be applied as a treatment to reduce the severity of fecal incontinence and potentially 
even remission of disease. Thus, we aim to test the efficacy of FMT for the treatment of fecal 
incontinence in women. 
2.2.1 
Assessment for Potential Study Products Drug-Drug Interactions 
Potential interaction between the study product and other drug products is currently unknown. As 
this information is unknown, individuals who are immunocompromised have been excluded 
from this protocol. Additionally, individuals who have chronic antibiotic use are excluded as 
investigators are currently unsure if this could potentially be a confounding variable. 
2.2.2 
Clinical Adverse Event Profile 
Based on the published literature for the use of FMT in other disease states, it is expected that 
gastrointestinal symptoms (including fever, aspiration, belching, bloating, nausea or vomiting, 
gastroesophageal reflux, abdominal cramps, abdominal pain, diarrhea, constipation) may be 
common post administration of the investigational products, both as a consequence of the 
underlying disease being treated, and potentially as an adverse effect of the administered product 
(Halkjaer, Gut, 2018; Johnsen, Lancet, 2018; Table 1). 
To distinguish a causal relationship between these adverse effects (AEs) and the investigational 
product, we will set a threshold of ≥ 50% increase in gastrointestinal symptom severity (e.g., 
number of stools or volume of diarrhea; number of vomiting episodes or hours/day of nausea) as 
compared to symptom severity in the one week period surrounding the intervention. 
2.2.3 
Dosing Rationale 
There are no pre-clinical or clinical data for treatment of FI with FMT product to inform optimal 
dose. Thus, we have relied on the standard dosage used in other disease states. There are 
extensive observational studies and several randomized trials that suggest an FMT dose derived 
from 30-100g of human stool is effective to treat other conditions including Irritable Bowel 
Disorder and recurrent CDI (Johnsen Lancet 2018; Halkjaer Gut 2018; van Nood NEJM 2013; 
Youngster JAMA 2014; Kelly CR 2016). 
The dose of the PMT investigational product to be employed in this study is based on the use of 
FMT in prior human studies (See Table 1). A single dose of up to 40g of donated stool, prior to 
processing into the final form, has been shown to be efficacious in these studies. The PMT 
products produced from these 40g stool mass contain a range of 1x108 – 1x1012 anaerobic 
bacterial CFUs. Given the lack of data for women with FI, we will use the dose that has 
previously been shown to be efficacious in recurrent CDI. 

 
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Table 1: FMT dosing and associated risks. 
Authors 
Publication 
Year 
Population 
Study Design 
FMT Dose 
(g stool) 
FMT 
Formulation 
FMT 
Administration 
Risks 
Hamilton et al 
2012 
R-CDI 
single-group trial 
50g stool 
250mL 
suspension 
colonoscopy 
diarrhea, flatulence 
van Nood et al 
2013 
R-CDI 
randomized trial 
(not reported) 
500mL 
suspension 
duodenal tube 
diarrhea, cramping, 
belching 
Youngster et al 
JAMA 
2014 
R-CDI 
single-group trial 
48g stool 
30 capsules 
oral 
cramping, bloating 
Kelly et al 
2016 
R-CDI 
randomized trial 
64g stool 
500mL 
suspension 
colonoscopy 
chills, abdominal 
pain, bloating, 
nausea, flatulence 
Kao et al 
2017 
R-CDI 
randomized trial 
80-100g stool 
40 capsules or 
180mL 
suspension 
oral or colonoscopy 
nausea, vomiting, 
fever, abdominal 
discomfort 
Weingarden et al 
2013 
R-CDI 
case series 
50g stool 
250mL 
suspension 
colonoscopy 
(not reported) 
Agrawal et al 
2015 
R-CDI 
case series 
~30-60g stool 
150-500mL 
suspension 
upper endoscopy, 
lower endoscopy, 
enema 
diarrhea, 
constipation, 
abdominal pain, ileus 
Aroniadis et al 
2015 
R-CDI 
case series 
(not reported) 
suspension 
upper endoscopy, 
lower endoscopy, 
enema, colonoscopy 
diarrhea, abdominal 
pain 
Fischer et al 
2015 
R-CDI 
case series 
50-100g stool 
300mL 
suspension 
sigmoidoscopy or 
colonoscopy 
treatment failure and 
death 
Fischer et al 
2017 
R-CDI 
case series 
50-100g stool 
300mL 
suspension 
sigmoidoscopy or 
colonoscopy 
treatment failure and 
death 
 

 
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2.3 
Risk/Benefit Assessment 
2.3.1 
Known Potential Risks 
The main risks of this study are related to administration of the investigational product. The most 
severe possible risks include allergic reaction, donor-derived infection, aspiration, and death. 
Other risks include nausea, vomiting, abdominal pain, diarrhea, flatulence, and fever. 
As noted above, potential risks of the FMT treatment for FI includes gastrointestinal symptoms 
(including fever, aspiration, belching, bloating, nausea or vomiting, gastroesophageal reflux, 
abdominal cramps, abdominal pain, diarrhea, constipation). This is the first attempt to administer 
FMT for FI in women, however the risks are not expected to be significantly different from that 
reported in the literature. 
Theoretical long-term risks may include: changes in metabolism, weight changes, development 
of autoimmune conditions. 
Other risks include loss of privacy or confidentiality, as a result of study staff interacting with 
subjects. 
These risks will be discussed with subjects during the informed consent process. The eligibility 
criteria will help mitigate these risks (e.g., excluding subjects with neutropenia or bowel 
perforation, and not permitting subjects at risk for aspiration to receive investigational product 
via upper gastrointestinal delivery). To minimize the risk of privacy and confidentiality loss, the 
minimum number of required study staff will interact with subjects, and all collected data will be 
protected as above. 
2.3.2 
Known Potential Benefits 
Currently, it is unknown if benefit will be received from participation. It is hypothesized that 
symptoms of FI will improve after administration of FMT. 
2.3.3 
Assessment of Potential Risks and Benefits 
Gastrointestinal symptoms have been reported following FMT administration in patients with R-
CDI (see Table 1). While FMT has not previously been administered for treatment of fecal 
incontinence, we anticipate that women recruited for this study will be most similar to subjects 
with irritable bowel syndrome who received FMT. In this patient population, no serious adverse 
event has been reported following treatment with FMT in several studies (Johnsen, Lancet, 2018; 
Halkjaer, Gut, 2018). Given the immense burden of FI on quality of life, the potential benefit of 
improvement in severity of fecal incontinence symptoms vastly outweighs the risk of transient 
gastrointestinal symptoms. 

 
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3 STUDY OBJECTIVES AND ENDPOINTS 
 
OBJECTIVES 
ENDPOINTS 
Primary 
 
Determine if fecal microbial transplantation 
leads to clinical improvement in refractory 
fecal incontinence in older women. 
Number of subjects that show significant 
improvement at 4 weeks after FMT, and will 
be maintained at 12 weeks, relative to baseline 
using the St. Mark’s Vaizey score, a measure 
of fecal incontinence severity. 
Primary Safety 
 
Determine the safety of FMT administration 
via naso-gastric tube in older women with 
FI. 
Frequency of adverse events, serious adverse 
events, and adverse events of special interest 
(including allergic reaction and gastrointestinal 
symptoms). 
Secondary 
 
Determine if FMT leads to improved quality 
of life for subjects. 
Number of subjects that have an improved 
quality of life at 4 and 12 weeks, measured by 
the FIQL scale. 
Determine if the effectiveness of microbial 
engraftment following fecal microbial 
transplantation is associated with the degree 
of clinical improvement. 
Concentration of microbiota present at baseline 
vs. at week 4 and at 12 weeks (optional)in 
subjects that demonstrate a significant 
improvement at 4 weeks after FMT, relative to 
baseline using the St. Mark’s Vaizey score. 
Tertiary 
 
Determine whether the baseline microbiota 
of the subject affects engraftment in fecal 
microbial transplantation for fecal 
incontinence. 
Concentration of microbiota at baseline vs. 
concentration of microbiota at 4 weeks and at 
12 weeks (optional). 

 
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4 STUDY PLAN 
4.1 
Study Design 
Traditional treatments of fecal incontinence directed at obstetric neuromuscular injury, such as 
pelvic floor exercises and sphincteroplasty, have remarkably low efficacy in older women. The 
proposed study will provide critical feasibility and safety data for conducting a future 
randomized clinical trial of FMT versus placebo for the treatment of refractory fecal 
incontinence. We plan a single arm open label clinical trial of FMT for the treatment of 
refractory fecal incontinence. Older women with fecal incontinence who have failed prior 
treatment with diet modification and pelvic floor exercises will be invited to participate in the 
study. Penn Microbiome Therapy – 002 (PMT-002), which is derived from healthy screened 
donors will be delivered to the duodenum via a nasogastric tube. All subjects will complete 
validated questionnaires on fecal incontinence and contribute a stool sample for microbiota 
analysis at baseline and at 4 and 12 weeks after the FMT procedure. 
4.2 
Scientific Rationale for Study Design 
For this first-of-its-kind pilot study, we plan to conduct a pre-post intervention study. No prior 
studies have assessed the impact of FMT on FI. Thus, we plan to assess the efficacy and safety of 
this treatment in this population prior to conducting larger placebo or alternate treatment 
comparison studies. 
4.3 
Justification for Dose and Route of Administration 
There are several routes available for the administration of FMT. For this proof of concept study, 
FMT will be performed via duodenal infusion of donor stool rather than FMT capsules as a 
single study showed lower efficacy of capsules in women with irritable bowel syndrome (IBS). 
Our rationale for choosing FMT via duodenal infusion over colonoscopy is as follows: 1) 
Duodenal infusion FMT is an office-based procedure performed in an awake patient as compared 
to FMT via colonoscopy in the operating room under sedation, with a risk of bowel perforation 
and with much higher associated costs. 2) Duodenal infusion FMT is well tolerated by older 
adults (van Nood, NEJM, 2013; Pinn, Am J Gastro, 2014; Vrieze, Gastroenterol, 2012). 3) 
Several studies show that FMT via colonoscopy or duodenal infusion have equivalent efficacy 
(Ramai, Ann Gastro 2019). As described above, the dosing regimen for FMT in recurrent 
Clostridium dificile (R-CDI) will be used as there have been no studies on optimal dosing of 
PMT-002 in women with FI. 
4.4 
End of Study Definition 
This clinical trial is considered completed (End of Study) when participants are no longer being 
examined or the last participant’s last study visit has occurred (including long follow up visits or 
contacts). 

 
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A participant is considered to have completed the study if the subject has completed all phases of 
the study including the last visit or the last scheduled procedure shown in the Schedule of 
Activities (SoA), Section 2.3. 
5 STUDY POPULATION 
5.1 
Inclusion Criteria 
• Women > 50 years of age with self-reported fecal incontinence defined as: 
− uncontrolled bothersome loss of liquid or solid fecal material that occurs at least 
weekly over the last 3 months and 
− failure of response to conservative management using fiber, diet modification, 
supervised pelvic floor exercises 
• Baseline St. Mark’s score of >12 
• Intolerance, unwillingness, or inadequate response to constipating medications 
• 
Self-reported current negative colon cancer screening based on the 2016 US preventive 
Services Task Force recommendation (applies to participants age 50-75). N/A if participant 
is over 75 
• Able and willing to sign the informed consent form and agree with study procedures 
5.2 
Exclusion Criteria 
• Known food allergy that could lead to anaphylaxis 
• Contraindications to nasogastric tube placement including: 
− Recent midface trauma 
− History of basilar skull fracture 
− Recent ENT surgery 
− Known coagulation abnormalities 
− Esophageal varices and/or esophageal strictures 
• Untreated prolapse beyond the hymen 
• History of Inflammatory Bowel Disease (does not include IBS) 
• Unrepaired rectovaginal fistula/chronic 4th degree laceration 
• Full thickness rectal prolapse 
• History of congenital anorectal malformation 
• History of bowel resection surgery for any indication 
• Minor anal procedures within 6 months for treatment of accidental bowel leakage (ABL) 
(injection of bulking agent or radiofrequency energy) or ligation of hemorrhoids 
• Prior pelvic or abdominal radiation 
• Diagnosis of cancer of the descending colon or anus 

 
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• Clinically significant neurological disorders known to affect anal incontinence 
• Chronic antibiotic use (>1 month continuous antibiotic) 
• Pregnant or planning to become pregnant during the study duration 1 year 
− N/A if participant is not of childbearing potential 
• Childbirth within the last 3 months 
• Unwilling to use an acceptable form of birth control method if participant is of 
childbearing potential 
− N/A if participant is of not of childbearing potential 
• Participation in another intervention trail impacting bowel function 
• Inability to provide informed consent, complete questionnaires independently or to attend 
intervention sessions 
• History of hepatitis C / HIV infection or other immunocompromised condition 
• History of bowel resection surgery or pelvic irradiation 
• Unable to speak, read, or write in English at a basic level 
• In the opinion of the investigator not suitable for participation in the trial 
5.3 
Lifestyle Considerations 
After administration of the investigational product (PMT-002) there is no way for investigators 
to stop or retrieve the product from the subject. Additionally, it is unknown how long the product 
will remain in the subject’s body; thus, subjects should be fully informed that withdraw of the 
investigational product is not possible and be comfortable with this information prior to 
administration. Furthermore, as this is a first in human trial for the indication of FI unforeseen 
side effects are expected. 
5.4 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently administered the study intervention or entered in the study. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure 
participants, to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, and any serious adverse event 
(SAE). 
Individuals who do not meet the criteria for participation in this trial (screen failure) because of 
inclusion/exclusion criteria for this protocol are not eligible for rescreening. 

 
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5.5 
Strategies for Recruitment and Retention 
Clinical Practices of Investigators 
Women presenting to the clinical practices of the Hospital of the University of Pennsylvania 
Health System Division of OB GYN (Urogynecology) for consultation/complaint or indication 
for FI (after clinical confirmation of their potential eligibility for admission into the study based 
on inclusion and exclusion criteria) will be approached to participate by the principal investigator 
(PI) or providing physician, in addition to the study coordinator. In the recruitment visit, study 
details including the intervention will be explained. Risks and benefits will be thoroughly 
discussed and consents given to the patient prior to any study procedures being performed. 
Hospital/Local Health Care Referrals 
Subjects will be recruited at each site from individual practice(s) of the investigators as noted 
above as well as faculty/resident clinics. Ongoing contact with practice and faculty members as 
well as with residents will be made by the investigators and coordinators, reminding them of the 
inclusion criteria, importance of the study, etc. In addition, the investigators will describe the 
study to members of other departments in the hospital, primarily family practice, medical 
endocrinology, and gynecology who also see and treat these patients. Contact with local 
physicians will be made and/or grand rounds will be given to disseminate information about the 
study. Letters will be mailed to potential subjects, which provides details of the study and contact 
information of the study team (to allow for subject to reach out for more information). Penn 
Datastore may be utilized to provide a list of potential subjects based on clinical practice 
information. 
Referrals from Study Participants 
Study participants often refer friends, acquaintances, and colleagues to be potential participants. 
The investigator will let the patient know that they can refer others to be considered for 
participation in the study. 
Previous Study Participants 
The trial will be offered to women who have previously participated in clinical trials offered by 
the study team, who have consented to be contacted for future participation via their preferred 
contact method (after confirmation of their potential eligibility for admission into the study based 
on inclusion and exclusion criteria). 
Web sites 
The study will be prominently displayed on the local Penn website. Information will also be 
available at clinicaltrials.gov. Social media and Craigslist will also be utilized, as this has been a 
proven source of recruitment in the past. Ads placed on social media, specifically Facebook and 
Instagram, will be one-way ads and the study team will not directly interact with subjects on 

 
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social media. The ads will highlight a contact number for the interested individual to call to 
discuss the study. Social media ads will be monitored by the University of Pennsylvania study 
coordinator to ensure they are being properly featured and not causing inappropriate comments. 
This monitoring will occur bi-weekly. If any problems arise with the social media ads they will 
be immediately removed, however, this is not anticipated as they are one-way ads. This type of 
advertising has been previously used for studies within the department and has been well 
received. 
Institutional Review Board (IRB) Approval 
It is expressly acknowledged that all informational material that could be construed to be 
advertising will be approved by the central IRB prior to dissemination. 
6 STUDY INTERVENTION 
6.1 
Study Intervention Administration 
6.1.1 
Study Intervention Description 
Fecal microbiota transplantation (FMT) is a treatment that involves administration of minimally 
manipulated microbial community from stool of a healthy donor into the patient’s intestinal tract. 
Clinically, FMT is performed with the intent of restoring normal function of the gut microbiota 
(Khoruts, 2016). 
6.1.2 
Dosing and Administration 
A single dose of PMT-002 will be administered via a gastroduodenal tube over 10 to 90 minutes 
(target 30 minutes). In brief, nasogastric duodenal tube will be placed by a physician and its 
location will be checked by X-Ray. Once placement is confirmed, the PMT-002 product will be 
delivered via the NGT using a syringe attached to the end of the tube. Once the product has been 
delivered, the NGT will be removed. The patient will be observed for 1 hour in the office for 
potential adverse events. 
6.2 
Preparation/Handling/Storage/Accountability 
6.2.1 
Acquisition and accountability 
Following the screening and consent visit, the lab director at the PMT manufacturing facility at 
the University of Pennsylvania will be notified of the date for visit 1 (FMT visit) to ensure the 
investigational product will be available for that date. On the day of the Study visit, study 
personnel will obtain the PMT product from the manufacturing facility and transport it to the 
office where it will be administered. The PMT-002 will be packaged on dry ice from the PMT 
manufacturing facility. The time of release from frozen storage will be documented and included 
in PMT product packaging. Upon receipt of the product by the Investigator, packaging will be 
inspected for integrity, and the product will be checked to ensure that it is still frozen and logged 

 
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in the investigational product accountability log. The investigational product label will also be 
checked to ensure that the proper product is received, and to ensure that the product has not 
expired. 
The volume of investigational product will be recorded at the time of drug product 
manufacturing, and the volume of residual investigational product (if any) will be recorded by 
the licensed medical professional performing administration after administration is completed (or 
stopped). Any remaining investigational product will be disposed of at the clinical site. 
6.2.2 
Formulation, Appearance, Packaging, and Labeling 
PMT-002 is composed of donor stool, glycerol, and saline contained in cryobags and labelled 
(according to FDA regulations 21CFR312.6) for upper GI use. These cryobags will also be 
labeled with a unique color label to facilitate identification as a PMT-002 drug product. 
The potency of each PMT-002 is 1x108-1012 CFU/dose (1 dose per cryobag), based on 
Quantitative Anaerobic Culture from Fecal Filtrate. The appearance of the PMT-002 is frozen 
aqueous solution within the product container is properly labeled, free of defects. Prior to release 
of the drug product, all serological, stool and multi-drug resistant organism (MDRO) testing will 
be confirmed to be negative. 
6.2.3 
Product Storage and Stability 
PMT-002 drug product should be stored as detailed on the investigational product labeling, prior 
to release to site. 
The investigational products are transported frozen on dry ice by courier or study staff to the 
clinical location. Investigational products are transported in containers labelled and maintained at 
a temperature in accordance with federal and local regulations for the transport of biological 
products. 
At the clinical location, administration of PMT-002 should be initiated within 180 total minutes 
of product release from frozen storage by the manufacturer. 
PMT-002 doses will be thawed at room temperature for 30-60 minutes prior to administration. 
Any doses released from frozen storage but not administered within the allotted time (180 
minutes) after release (e.g., due to delays in transport) should be destroyed. In such cases, 
eligible subjects should be offered another dose, and the release process should be re-initiated. 
6.2.4 
Preparation 
Preparation of the investigational product [PMT-002 (Suspension)] will be performed at the 
PMT manufacturing facility at the University of Pennsylvania. PMT-002 is packaged in EVA 

 
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bags suitable for storage at < -70°C (target -80°C). The investigational products will be packaged 
in single doses. 
6.3 
Measures to Minimize Bias: Randomization and Blinding 
Neither subjects nor investigators will be blinded. 
7 STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
7.1 
Participant Discontinuation/Withdrawal from the Study 
Participants are free to withdraw from participation in the study at any time upon request and 
without impact to their regular medical care, but they will receive no further treatment with this 
investigational product. 
An investigator may discontinue or withdraw a participant from the study for the following 
reasons: 
• Significant study intervention non-compliance. 
• If any clinical adverse event (AE), laboratory abnormality, or other medical condition or 
situation occurs such that continued participation in the study would not be in the best 
interest of the participant. 
• If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation. 
The reason for participant discontinuation or withdrawal from the study will be recorded on the 
Case Report Form (CRF). Subjects who sign the informed consent form and do not receive FMT 
will be replaced. 
7.2 
Lost To Follow-Up 
A participant will be considered lost to follow-up if they fail to return for greater than 2 
scheduled visits and is unable to be contacted by the study site staff. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The site will attempt to contact the participant and reschedule the missed visit within 2 
weeks and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain if the participant wishes to and/or should continue in the study. 

 
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• Before a participant is deemed lost to follow-up, the investigator or designee will make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, if 
necessary, a certified letter to the participant’s last known mailing address or local equivalent 
methods). These contact attempts should be documented in the participant’s medical record 
or study file. 
• Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
8 STUDY ASSESSMENT AND PROCEDURES 
8.1 
Efficacy Assessments 
8.1.1 
Screening Visit 
Potential candidates will be evaluated for eligibility per sections 6.1 and 6.2 and written 
informed consent will be obtained. Consented participants will be required to complete the 
following forms during their Baseline visit: 
• Consent 
• Eligibility Check List (includes St. Mark’s Vaizey questionnaire) 
• Pregnancy Test (if childbearing age) 
If eligible, the following will be completed: 
• Dietary Screener 
• Questionnaires (Demographics, Medical History, SF-12, PFDI-20, ABLe Questionnaire, 
FIQL, Bristol Stool Index, PFIQ-7, Adaptation Index, PACSYM) 
• Abbreviated Physical Exam 
• Medication Log 
Subjects will also be required to take the following home to complete prior to their treatment 
visit. 
• One-week BM diary 
• Stool Collection Kit (see stand-alone collection instructions) 

 
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8.1.2 
Visit 1: Treatment 
At this visit, the study coordinator will collect the one-week BM diary and stool sample from the 
subject. The PI or another trained physician will meet with the patient. Vital signs will be done to 
document temperature, blood pressure, heart rate, and oxygen saturation. A nasogastric tube will 
be placed and secured. The subject will then be escorted to the radiology suite by the study 
coordinator. A chest x-ray will be performed to ensure adequate placement of the nasogastric 
tube. The PI or trained physician will confirm adequate placement of the tube with the attending 
radiologist. The subject will then be escorted back to the office suite by the study coordinator. 
The PI or trained physician will then administer the treatment. The PMT-002 product will be 
drawn into a syringe and the syringe will be connected to the nasogastric tube (NGT) and the 
product will be pushed into the tube until all of the FMT product is administered. The NGT will 
then be removed by the PI or trained physician. The subject will remain in the office for one hour 
following the administration of the PMT product. 
8.1.2.1 
Post-PMT Administration monitoring: Bedside for 60 Minutes 
Subjects will be monitored at 30 and 60 minutes following completion of PMT administration. 
Subjects will be visually observed for signs of aspiration or other respiratory distress, abdominal 
pain, vomiting, other signs of allergic reaction, and changes in vital signs. Vital signs 
(temperature, heart rate, respiratory rate, blood pressure, and oxygen saturation) will be checked. 
The following vital sign changes will be recorded if observed: (1) heart rate increase or decrease 
by greater than or equal to 30 beats per minute; (2) respiratory rate increase or decrease by 
greater than or equal to 10 breaths per minute or if respiratory rate drops below 10 or increases 
above 25 (if respiratory rate not already outside these ranges); (3) temperature: increase or 
decrease by greater than or equal to 2 degrees Fahrenheit, or if temperature drops below 96°F or 
increases above 100.4°F (if temperature not already outside these ranges); (4) oxygen saturation 
decrease by greater than or equal to 5% (sustained for more than 20 seconds) or if oxygen 
saturation drops below 90% (on current amount of oxygen delivered, sustained for more than 20 
seconds); (5) blood pressure decrease by more than 30 mmHg systolic or 15 mmHg diastolic, or 
if blood pressure drops below 90/60 (if blood pressure not already outside these ranges). 
During the monitoring period, information will be solicited from the patient regarding the 
following adverse events associated with FMT including aspiration, belching, bloating, nausea, 
vomiting, gastroesophogeal reflux, abdominal cramps, abdominal pain, diarrhea, and 
constipation. 
Subjects will be sent home with: 
• Second one-week BM diary. The diary will include a card for the collection of all 
solicited adverse events. 
• Thermometer 

 
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• Temperature and Adverse Events log form 
• Stool Collection Kit 
8.1.3 
Phone Contact 1 (1 week post treatment) 
The study coordinator will call to review the temperature log and assess for any adverse 
events. The study coordinator will inform the PI immediately if any subject reports an oral 
temperature of >100.4. The PI or other trained physician will phone triage patients reporting 
elevated temperatures and bring them in for a study visit / direct them to the emergency room if 
necessary. If a subject is asked to come in for a visit, the visit will follow the procedures 
described in section 9.1.8. 
8.1.4 
Visit 2 (4 weeks post treatment) 
Subjects will come to the office for a visit 4 weeks (± 7 days) after administration of the FMT 
treatment or be conducted by telemedicine or telephone. 
During their first follow-up visit, the subjects will return to the clinical site in person or via mail: 
• Second one-week bowel movement (BM) diary 
• Temperature and Adverse Events log form 
• Stool specimen 
During the visit, the following forms will be completed: 
• Medication Log 
• Adaption Index 
• SF-12 
• PFDI-20 (Pelvic Floor Disability Index) 
• ABLe Questionnaire 
• FIQL (Fecal Incontinence quality of life) 
• Bristol Stool Index 
• St. Mark’s Score 
• PGSC (Patient Global Symptom Control) 

 
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• Global Impression Improvement 
• PACSYM 
• PFIQ-7 
• AE/SAEs 
Subjects will be sent home with a final one-week BM diary that they will return during their 12-
week visit. The diary will include a card for the collection of all solicited adverse events. 
Subjects will also be sent home with a stool collection kit to be returned at the 12-week visit or 
be returned by mail if a telemedicine or telephone visit (optional). 
8.1.5 
Visit 3 (12 weeks post treatment) 
Participants will return to the office for visit 3, twelve weeks (± 7 days) after the FMT treatment. 
The clinical research coordinator will collect final one-week BM diary as well as the stool 
sample (if available). This visit may occur via telemedicine or telephone, and samples provided 
via mail or drop off at the clinical site. The following questionnaires will be completed: 
• Medication Log 
• Adaption Index 
• PFIQ-7 
• SF-12 
• PFDI-20 
• ABLe Questionnaire 
• FIQL 
• Bristol Stool Index 
• St. Mark’s Score 
• PGSC 
• Global Impression Improvement 
• PACSYM 
• AE/SAEs 

 
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8.1.6 
Phone Contact 2 (End-of-study at 180 days) 
The study will conclude after subjects are contacted by telephone or in-person at 180 days (+/-10 
days) after final FMT for a final interview focused on potential adverse events. 
8.1.7 
Early Termination Visits 
If the subject decides to withdraw from the study, the subject will be asked to complete all 
follow-up activities that would have been performed at the next scheduled follow-up visit. 
8.1.8 
Unscheduled Visits 
Data collected from subjects who contact the study team (by telephone or in-person) outside of 
the scheduled visits (as above) will be associated with the next scheduled study visit, as each 
study visit is intended to retrospectively cover the time period since the last study visit. 
8.2 
Safety and Other Assessments 
For all women of childbearing potential, a urine pregnancy test will be performed prior to FMT 
and at all subsequent study visits. If a subject’s urine pregnancy test is positive prior to treatment 
with FMT, the subject will be removed from the study. It is recommended that women not 
become pregnant as it is unknown how this treatment will effect pregnancies. If a subject does 
become pregnant on study, the pregnancy will be followed. 
To monitor for signs of infection subjects will be required to keep a temperature log for 7 days 
following FMT (a digital thermometer will be provided). Subjects will be instructed to call the 
study doctor if their temperature rises above 100.4 degrees or drops below 96 degrees. The study 
doctor will phone triage patients reporting elevated temperatures and bring them in for a study 
visit or direct them to the emergency room if necessary. 
Subjects will also be provided with a card for the collection of all solicited adverse events in 
their study diary. The card will be reviewed with the diary for any adverse events. 
8.3 
Adverse Events and Serious Adverse Events 
8.3.1 
Definition of Adverse Events (AE) 
An adverse event (AE) is any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. Intercurrent illnesses or injuries should be 
regarded as adverse events. 
A pre-existing condition should be recorded as an adverse event if the frequency, intensity, or the 
character of the condition changes. 

 
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8.3.2 
Definition of Serious Adverse Events (SAE) 
Adverse events are classified as serious or non-serious. A serious adverse event (SAE) is any AE 
that, in the view of either the Investigator or the Sponsor, is: 
• fatal 
• life-threatening 
• requires or prolongs hospital stay 
• results in persistent or significant disability or incapacity 
• a congenital anomaly or birth defect 
• an important medical event 
Important medical events are those that may not be immediately life threatening but are clearly 
of major clinical significance. They may jeopardize the subject and may require intervention to 
prevent one of the other serious outcomes noted above. For example, drug overdose or abuse, a 
seizure that did not result in in-patient hospitalization, or intensive treatment of bronchospasm in 
an emergency department would typically be considered serious. 
All fatal or life-threatening related SAEs or suspected unanticipated serious adverse events 
(SUSARs) should be reported to the Food and Drug Administration (FDA) within 7 calendar 
days of knowledge of the event and that non-life threatening SAEs/SUSARs should be reported 
to the FDA as soon as possible but no later than 15 calendar days after knowledge of the event 
(21 CFR 312.32). 
8.3.3 
Classification of an Adverse Event 
8.3.3.1 
Severity of Event 
For adverse events (AEs) not included in the protocol defined grading system, the following 
guidelines will be used to describe severity. 
• Grade 1: Mild – Events require minimal or no treatment and do not interfere with the 
participant’s daily activities. 
• Grade 2: Moderate – Events result in a low level of inconvenience or concern with the 
therapeutic measures. Moderate events may cause some interference with functioning. 
• Grade 3: Severe – Events interrupt a participant’s usual daily activity and may require 
systemic drug therapy or other treatment. Severe events are usually potentially life-
threatening or incapacitating. 
• Grade 4: Life-threatening 
• Grade 5: Death 

 
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8.3.3.2 
Relationship to Study Intervention 
All adverse events (AEs) must have their relationship to study intervention assessed by the 
clinician who examines and evaluates the participant based on temporal relationship and his/her 
clinical judgment. The degree of certainty about causality will be graded using the categories 
below. In a clinical trial, the study product must always be considered. 
• Definitely Related – There is clear evidence to suggest a causal relationship, and other 
possible contributing factors can be ruled out. The clinical event, including an abnormal 
laboratory test result, occurs in a plausible time relationship to study intervention 
administration and cannot be explained by concurrent disease or other drugs or chemicals. 
• Probably Related – There is evidence to suggest a causal relationship, and the influence 
of other factors is unlikely. The clinical event, including an abnormal laboratory test result, 
occurs within a reasonable time after administration of the study intervention, is unlikely to 
be attributed to concurrent disease or other drugs or chemicals, and follows a clinically 
reasonable response on withdrawal (de-challenge). Re-challenge information is not required 
to fulfill this definition. 
• Potentially Related – There is some evidence to suggest a causal relationship (e.g., the 
event occurred within a reasonable time after administration of the trial medication). 
However, other factors may have contributed to the event (e.g., the participant’s clinical 
condition, other concomitant events). Although an AE may rate only as “possibly related” 
soon after discovery, it can be flagged as requiring more information and later be upgraded to 
“probably related” or “definitely related”, as appropriate. 
• Unlikely to be related – A clinical event, including an abnormal laboratory test result, 
whose temporal relationship to study intervention administration makes a causal relationship 
improbable (e.g., the event did not occur within a reasonable time after administration of the 
study intervention) and in which other drugs or chemicals or underlying disease provides 
plausible explanations (e.g., the participant’s clinical condition, other concomitant 
treatments). 
• Not Related – The AE is completely independent of study intervention administration, 
and/or evidence exists that the event is definitely related to another etiology. Note: there must 
be an alternative, definitive etiology documented by the clinician. 
8.3.3.3 
Expectedness 
We expect that gastrointestinal symptoms (including fever, aspiration, belching, bloating, nausea 
or vomiting, gastroesophageal reflux, abdominal cramps, abdominal pain, diarrhea, constipation) 
may be common post administration of the investigational products, both as a consequence of the 
underlying disease being treated, and potentially as an adverse effect of the administered 
product. 

 
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In the initial, 60-minute bedside observation period following administration of investigational 
product, subjects will be monitored with close attention to the following: 
• allergic reaction (temperature, skin rash, heart rate, or blood pressure change as already 
described) 
• sepsis or shock (temperature, heart rate, or blood pressure change as already described) 
• bowel injury (abdominal pain change) 
• aspiration (respiratory rate or oxygen saturation change) 
• gastrointestinal symptoms (belching, bloating, nausea, vomiting, GERD, abdominal 
cramps, abdominal pain, diarrhea, and constipation) 
In the subsequent, 7-day monitoring period following administration of investigational product, 
subjects will be monitored with close attention to the following: 
• donor-derived infection (temperature or abdominal pain change) 
• gastrointestinal symptoms (aspiration, belching, bloating, nausea, vomiting, GERD, 
abdominal cramps, abdominal pain, diarrhea, and constipation) 
In the subsequent, 28-, 48-, and 180-day monitoring periods, subjects will be monitored with 
close attention to the following: 
• transmitted infection (temperature or abdominal pain change as already described) 
• metabolic changes (polydipsia, polyuria, weight gain, or weight loss) 
 
8.3.4 
 Adverse Events of Special Interest 
Any gastrointestinal symptom or allergic reaction adverse event grade 3 or higher will be 
classified as an adverse event of special interest. These events may be related to the use of the 
FMT product and should be recorded as an adverse event of special interest and reported to the 
sponsor. Reporting of Adverse Events of Special Interest should follow the reporting pathway 
described for Serious Adverse Events.  
8.3.5 
Time Period and Frequency for Event Assessment and Follow-Up 
Safety will be assessed by monitoring and recording potential adverse effects using the Common 
Toxicity Criteria version 5.0 (CTCAE V5.0) at each study visit or participant contact (phone 
call/email). Participants will be monitored by medical histories, physical examinations, and 

 
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baseline status. If CTCAE V5.0 grading does not exist for an adverse event, the severity of mild, 
moderate, severe, life-threatening, and death, corresponding to Grades 1-5, will be used 
whenever possible. 
At each contact with the subject, the investigator will seek information on adverse events by non-
directive questioning and, as appropriate, by examination. Adverse events may also be detected 
when they are volunteered by the subject during the screening process or between visits, or 
through physical examination, laboratory test, or other assessments. Additionally, the subject 
study diary will include a card for the collection of all solicited adverse events. Information on 
all adverse events will be recorded in the source documentation. To the extent possible, adverse 
events will be recorded as a diagnosis and symptoms used to make the diagnosis recorded within 
the diagnosis event. 
As much as possible, each adverse event or follow-up information will be evaluated to 
determine: 
1. Severity grade (CTCAE V5.0 Grade 1-5) 
2. Duration (start and end dates) 
3. Relationship to the study treatment or process – [Reasonable possibility that an AE is 
related: No (unrelated/ not suspected) or Yes (a suspected adverse reaction)]. If yes 
(suspected) - is the event possibly, probably, or definitely related to the investigational 
treatment? 
4. Expectedness to study treatment or process – [Unexpected – if the event, severity, and/or 
frequency is not described in the investigator brochure (if applicable) or protocol]. 
5. Action taken with respect to study or investigational treatment or process (none, dose 
adjusted, temporarily interrupted, permanently discontinued, unknown, not applicable). 
6. Whether medication or therapy taken (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy). 
7. Whether the event is serious. 
Once an adverse event is detected, it should be followed until its resolution or until it is judged to 
be permanent, and assessment should be made at each visit (or more frequently, if necessary) of 
any changes in severity, the suspected relationship to the study treatment, the interventions 
required to treat it, and the outcome. 

 
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8.3.6 
Adverse Event Reporting 
Reporting period 
Adverse events will be reported from the time of informed consent until study completion (180 
days). 
Investigator reporting: notifying the study Sponsor 
Every SAE, regardless of suspected causality (e.g., relationship to study product(s) or study 
procedure(s) or disease progression) must be reported to the Sponsor within 24 hours of learning 
of its occurrence. 
Recurrent episodes, complications, or progression of the initial SAE must be reported to the 
Sponsor as a follow-up to the original episode within 24 hours of the investigator receiving the 
follow-up information. A SAE considered completely unrelated to a previously reported one 
should be reported separately as a new event. 
Send the SAE report to the Sponsor. 
New information regarding the SAE will be reported as it becomes available and in the same 
manner that the initial SAE (i.e. SAE form). The investigator must follow the event to resolution 
or until the event is deemed and documented irreversible, whichever is longer. 
Investigator Reporting: Local Reporting Requirements 
The investigator will report AEs and SAEs to the IRB of record and other local regulatory groups 
per the local requirements. 
8.3.7 
Serious Adverse Event (SAE) Reporting 
The study clinician will immediately report to the Sponsor any serious adverse event, whether or 
not considered study intervention related, including those listed in the protocol or investigator 
brochure and must include an assessment of whether there is a reasonable possibility that the 
study intervention caused the event. Study endpoints that are serious adverse events (e.g., all-
cause mortality) must be reported in accordance with the protocol unless there is evidence 
suggesting a causal relationship between the study intervention and the event (e.g., death from 
anaphylaxis). In that case, the investigator must immediately report the event to the Sponsor. 
New information regarding the SAE will be reported as it becomes available and in the same 
manner that the initial SAE (i.e. SAE form). All serious adverse events (SAEs) will be followed 
until satisfactory resolution or until the site investigator deems the event to be chronic or the 
participant is stable. Other supporting documentation of the event may be requested by the study 
Sponsor and should be provided as soon as possible. 

 
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The SAE reports to the Sponsor should be sent to the pharmacovigilance coordinator. 
In addition, all unexpected fatal or life-threatening suspected adverse reactions will be reported 
to the FDA as soon as possible but in no case later than 7 calendar days after the Sponsor’s initial 
receipt of the information. Other SAEs that are both, unexpected and related to the study drugs 
(SUSAR) will be reported to the FDA as soon as possible but no later than 15 calendar days after 
knowledge of the event. 
Investigator Reporting: Local Reporting Requirements 
The investigator will report AEs and SAEs to the IRB of record and other local regulatory groups 
per the local requirements. 
8.3.8 
Stopping/Halting Rules 
A study wide pause of PMT administration will be instituted if one of the following occur: 
• Death attributable to FMT 
• Suspected transmission of infection from donor to patient 
• If two (2) or more subjects experience the same Grade 3 or higher AE 
• If two (2) or more subjects experience an SAE related to the study product 
• There is an increase in frequency of long-term adverse events (e.g., IBD, metabolic 
disease) in > two (2) FMT treatment subjects 
8.3.9 
Unanticipated Problems 
8.3.9.1 
Definition of Unanticipated Problems (UP) 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving 
risks to participants or others to include, in general, any incident, experience, or outcome that 
meets all of the following criteria: 
• Unexpected in terms of nature, severity, or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the Institutional Review Board 
(IRB)-approved research protocol and informed consent document; and (b) the characteristics 
of the participant population being studied; 
• Related or possibly related to participation in the research (“possibly related” means there 
is a reasonable possibility that the incident, experience, or outcome may have been caused by 
the procedures involved in the research); and 

 
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• Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
8.3.9.2 
Unanticipated Problem Reporting 
Unanticipated problems (UPs) should be reported by the investigator to the reviewing IRB and 
OCR. 
9 STATISTICAL CONSIDERATIONS 
9.1 
Statistical Hypotheses 
OBJECTIVES 
Hypothesis 
9.2 
Primary 
 
Determine if fecal microbial transplantation 
leads to clinical improvement in refractory fecal 
incontinence in older women. 
Our working hypothesis is that the St. Mark’s 
Vaizey score, a measure of fecal incontinence 
severity, will significantly improve at 4 weeks after 
FMT, and will be maintained at 12 weeks, relative 
to baseline. A secondary outcome will be quality of 
life at 4 and 12 weeks. 
Primary Safety 
 
Determine the safety of FMT administration via 
NG tube in older women with FI. 
Our hypothesis is that there will be low occurrence 
of serious adverse events following administration 
of FMT via NG tube. 
Secondary 
 
Determine whether the effectiveness of 
microbial engraftment following fecal microbial 
transplantation is associated with the degree of 
clinical improvement. 
Our working hypothesis is that more transplanted 
strains will be present at 4 weeks in subjects with a 
higher response score. 
Tertiary 
 
Determine whether the baseline microbiota 
configuration affects engraftment in fecal 
microbial transplantation for fecal incontinence. 
Our working hypothesis is that the transplant will 
be more effective in baseline samples with lower 
microbial diversity. 
9.3 
Sample Size Determination 
Initial open label clinical trials of FMT for irritable bowel syndrome were performed with 10-15 
patients. (Holvoet, Gut 2017; Pinn ,Am J Gastro, 2014; Mazzawi, PLoS One, 2018) In the 
proposed pilot study, we will examine 15 evaluable women with refractory fecal incontinence to 
gather essential feasibility and outcomes data to conduct a future RCT of FMT. In a prior study 
of 13 adults with irritable bowel syndrome, significant differences in signals for several bacteria 
(Bacteroides, Desulfitispora, Bifidobacteria) were noted between 8 responders and 5 non-

 
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responders to FMT (response rate 60%). (Mazzawi PLoS One, 2018) If the response rate is near 
60% in our pilot study, we will be able to detect a difference in bacterial engraftment of 1.59 
standard deviations. Our power will be decreased if the response rate is either very low (<3) or 
very high (>12). With 15 subjects in a single arm study, the response rate will be determined to 
within 10% (interquartile range). 
9.4 
Statistical Analyses 
9.4.1 
General Approach 
Data on safety outcomes will be summarized using descriptive statistics. Feasibility of 
conducting a clinical trial of FMT will be calculated by measuring the feasibility of conducting a 
clinical trial of FMT will be calculated by percentage of screened patients who enroll in the study 
(Number enrolled / Number screened x 100). Fecal incontinence severity symptom and quality of 
life (QOL) scores at baseline, 4 and 12 weeks after FMT treatment will be compared using 
Friedman test (repeated measures ANOVA for non-parametric data) Responder will be defined 
as 5 point or greater improvement in St. Mark's score from baseline to 4 weeks following FMT. 
9.4.2 
Analysis of Stool Samples 
Sequence reads from shotgun metagenomic sequencing will be subjected to quality control, 
taxonomic assignment, gene function analysis, and metagenomic assembly using the Sunbeam 
metagenomics pipeline, which was co-written by CHOP Microbiome Center researchers. 
The FMT inoculum will be sequenced alongside fecal samples collected from subjects before 
and after the FMT procedure. DNA sequence reads from the inoculum will be assembled into 
contigs (overlapping DNA segments) using MEGAHIT (Li Bioinformatics, 2015). The 
metagenomic contig sequences represent segments of bacterial genomes from the microbiota. 
We will identify protein coding genes in the contig sequences, and use this gene set as unique 
identifiers for the genomes in the inoculum. Reads from patients before and after FMT will be 
aligned to the inoculum marker gene sequences. Gene sequences which are present in patients 
before the transplant will be removed from the set of inoculum marker genes. The percentage of 
total non-human reads aligning to the inoculum marker gene set will be used as a measure of 
bacterial engraftment following FMT. 
 

 
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10 SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1 Regulatory, Ethical, and Study Oversight Considerations 
10.1.1 
Informed Consent Process 
10.1.1.1 
Consent/Assent and Other Informational Documents Provided To 
Participants 
Consent forms describing in detail the study intervention, study procedures, and risks are given 
to the participant and written documentation of informed consent is required prior to starting 
intervention/administering study intervention. 
10.1.1.2 
Consent Procedures and Documentation 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in 
the study and continues throughout the individual’s study participation. Consent forms will be 
IRB-approved and the participant will be asked to read and review the document. The 
investigator will explain the research study to the participant and answer any questions that may 
arise. A verbal explanation will be provided in terms suited to the participant’s comprehension of 
the purposes, procedures, and potential risks of the study and of their rights as research 
participants. Participants will have the opportunity to carefully review the written consent form 
and ask questions prior to signing. The participants should have the opportunity to discuss the 
study with their family or surrogates or think about it prior to agreeing to participate. The 
participant will sign the informed consent document prior to any procedures being done 
specifically for the study. Participants must be informed that participation is voluntary and that 
they may withdraw from the study at any time, without prejudice. A copy of the informed 
consent document will be given to the participants for their records. The informed consent 
process will be conducted and documented in the source document (including the date and time), 
and the form signed, before the participant undergoes any study-specific procedures. The rights 
and welfare of the participants will be protected by emphasizing to them that the quality of their 
medical care will not be adversely affected if they decline to participate in this study. 
10.1.2 
Study Discontinuation and Closure 
This study may be temporarily suspended or prematurely terminated by the Sponsor or the PI at 
any site if there is sufficient reasonable cause. Written notification, documenting the reason for 
study suspension or termination, will be provided by the suspending or terminating party to study 
participants, investigator, funding agency, the Investigational New Drug (IND) Sponsor and 
regulatory authorities. If the study is prematurely terminated or suspended, the Principal 
Investigator (PI) will promptly inform study participants, the IRB, and Sponsor and will provide 
the reason(s) for the termination or suspension. Study participants will be contacted, as 
applicable, and be informed of changes to study visit schedule. 

 
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Circumstances that may warrant termination or suspension include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to participants 
• Demonstration of efficacy that would warrant stopping 
• Insufficient compliance to protocol requirements 
• Data that are not sufficiently complete and/or evaluable 
• Determination that the primary endpoint has been met 
• Determination of futility 
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the Sponsor, IRB and/or Food and Drug Administration (FDA). 
In terminating the study, the Sponsor and the Principal Investigator will assure that adequate 
consideration is given to the protection of the subjects’ interests. 
10.1.3 
Confidentiality and Privacy 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the Sponsor and their interventions. This confidentiality is extended to cover 
testing of biological samples and genetic tests in addition to the clinical information relating to 
participants. Therefore, the study protocol, documentation, data, and all other information 
generated will be held in strict confidence. No information concerning the study or the data will 
be released to any unauthorized third party without prior written approval of the Sponsor. 
All research activities will be conducted in as private a setting as possible. 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA). 
The study monitor, other authorized representatives of the Sponsor, representatives of the IRB, 
regulatory agencies or pharmaceutical company supplying study product may inspect all 
documents and records required to be maintained by the investigator, including but not limited 
to, medical records (office, clinic, or hospital) and pharmacy records for the participants in this 
study. The clinical study site will permit access to such records. 
The study participant’s contact information will be securely stored at the clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure 
location for as long a period as dictated by the reviewing IRB, Institutional policies, or Sponsor 
requirements. 

 
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10.1.4 
Future Use of Stored Specimens and Data  
Data collected for this study will be analyzed and stored at the University of Pennsylvania. After 
the study is completed, the de-identified data will be stored for future use by other researchers 
with IRB approval to do so. Biological specimens (stool samples) will be preserved in frozen 
storage for future analysis utilizing the same guidelines. 
10.1.5 
Safety Oversight 
Safety oversight will be under the direction of a Data and Safety Monitoring Board (DSMB) 
composed of individuals with the appropriate expertise. Members of the DSMB should be 
independent from the study conduct and free of conflict of interest, or measures should be in 
place to minimize perceived conflict of interest. The DSMB will meet at least semiannually to 
assess safety and efficacy data of the study. The DMSB will operate under the rules of an 
approved charter that will be written and reviewed at the organizational meeting of the DSMB. 
10.1.6 
Clinical Monitoring 
A monitoring plan that satisfies the International Council on Harmonisation (ICH) Good Clinical 
Practices (GCP) guidelines for clinical monitoring will be used. The investigator will allocate 
adequate time for such monitoring activities. The Investigator will also ensure that the monitor or 
other compliance or quality assurance reviewer is given access to all study-related documents 
and study related facilities (e.g. pharmacy, diagnostic laboratory, etc.), and has adequate space to 
conduct the monitoring visit. The monitor, a member of the Women’s Health Clinical Research 
Center, will lead this effort, and report findings to the PI and the DSMB when necessary. The 
monitor will have full knowledge of the study protocol, Manuals of Procedures, and is familiar 
with the database system, REDCap (Research Electronic Data Capture) and is trained to review 
patient charts. The monitor along with the Project Manager/Lead Study Coordinator at the site 
will be responsible for training and supervising other personnel. 
10.1.7 
Quality Assurance and Quality Control 
During monitoring visits, the monitor will review CRFs to ensure data accuracy, completeness, 
and clarity, including laboratory reports and other subject records with the stipulation that subject 
confidentiality will be strictly maintained in accordance with local and federal regulations, 
including HIPAA requirements. Instances of missing or uninterruptible data will be resolved in 
coordination with the Investigator. 
10.1.8 
Data Handling and Record Keeping 
10.1.8.1 
Data Collection and Management Responsibilities 
Data will be collected prospectively by designated research personnel at the study site, 
supervised by the PI. Original source documents will be kept in the study subject folder. Well-
designed data collection forms (CRFs) will be developed to minimize data collection and 

 
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recording errors. CRFs will be completed, with copies and will be printed and stored in binders 
in a secure location to which only study personnel will have access. Subject diaries will also be 
collected and stored in a secure location. Subjects will be assigned a unique study identification 
number, and PHI will be kept separately with a master file stored on a secure, password-
protected computer. Linkage to PHI will be stored until study analysis and publication 
completion, and then will be destroyed. Administrative forms will be designed, such as visit 
procedure checklists, to assist the research staff in complying with protocol procedures. All data 
are being collected solely for the purpose of research and do not become part of the subject’s 
medical record. 
10.1.8.2 
Study Records Retention 
Data (electronic and paper) will be stored in a secure location until study analysis and 
publication completion, after which any linkage to PHI will be destroyed. Anonymized microbial 
nucleic acid sequence data and associated metadata will be uploaded on public databases (i.e., 
the National Center for Biotechnology Information’s Sequence Read Archive) as required by 
funding agencies. Final records will be retained per institutional guidelines. 
10.1.8.3 
Publication Plan 
The investigator is responsible for authoring a final clinical study report and sharing with the 
Sponsor team. The Clinical Study Report will be issued within 12 months of data lock and the 
results summary will be posted to clinicaltrials.gov. as required by legal agreement, local law, or 
regulation. A manuscript will be progressed for publication in the scientific literature if the 
results provide important scientific or medical knowledge. 
10.1.9 
Protocol Exceptions and Deviations 
10.1.9.1 
Exception (Prospective action) 
An exception is defined as a one-time, intentional action or process that departs from the 
approved study protocol, intended for one occurrence. If the action disrupts the study progress, 
such that the study design or outcomes may be compromised, or the action compromises the 
safety and/or welfare of study subjects, advance documented approval from the Regulatory 
Sponsor and local regulatory review committees, per institutional guidelines, is required. 
Approval from the Regulatory Sponsor must be received prior to submission to the local 
regulatory review committees. 
10.1.9.2 
Deviation (Retrospective action) 
A deviation is defined as a one-time, unintentional action or process that departs from the 
approved study protocol, involving one incident and identified retrospectively. If the deviation 
disrupts study progress, such that the study design or outcomes may be compromised, or the 
deviation compromises the safety and/or welfare of study subjects, the deviation must be 

 
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reported to the Regulatory Sponsor within 24 – 48 hours of PI knowledge and to local regulatory 
review committees per institutional guidelines. 
The PI and the study team should document all scenarios where the protocol is not followed and 
provide, in particular: 
• Who deviated from the protocol; 
• What was the deviation; 
• When did the deviation occur; 
• How did the deviation happen; 
• What is the impact of the deviation; 
• A root cause analysis of why the deviation occurred. 
If the assessment is determined to be of limited impact (minor deviation), the documentation for 
this assessment and the outcome should be reported to the Sponsor at the time of annual report. 
Reporting to the IRB should follow specific local requirements. 
If the assessment results in a determination that any of the following are potentially affected, the 
deviation would be considered of significant impact: 
• having the potential to adversely affect subject safety; OR 
• increases risks to participants; OR 
• adversely affects the integrity of the data; OR 
• violates the rights and welfare of participants; OR 
• affects the subject’s willingness to participate in research; 
• there is a potential for an overall impact on the research that should be shared with the 
IRB for consideration and development of next best steps to address it. 
Report the following information on the Sponsor’s exception/deviation form: 
• Protocol number; 
• Subject number; 
• Description of the exception or deviation; 

 
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• Impact on subject safety; 
• Impact on data integrity. 
Deviations that are assessed by the PI to not disrupt the study progress, such as not affecting the 
study design or outcome, or compromising the safety and/or welfare of study subjects, should be 
documented in site records and contain documentation of the PI’s assessment. 
These scenarios should be reported to the Sponsor within 24 – 48 hours of discovery. Reporting 
to IRB should follow local requirements. 
10.1.10 
Conflict of Interest Policy 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who have 
a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed 
and managed. Furthermore, persons who have a perceived conflict of interest will be required to 
have such conflicts managed in a way that is appropriate to their participation in the design and 
conduct of this trial. 
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