Conditions: Clostridium Difficile Infection Recurrence
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 3
Healthy volunteers: no

Brief summary:
The objective is to examine the effect of Fecal Microbiota Transplantation (FMT) compared with vancomycin for cure of recurrent C. diff infection (CDI) in solid organ transplant (SOT) recipients in a randomized, controlled clinical trial.

Detailed description:
Clostridium difficile (C.difficile) is a pathogen of major public health importance, especially in individuals with comorbid conditions such as solid organ transplantation (SOT). The incidence and adverse outcomes of CDI are greatly amplified in the setting of SOT, due to healthcare exposure, antibiotic use and immunosuppression, all of which are ubiquitous in SOT recipients. There are currently no effective treatment options to achieve a sustained cure of recurrent CDI and prevent further recurrence in SOT recipients. A novel approach that has recently gained attention is restoration of the CDI impaired gut microbiome by instillation of stool from a healthy donor into the intestine of a CDI patient. This treatment, called Fecal Microbiota Transplantation (FMT) has been found in non-comparative studies to reduce CDI recurrence dramatically with a reported efficacy of over 95%, however its efficacy in SOT recipients has not been studied and cannot be extrapolated from results in the non-SOT population because SOT recipients are a unique study population due to profound immunosuppression, frequent antibiotic use and frequent opportunities for exposure to CDI all of which markedly, repeatedly and persistently disrupt the gut microbiome. Thus, this critical gap in the field needs to be addressed by a trial of FMT in SOT recipients with CDI.

Arms:
arm 1: FMT plus placebo vancomycin arm 2: Vancomycin plus FMT enema placebo

Interventions: intervention 1: FMT oral capsule intervention 2: Oral Vancomycin intervention 3: FMT oral placebo intervention 4: Oral Vancomycin placebo
Intervention descriptions: intervention 1: FMT oral capsules, single dose of 5 capsules intervention 2: Oral Vancomycin 125 mg capsules every 6 hours for 14 days, followed by 125 mg oral placebo every 12 hours for 7 days, followed by 125 mg oral placebo once daily for 7 days, followed by 125 mg oral placebo every 3 days for 14 days intervention 3: Placebo oral capsules, single dose of 5 capsules intervention 4: Placebo oral vancomycin capsules every 6 hours for 14 days, followed by 125 mg oral vancomycin every 12 hours for 7 days, followed by 125 mg oral vancomycin once daily for 7 days, followed by 125 mg oral vancomycin every 3 days for 14 days.

Protocol document:
Prot_SAP_005.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
Fecal Microbiota Transplantation (FMT) 
For C. difficile Infection (CDI) in 
Solid Organ Transplant (SOT) Recipients 
 
 
 
Protocol Number: 2018-1056 
 
National Clinical Trial (NCT) Identified Number:  NCT03617445 
 
Principal Investigator & IND Sponsor: Nasia Safdar, MD, PhD 
 
Funded by: NIAID 
NIAID DMID Protocol Number 20-0018 
 
Version Number: 10 
Date: 24AUG2022 
 
 
 
 
This document is confidential. 
No part of it may be transmitted, reproduced, published, or used by other persons without prior written 
authorization from the Sponsor or Principal Investigator. 
 
 
 
 
 
 
 


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PROTOCOL VERSION HISTORY 
 
Version 
Date 
Comment 
 
1.0 
13AUG2018 
Initial version 
1.1 
29AUG2018 
Amendment per FDA 
2.0 
24JUL2019 
Amendment per FDA and Steering Committee 
3.0 
12MAR2020 
Amendment 
4.0 
24AUG2020 
Amendment 
5.0 
05JAN2021 
Amendment – FMT route of administration 
6.0 
15APR2021 
Amendment per FDA 
7.0 
23MAY2021 
Amendment to match versions with IRB/FDA 
8.0 
13SEP2021 
Amendment to clarify eligibility criteria and per NIH/Steering Committee 
9.0 
20MAY2022 
Amendment – compensation/DMC information/ CMV eligibility 
change 
10.0 
24AUG2022 
Amendment – Taper change/Research Lab test update 
 
 
 
 
 
 


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TABLE OF CONTENTS 
1.0 
STATEMENT OF COMPLIANCE .............................................................................................................5 
2.0 
LIST OF ABBREVIATIONS .....................................................................................................................6 
3.0 
TERMINOLOGY .......................................................................................................................................7 
4.0 
STUDY SUMMARY ..................................................................................................................................7 
 
Schematic of Study Design ........................................................................................................................... 9 
5.0 
KEY PERSONNEL .................................................................................................................................10 
6.0 
INTRODUCTION ....................................................................................................................................12 
 
Background ................................................................................................................................................. 12 
 
Rationale ..................................................................................................................................................... 12 
7.0 
STUDY OBJECTIVES AND ENDPOINTS .............................................................................................14 
 
Primary Objective ........................................................................................................................................ 14 
 
Secondary Objectives ................................................................................................................................. 14 
 
Primary Outcome Measure ......................................................................................................................... 16 
 
Secondary Outcome Measures .................................................................................................................. 16 
8.0 
STUDY DESIGN .....................................................................................................................................20 
 
General Design ........................................................................................................................................... 20 
 
Rationale for Intervention ............................................................................................................................ 20 
 
Study Risk/Benefit Assessment .................................................................................................................. 21 
 
End of Study Definition ............................................................................................................................... 23 
9.0 
SUBJECT SELECTION ..........................................................................................................................24 
 
Inclusion/Exclusion Criteria ......................................................................................................................... 24 
 
Recruitment ................................................................................................................................................. 25 
 
Retention Strategies ................................................................................................................................... 25 
 
Early Termination and Withdrawal .............................................................................................................. 25 
10.0 
STUDY INTERVENTION ........................................................................................................................27 
 
Study Intervention Description .................................................................................................................... 27 
 
Source ......................................................................................................................................................... 27 
 
Packaging and Labeling .............................................................................................................................. 28 
 
Preparation ................................................................................................................................................. 28 
 
Storage and Stability ................................................................................................................................... 29 
 
Accountability .............................................................................................................................................. 29 
 
Dosing and Administration .......................................................................................................................... 29 
 
Randomization and Blinding ....................................................................................................................... 30 
 
Unblinding Procedures ................................................................................................................................ 30 
 
Study Intervention Compliance ................................................................................................................... 30 
 
Concomitant Therapy .................................................................................................................................. 30 
11.0 
STUDY VISITS AND PROCEDURES ....................................................................................................31 
 
Screening and Enrollment........................................................................................................................... 31 
 
Visit 1 (Baseline) ......................................................................................................................................... 32 
 
Visit 2 (Randomization) ............................................................................................................................... 32 
 
Study Drug Administration Follow-up Call .................................................................................................. 33 
 
Visit 3 (in-person) ........................................................................................................................................ 33 
 
Visit 4 (in-person or phone call) .................................................................................................................. 33 


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Visit 5 (in-person or phone call) .................................................................................................................. 33 
 
Visit 6 (in-person or phone call) .................................................................................................................. 34 
 
Visit 7 (in-person or phone call) .................................................................................................................. 34 
 
Telephone Contact ...................................................................................................................................... 34 
 
Unscheduled Visit ....................................................................................................................................... 34 
 
Early Termination and Withdrawal .............................................................................................................. 34 
 
Study Calendar ........................................................................................................................................... 36 
 
Study Procedures ....................................................................................................................................... 38 
12.0 
DATA COLLECTION, HANDLING AND RECORD KEEPING ..............................................................40 
 
Types of Data .............................................................................................................................................. 40 
 
Data Collection ............................................................................................................................................ 40 
 
Data Capture Methods ................................................................................................................................ 41 
 
Data Confidentiality ..................................................................................................................................... 42 
 
Records Retention ...................................................................................................................................... 42 
 
Specimen Banking ...................................................................................................................................... 42 
13.0 
ASSESSMENT OF SAFETY ..................................................................................................................44 
 
Adventitious Findings .................................................................................................................................. 44 
 
Adverse Event (AE) Definition .................................................................................................................... 44 
 
Serious Adverse Event (SAE) Definition ..................................................................................................... 44 
 
Unanticipated Problem (UP) Definition ....................................................................................................... 44 
 
Classification of an Adverse Event ............................................................................................................. 45 
 
Collection and Reporting of AEs, SAEs & UPs .......................................................................................... 46 
 
Stopping Rules ............................................................................................................................................ 46 
14.0 
STUDY ANALYSIS .................................................................................................................................48 
 
Statistical Hypothesis .................................................................................................................................. 48 
 
Primary Efficacy Objective .......................................................................................................................... 48 
 
Primary Safety Objective ............................................................................................................................ 48 
 
Secondary Objectives ................................................................................................................................. 48 
 
Sample Size Justification ............................................................................................................................ 49 
 
Subject Population(s) for Analysis .............................................................................................................. 49 
 
Statistical Methods ...................................................................................................................................... 50 
 
Subgroup Analysis ...................................................................................................................................... 52 
 
Handling Missing Data ................................................................................................................................ 52 
 
Exploratory Analysis ................................................................................................................................... 52 
 
Interim Analysis ........................................................................................................................................... 52 
 
Multiplicity of Endpoints and Multiple Testing ............................................................................................. 52 
15.0 
REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS .......................................54 
 
Quality Management ................................................................................................................................... 54 
 
Safety Oversight ......................................................................................................................................... 54 
 
Study Monitoring ......................................................................................................................................... 55 
 
Protocol Deviations ..................................................................................................................................... 55 
 
Publication Plan .......................................................................................................................................... 56 
16.0 
MULTISITE RESEARCH COMMUNICATION PLAN .............................................................................57 
 
Statement of Compliance with NIH Single IRB Policy ................................................................................ 57 
 
UW-Madison Health Sciences IRB ............................................................................................................. 57 
 
Participating Sites Agreement to Rely on sIRB .......................................................................................... 57 
 
Communication between Sites and the sIRB ............................................................................................. 57 
REFERENCES ...................................................................................................................................................59 
17.0 
APPENDICES .........................................................................................................................................61 
17.1 
Quality of Life Questionnaire (Cdiff-32 ........................................................................................................ 61 


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Stool Diary .................................................................................................................................................. 73 
 
Subject Instructions for Stool Collection ..................................................................................................... 78 
 
Medication Diary ......................................................................................................................................... 79 
 
Data Safety Monitoring Board Charter and Membership ............................................................................ 82 
 
1.0 
STATEMENT OF COMPLIANCE 
 
The signature below constitutes that the research will be carried out in accordance with International 
Conference on Harmonisation Good Clinical Practice (ICH GCP) and the United States (US) Code of 
Federal Regulations (CFR) applicable to clinical studies (45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 
56, 21 CFR Part 312, and/or 21 CFR Part 812)  
 
I agree to ensure that all staff members involved in the conduct of this study are informed about their 
obligations in meeting the above commitment.  
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the Institutional Review Board (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.  In addition, 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. 
 
 
 
 
PRINTED OR TYPED NAME 
 
 
 
SIGNATURE 
 
 
 
DATE 
Nasia Safdar, MD, PhD 
 
 
 
 
8/13/2018 
Principal Investigator(s)  
 
 
 
 
 
 
 


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2.0 
LIST OF ABBREVIATIONS 
 
 
AE 
Adverse Event 
CCC 
Clinical Coordinating Center 
CDC 
Centers for Disease Control and Prevention 
CDI 
Clostridioides difficile infection 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
DCC 
Data Coordinating Center 
DMC 
Data Monitoring Committee 
eCRF 
Electronic Case Report Forms 
FDA 
Food & Drug Administration 
 
 
FMT 
Fecal Microbiota Transplantation 
FRGNB 
Fluoroquinolone-resistant Gram-negative Bacteria 
FSTRF 
Frontier Science & Technology Research Foundation 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
HMP 
Human Microbiome Project 
ICH E6 
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use Good Clinical Practice 
ICTR 
Institute for Clinical and Translational Research 
IgG 
Immunoglobulin G 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
KAAS 
Kyoto Automated Annotation Server 
KEGG 
Kyoto Encyclopedia of Genes and Genomes 
KO 
KEGG orthology 
MARCH 
Midwest Area Research Consortium for Health 
MDRO 
Multiple-drug resistant organism 
MOP 
Manual of Procedures 
MRSA 
Methicillin-resistant Staphylococcus aureus 
N 
Number (typically refers to subjects) 
NG 
Nasogastric 
NIAID 
National Institute of Allergy and Infectious Diseases, NIH, DHHS 
OTU 
Operational taxonomic unit 
PCR 
Polymerase chain reaction 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
QoL 
Quality of Life 
RCT 
Randomized Controlled Trial  
SAE 
Serious Adverse Event 


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SC 
Steering Committee 
SOC 
Standard of care 
SOT            Solid Organ Transplant 
US 
United States 
UW 
University of Wisconsin-Madison 
VRE 
Vancomycin-resistant Enterococcus 
 
 
 
 
 
 
 
3.0 
TERMINOLOGY 
 
Fecal Microbiota Transplantation (FMT) is a procedure to restore Clostridioides difficile infection (CDI) 
impaired gut microbiome by instillation of stool from a healthy donor into the intestine of a CDI patient. 
There are multiple routes of administration for FMT: colonoscopy, enema, nasogastric tube or oral. In 
this study, FMT will be administered orally, using human stool that is freeze-dried and encapsulated, and 
administered to subjects as capsules to be swallowed. The formulation of encapsulated fecal microbiota 
being used in this study is called MTP-101-C.  
 
Throughout this protocol, the term FMT will refer to the fecal microbiota transplantation procedure. The 
terms MTP-101-C and encapsulated fecal microbiota will be used to describe the investigational product. 
 
 
 
 
4.0 
STUDY SUMMARY 
 
 
Full Title: 
Fecal Microbiota Transplantation (FMT) for C. difficile Infection (CDI) in Solid 
Organ Transplant Recipients 
Short Title: 
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Protocol Number: 
2018-1056 
ClinicalTrials.gov: 
NCT03617445 
IND Number: 
 27262 
IND Sponsor 
Nasia Safdar, MD, PhD 
Funding Source: 
U01AI125053, National Institute of Allergy and Infectious Diseases (NIAID)  
Phase: 
Phase II 
Précis: 
A multisite, randomized, double-blind, doubly placebo-controlled phase II trial 
comparing the safety and efficacy of fecal microbiota transplant (FMT) versus 
oral vancomycin for prevention of CDI recurrence in solid organ transplant  
(SOT) recipients  
Study Center(s): 
Five sites in the United States 
Objective(s): 
 
Primary Objective:  Evaluate the safety and efficacy of FMT compared to 
oral vancomycin for the prevention of CDI recurrence in SOT recipients 
 
Secondary Objectives:  
 
Assess the CDI-related quality of life in SOT recipients treated with 
FMT compared with oral vancomycin 
 
Compare the change in gut microbiota using multiple metrics of 
microbiota structure and function and to evaluate the association 
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 
Evaluate the short- and medium-term safety of FMT in SOT patients 
 
Compare the effects of FMT and oral vancomycin on intestinal 
colonization by multidrug-resistant organisms other than C. difficile in 
SOT recipients. 
Main Eligibility Criteria: 
Adult Solid Organ Transplant (SOT) recipients with at least a first recurrence 
of CDI. 
Study Product: 
MTP-101-C: screened, freeze-dried, encapsulated fecal microbiota from 
healthy human donors.  
FDA Status 
The Food & Drug Administration (FDA) considers MTP-101-C an 
investigational new drug (IND).   
Reference Therapy: 
125 mg oral vancomycin every 6 hours for 14 days, followed by 125 mg oral 
vancomycin every 12 hours for 7 days, followed by 125 mg oral vancomycin 
once daily for 7 days, followed by 125 mg oral vancomycin every 3 days for 
14 days.  
Sample Size: 
A total of 158 subjects will be recruited from 5 study sites (i.e., approximately 
30 subjects per site).  
Study Duration 
Study enrollment and follow-up will occur over 4 years.  The duration of the 
study for each subject is approximately 30 weeks.  
 
 
 
 
 


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Schematic of Study Design 
 


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5.0 
KEY PERSONNEL 
 
Sponsor and Medical Monitor 
Nasia Safdar, MD, PhD 
Department of Infectious Diseases 
University of Wisconsin-Madison   
UW Medicine Foundation Centennial Building 
1685 Highland Ave 
Madison, WI, 53705 
ns2@medicine.wisc.edu 
(608) 213-4075 
 
Clinical Coordinating Center 
Midwest Area Research Consortium for Health (MARCH) 
School of Medicine and Public Health 
University of Wisconsin-Madison  
2112 Health Sciences Learning Center 
750 Highland Avenue 
Madison, WI 53705 
recoverstudy@ictr.wisc.edu  
 
Data Coordinating Center 
KyungMann Kim, PhD 
Department of Biostatistics and Medical Informatics 
School of Medicine and Public Health 
University of Wisconsin-Madison 
265J Warf Office Building 
610 Walnut St 
Madison, WI 53726 
kyungmann.kim@wisc.edu  
(608) 265-6380 
 
Clinical Trials Data Management Center and Monitoring 
Ken Wood, MS 
Project Manager, Data Manager 
Frontier Science and Technology Research Foundation, Inc. 
4033 Maple Road 
Amherst, NY 14226 
recover.dmc@fstrf.org  
(716)-834-0900 x7235 
 
Holly Shaw, MS, CCRP 
Andrew Lohrum, MLS 
Study Monitors 
Frontier Science and Technology Research Foundation, Inc. 
4033 Maple Road 
Amherst, NY 14226 
recover.monitoring@fstrf.org 
 
Research Laboratory 
Infectious Disease Research Lab 
600 Highland Avenue 
H4/663 Clinical Science Center 
Madison, WI 53792 
 
 


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Investigational Product Distribution  
Alexander Khoruts, MD 
University of Minnesota Microbiota Therapeutics Program 
1479 Gortner Ave 
Falcon Heights, MN 55108 
khoru001@umn.edu 
(763)-227-1635 
 
 
Funding Agency 
National Institute of Allergy and Infectious Diseases, National 
Institutes of Health (NIH) 
Program Officer, Enteric & Hepatic Diseases Branch 
5601 Fishers Lane, Room 8F46 
Rockville, MD  20852  
Local Site Investigators 
Todd Pesavento, M.D. 
Ohio State University 
Department of Medicine 
395 W 12th Ave. Ground Floor 
Columbus, OH 43210 
 
Michael Angarone, DO 
Northwestern University 
Division of Infectious Diseases 
645 N Michigan Ave, Ste 900 
Chicago, IL 60611 
 
Sahil Khanna, MBBS, MS 
Mayo Clinic 
Division of Gastroenterology and Hepatology 
200 First Street SW 
Rochester, MN 55905 
 
Monika Fischer, MD 
Indiana University 
Department of Medicine, Division of Gastroenterology & 
Hepatology 
550 N. University Blvd., UH 1634 
Indianapolis, IN 46202 
 
Christopher Saddler, MD 
University of Wisconsin - Madison 
Division of Infectious Disease 
1685 Highland Ave 
5th Floor MFCB 
Madison, WI 53705 
 
 
 
 


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6.0 
INTRODUCTION 
 
 
Background  
Clostridioides difficile (C. difficile) is a pathogen of major public health importance, especially in 
individuals with comorbid conditions such as solid organ transplantation (SOT). The Centers for 
Disease Control and Prevention (CDC) estimate that 165,000 serious C. difficile infections (CDI) 
occur in the US annually, at a cost of 1.3 billion dollars, resulting in 28,000 deaths.1,2, 3 National 
data show that rates of C. difficile infection among hospitalized patients aged ≥65 years have 
increased 200%. The incidence and adverse outcomes of CDI are greatly amplified in the setting of 
SOT, due to healthcare exposure, antibiotic use and immunosuppression, all of which are 
ubiquitous in SOT recipients4. In recent years, CDI has been increasingly recognized as an 
important etiology of diarrhea in this population. An estimated 14-16% of SOT recipients develop 
CDI, compared with 1-2% of general non-SOT inpatients. The consequences of CDI in the SOT 
population are dire: higher rates of fulminant colitis, treatment failure, recurrence and mortality. At 
UW-Madison, the third largest abdominal transplant program in the country, the recurrence/relapse 
rate in SOT recipients is 35%; this is largely due to a combination of 1) impaired host immunity and 
2) reduced diversity and health of the normal gut microbiota due to immunosuppression, surgical 
procedures and devices, repeated exposures to healthcare and antibiotic use. There are currently 
no effective treatment options to prevent further recurrence of CDI in SOT recipients. Usual care 
recommended in national guidelines involves oral vancomycin which has low efficacy for prevention 
of recurrence with side effects of gut dysbiosis and promotes vancomycin-resistant enterococci. 
 
A novel approach that has recently gained attention is restoration of the CDI impaired gut 
microbiome by instillation of stool from a healthy donor into the intestine of a CDI patient. This 
treatment, called Fecal Microbiota Transplantation (FMT) has been found in non-comparative 
studies to reduce CDI recurrence dramatically with a reported efficacy of over 95%5-9; its efficacy in 
SOT recipients has not been studied and cannot be extrapolated from results in the non-SOT 
population because SOT recipients are a unique study population due to profound 
immunosuppression, frequent antibiotic use and frequent opportunities for exposure to CDI all of 
which markedly, repeatedly and persistently disrupt the gut microbiome. Thus, this critical gap in 
the field needs to be addressed by a trial of FMT in SOT recipients with CDI.  The FMT may be 
delivered via any of several routes; oral, via nasogastric (NG) tube, enema or colonoscopy. All 
routes have good efficacy with 80% reported for oral encapsulated product compared with 90% for 
FMT via enema or colonoscopy.5-9 
 
 
Rationale 
There have been recent published randomized controlled trials (RCTs) in this area, and thus far, 
have included non-SOT recipients, performed FMT by way of NG tube rather than oral route with 
one study reporting an over 85% success rate compared with oral vancomycin taper (30% success 
rate) in 26 patients with recurrent CDI in the Netherlands.10 While these results are very 
encouraging, there are a number of reasons why a RCT of FMT in SOT recipients is needed. 
These include the following:  
 
The  RCT had a very small sample size and an unplanned interim analysis resulted in 
premature termination of the study. This approach was criticized in multiple letters to the editor 
on the grounds that “small, index trials such as this one are vulnerable to exaggerated 
treatment effects; there may have been inequalities among the three treatment groups in terms 
of either the number of pretreatment recurrences of C. difficile infection or post-treatment 
exposure to an antimicrobial agent or proton-pump inhibitor (both of which are well-defined 
risks for recurrence).”11 
 
The cure rate in the control group treated with vancomycin was half of that reported in two 
randomized trials and it was this unexpectedly low cure rate in the control group that produced 
an inflated estimate of the efficacy of FMT thus leading to the trial's early termination. 
 
The route of FMT in that study was by nasogastric tube which has a higher risk of side effects 
than other delivery routes. Given the far fewer side effects expected with oral administration, 


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the optimal route of FMT deserves further study. A recent systematic review found equivalent 
outcomes in case series using FMT by fecal enema or colonoscopy.12 Oral FMT has largely 
similar efficacy to enema/colonoscopy and high patient acceptance.  
 
The SOT population is at high risk for recurrent CDI due to age and comorbid illnesses and 
therefore potentially promising therapies such as FMT should be studied in this population. 
 
Follow-up in previous studies ranged from 1 week to 8 weeks; a standardized approach to 
follow-up for at least 12 weeks is needed to detect recurrence of CDI. 
 
Given multiple possible causes of diarrhea in the SOT population and a higher prevalence of C. 
difficile colonization which may be mistakenly diagnosed as CDI, objective blinded assessment 
of outcomes is essential. The SOT population is also at risk for potential adverse events from 
FMT by transmission of pathogens and potential precipitation of rejection of the solid organ. 
Thus, trials of FMT in non-SOT patients cannot be applied to SOT recipients. 
 
An adequately powered, multisite, double-blind placebo controlled study of FMT versus oral 
vancomycin in SOT recipients followed for 30 weeks with outcomes of recurrence and rigor in 
addressing safety and rejection will address all of the aforementioned shortcomings.  
 
A review of www.clinicaltrials.gov yielded 27 FMT trials for the treatment of CDI. Only a few are 
evaluating administration by enema, one in the VA population is assessing FMT via oral route but 
no trials are assessing safety and efficacy in SOT recipients.  Thus, the proposed study will be the 
first to evaluate the safety and efficacy of FMT for CDI treatment in this patient population. 
 
 


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7.0 
STUDY OBJECTIVES AND ENDPOINTS 
 
 
Primary Objective 
The primary objective is to compare the effects of FMT and oral vancomycin on the recurrence of 
CDI in SOT recipients in a randomized controlled trial.  
 
 
Secondary Objectives 
 
7.2.1 
Secondary Objective #1 
Secondary Objective #1 is to assess Quality of Life (QoL) in SOT recipients with CDI.  
Patients with recurrent CDI have a markedly compromised quality of life. There is a 
dearth of data on CDI-related QoL in SOT recipients. A validated instrument, Cdiff-32, 
will be used to assess CDI-related QoL comparing the FMT arm with the oral 
vancomycin arm.1 
 
7.2.2 
Secondary Objective #2 
Secondary Objective #2 is to compare the change in gut microbiota using multiple 
metrics of microbiota structure and function and to evaluate the association between the 
change in gut microbiota and recurrence of CDI. 
 
The human intestine is colonized by 1013 to 1014 microbes, the vast majority of which 
belong to the phyla Firmicutes and Bacteroidetes. The composition of the human 
intestinal microbiota is individual-specific at the species level and is stable over time in 
healthy adults.2 The composition and activities of the microbiota may be influenced by 
numerous factors including chronic conditions, age, diet, and antibiotic treatment.3-5 For 
example, obesity and inflammatory bowel disease cause significant alterations in the 
microbiome.6 Similarly, the microbiota of older people displays greater inter-individual 
variation than that of younger adults (Figure 1).3  
 
Figure 1: Variations in microbial numbers across the length of the 
gastrointestinal tract by age.2 
 
 
(a)  Variations  in  microbial  numbers  across  the  length  of  the  gastrointestinal  tract.  (b)  Selected features 
affecting the establishment and maintenance of the microbiota and factors influencing the composition of the 
microbiota. Micro-organisms are listed where their abundance is related to a particular environmental factor. difficile 


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 The Relationship between CDI and Gut Microbiota 
Perturbations to the gut microbiota may result in a loss of colonization resistance 
against C. difficile. Although CDI is commonly associated with antibiotic use, the 
precise alterations to the microbiota associated with CDI have only recently been 
examined. For example, Schubert et al. used a variety of antibiotic perturbations 
to generate a diverse array of gut microbiota structures, which were then 
challenged with C. difficile spores. They observed that C. difficile resistance was 
the result of multiple microbiota members interacting in a context-dependent 
manner. They found that populations associated with the Porphyromonadaceae, 
Lachnospiraceae, Lactobacillus, and Alistipes were protective, while populations 
associated with Escherichia and Streptococcus had high levels of C. difficile 
colonization. Their results showed that multiple diverse assemblages act in 
concert to mediate colonization resistance.7 
 
 Relationship of CDI with Fecal Cytokines  
Recent data suggest that outcomes of CDI may be modulated by inflammation, 
as measured by high levels of fecal cytokines8-11 or fecal lactoferrin12 rather than 
bacterial burden alone. CXCL-5/ENA-78,11 and CXCL-8/IL-8 (Quantikine R&D 
Systems, Minneapolis, MN), levels of quantitative lactoferrin will be measured.  
 
 Impact of FMT on Gut Microbiome 
FMT rapidly replenishes the gut microbiota and the recipient microbiota becomes 
similar to that of the donor.17-19 In particular, FMT is known to alter the recipient 
microbiota in a number of ways. First, introducing a fecal microbiota from healthy 
donors that has greater diversity than that of the recipient encourages the 
establishment of specific taxa within CDI patients and allows for alteration of the 
patient microbiota that effectively minimizes the effects of CDI. Under this model, 
specific microbes from the FMT are able to colonize and establish in CDI 
patients, a concept known as engraftment.20 Importantly, the engraftment of FMT 
bacteria can further help to reprogram the gut microbiota of CDI patients by 
allowing for other microbes to colonize the gut from other sources (e.g. diet, the 
environment) and reestablish a highly-diverse healthy gut microbiota. We 
anticipate that overall gut microbiota health, as determined by diversity metrics, 
abundance indicators, and the ability of FMT microbes to engraft, will improve in 
the recipients of FMT. In contrast, patients treated with vancomycin are expected 
to have long lasting deleterious effects on the normal gut microbiota by limiting 
the ability of a healthy gut microbiota to establish.21  
7.2.3 
Secondary Objective #3 
Secondary objective #3 is to evaluate the short- and medium-term safety of FMT in SOT 
patients. The literature supports the safety of FMT in non-SOT recipients delivered by 
any route; however, the safety of FMT in SOT recipients has not been systematically 
evaluated, particularly regarding non-infectious outcomes, such as graft function and 
rejection. Our study will provide much needed data on FMT safety in SOT, which will be 
essential for any therapeutic development for recurrent CDI for this population.   
 
7.2.4 
Secondary Objective #4 
Secondary objective #4 is to compare the effects of FMT and oral vancomycin on 
intestinal colonization by multidrug-resistant organisms other than C. difficile in SOT 
recipients. The normal gut microbiota poses resistance to invasion by pathogenic 
organisms. Once the normal gut microbiota is impaired by CDI, surgery, being 
immunocompromised, or antibiotics, pathogenic organisms may establish a niche of 
colonization and later manifest as infection. In the healthcare setting, to which SOT 
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and include vancomycin-resistant Enterococcus (VRE), fluoroquinolone-resistant Gram-
negative bacteria (FRGNB), methicillin-resistant Staphylococcus aureus (MRSA) and 
most recently, the subject of several news reports and editorials, the dreaded 
carbapenem-resistant Enterobacteriaceae, which are resistant to virtually all anti-
infectives. There is currently no effective way to eradicate gastrointestinal colonization 
by these multidrug resistant organisms. In SOT recipients, infections caused by these 
pathogens are associated with major morbidity and mortality.22, 23 Our previous studies 
on infections in SOT recipients found that 25% had gastrointestinal colonization by VRE, 
10% by MRSA, and over 30% by FRGNB.24, 25 We will study colonization of VRE, 
MRSA, and FRGNB because these are major causes of infections in SOT recipients 
and are all gut-associated pathogens. The potential benefit of FMT for eradication of 
non-CDI enteric pathogens has been shown in case reports; our study will provide a 
robust assessment of the role of FMT for non-CDI multidrug-resistant organisms.  
 
There is scant data on outcomes of FMT for CDI in immunocompromised patients 37-39 
and data specific to outcomes of FMT for CDI in SOT recipients is limited to two 
descriptive case series.38, 40 Considerations unique to SOT recipients that may impact 
the role of FMT in CDI are nutritional status, co-infections, long-term effect of FMT on 
graft function, and cumulative immunosuppression. Data on these factors will be 
collected and incorporated in analyses.    
 
 
Primary Outcome Measure 
The primary outcome measure is recurrence of CDI in SOT recipients with recurrent CDI as a 
dichotomous variable. Recurrence of CDI is defined as diarrhea (≥3 loose stools that take the 
shape of the container in a 24-hour period) for 2 consecutive days with a positive stool test for C. 
difficile toxin by ELISA within a 60-day period following completion of treatment. Recurrent CDI will 
be assessed using stool diary and will be monitored by regular phone calls by study staff to 
determine signs and symptoms of diarrhea during the 24-week assessment period following 
enrollment (60 days for recurrence and 24 weeks to assess fecal microbiome). For subjects with 
diarrhea, a stool collection to determine C. difficile will be performed as part of standard of care. 
 
 
Secondary Outcome Measures 
7.4.1 
Secondary Outcome Measure #1 
Cdiff32 (Appendix 16.2), a validated instrument for CDI-related quality of life, will be 
completed at baseline (visit 1), end of study treatment (visit 3), end of follow-up (visit 7), 
and early termination.   
7.4.2 
Secondary Outcome Measure #2 
Change in microbiota will be measured using multiple metrics of microbiota structure 
and function, as detailed below. 
 
 Multiplex sequencing of amplicons generated from bacterial 16S rRNA genes 
Genomic DNA will be extracted from feces using a bead-beating protocol.47 We 
will generate multiplexed barcoded amplicons from the variable region V3-V4 of 
bacterial 16S rRNA genes, and perform 2x250 paired-end sequencing using an 
Illumina MiSeq, as previously described.48 This technology allows analysis of 
>300 samples in parallel.  
 
 Composition and structure of the gut microbiota  
The composition and structure of the gut microbiota will be determined via 16S 
rRNA gene analysis. Two analyses will be performed, including an operational 
taxonomic unit (OTU) analysis, which determines the specific taxa of bacteria 
present in a microbiota and their relative abundances, and a Bray-Curtis 
dissimilarity analysis,49 which quantifies the compositional dissimilarity between 


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microbial communities in terms of both total diversity and phylogenetic distance 
and visualized as a principal component analysis (PCA). An important 
consideration for the establishment of a healthy gut microbiota is the specific 
taxa capable of colonizing CDI patients treated with FMT. Therefore, identifying 
broad groups of bacteria strongly correlated with post-FMT microbiota will help 
understand which groups colonize the gut of CDI patients. A downstream 
correlation analysis will be performed on total community structure (Bray-Curtis 
dissimilarity and relative abundance) and composition using analysis of similarity 
(ANOSIM) in R. Taken together, these analyses will determine which specific 
OTUs are found to contribute significantly to the overall composition of the 
microbiota that established in CDI patients after FMT treatment. 
 
 Metagenomic analysis  
Shotgun metagenomics will be performed on all fecal DNA samples using a 
Illumina Hi-Seq 500 (paired-end 2x250). All sequences passing quality control 
(QC) will be assembled using MEGAHIT 50 to generate contigs and used to 
predict open reading frames using the program prodigal.51 This library of genes 
within a given sample will serve as the basis for all downstream analyses using 
our metagenomics data, as follows: 
 
 
Strain-level identification using metagenomics: A key study goal is to 
determine if specific strains of bacteria are found to colonize CDI patients 
treated with FMT, and thereby minimize the effects of CDI. After FMT, the 
conventional hypothesis is that bacterial strains present in the FMT are 
capable of establishing within CDI patients and proliferating (engraftment). 
However, an alternative hypothesis is that the initial engraftment of FMT 
bacteria allows for the colonization of bacteria from other sources (e.g. 
environment, diet) and thereby facilitate reprogramming to a healthy gut 
microbiota. Detecting these fine-scale taxonomic resolutions is not possible 
with current IIlumina-based 16S rRNA analysis. To address this, 
metagenomics data will be used to compare against both metagenomics 
data generated from the FMT itself, and the Human Microbiome Project 
(HMP, http://hmpdacc.org/), which contains over 3,000 genomes of human-
associated bacterial strains, including over 800 from the gut alone. First, all 
reads generated from metagenomics sequencing will be compared against a 
custom database generated from the HMP and FMT samples using the 
phylogenetic binning program kraken.52 A single-nucleotide polymorphism 
(SNP) analysis will then be conducted to determine if a given read can be 
identified as belonging to specific strains/species of gut-associated human 
microbes. This analysis will result in the following outcomes; (a) which 
specific strains from the FMT treatment can colonize CDI patients; and (b) 
what non-FMT related microbes are capable of colonizing CDI patients. 
 
 
Function of the gut microbiota: Metagenomic data also provides the 
opportunity to determine if specific genes are associated with the successful 
establishment of a healthy microbiota in CDI patients treated with FMT. The 
predicted ORF translations from the assembled metagenomes will be 
subjected to functional annotation using the Kyoto Encyclopedia of Genes 
and Genomes (KEGG) Automated Annotation Server (KAAS) to annotate 
each predicted protein according to the KEGG orthology (KO).53 These will 
be mapped back to their respective metabolic pathways and normalized 
based on metagenome size. Comparisons between metagenomes will be 
conducted using chi-square test to determine if a given sample is enriched 
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using a pairwise comparison employing Spearmann’s rank correlation will be 
conducted to determine which metagenomes are most similar to each other. 
Further comparisons will be conducted against the FMT-derived 
metagenomes and those pathways encoded by the HMP. In this way, not 
only will genes important in colonization be determined, but those derived 
from the FMT will also be identified as well. 
 
 
Microbiologic methods: Culture and polymerase chain reaction (PCR) will be 
used to recover MRSA, VRE and FRGNB. Molecular typing will be employed 
to show strain relatedness between the isolates at baseline and at the 
subsequent time points for these organisms and C. difficile.  
 
 
Stool lactoferrin and cytokines: For each stool collected, C. difficile will be 
cultured and PCR will be used for toxin-- quantitation. All isolates will be 
stored for future strain typing and characterization. Fecal cytokines will be 
assayed using ELISA. Levels of CXCL-5/ENA-78,24, CXCL-8/IL-8 and 
quantitative lactoferrin will be compared between treatment arm, with the 
anticipation that subjects assigned to FMT will have lower levels of cytokines 
and lactoferrin. 
 
 
Correlative outcomes: Diversity of the gut microbiota will be determined 
using either the reciprocal of Simpson’s index or the Shannon’s index. The 
reciprocal of Simpson’s index takes into account both the number of species 
present and the abundance of each species.  It has been used frequently in 
microbiota studies and is considered a standard measure of microbiota 
diversity. The Shannon’s index is a complementary index of diversity that 
considered both the abundance and evenness of species.  Metagenomic 
data as well as cytokines, CXCL-5/ENA-78 and CXCL-8/IL-8, and levels of 
quantitative lactoferrin will be determined using methods described above. 
 
7.4.3 
Secondary Outcome Measure #3 
The following variables will be used to assess short- and medium-term safety of FMT in 
SOT patients:   
 
Short term safety outcomes include: 
 
bloodstream infection from FMT 
 
immune phenomenon 
 
Medium term safety outcomes: 
 
rejections 
 
malignancy 
 
metabolic syndrome 
 
organ function 
 
infections other than CDI 
 
viral (EBV, CMV) infections 
 
fungal infections 
 
hospitalizations 
 
emergency department visits 
7.4.4 
Secondary Outcome Measure #4 
Intestinal colonization by multidrug-resistant organisms other than C. difficile in SOT 
recipients will be assessed by microbiologic methods as dichotomous variables. Stool 
specimens will be cultured and PCR will be used to recover methicillin-resistant 


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Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE), and 
fluoroquinolone-resistant Gram-negative bacteria (FRGNB). Molecular typing will also 
be used to show strain relatedness between the isolates at baseline and at subsequent 
time points. 
 
Following enrollment, subjects will complete a daily stool diary during the course of 
therapy with follow-up visits at day 34, week 9, week 13, week 17, and week 29. 
 
 


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8.0 
STUDY DESIGN 
 
 
General Design  
This phase II multi-site randomized, double-blind, doubly placebo-controlled trial will compare the 
safety and efficacy of fecal microbiota transplantation (FMT) versus oral vancomycin for prevention 
of CDI recurrence in solid organ transplant (SOT) recipients.   
 
The study population will consist of 158 adult SOT recipients with at least a first recurrence of CDI. 
Recurrence of CDI is defined as diarrhea (3 or more loose stools) in a 24-hour period for 2 
consecutive days with a positive stool test for C. difficile toxin within a 180-day period following 
completion of treatment. 
 
Subjects will be enrolled while receiving C. difficile treatment as standard of care, they will be 
monitored and those that achieve symptomatic response between Day 4 and Day 10 of C. difficile 
treatment will be randomized to one of two treatment arms as follows: 
 
 
Arm 1: Single dose of MTP-101-C and vancomycin matching placebo taper.  
 
Arm 2: Single dose of MTP-101-C matching placebo and vancomycin taper. 
 
MTP-101-C/Matching Placebo: Subjects will take a single dose at Visit 2. Visit 2 must occur ≤14 
days of starting standard of care C.difficile treatment. A single dose consists of 5 capsules, each 
swallowed individually with water.  
 
Vancomycin/Matching Placebo: Subjects will take one capsule by mouth every 6 hours for a total of 
14 days (14 days is inclusive of 4-14 days days of SOC C. difficile treatment taken prior to Visit 2), 
after which they will undergo a taper as described in section 10.7.2. 
 
Subject accrual will occur over four years at 5 U.S. sites.  Subjects will complete 7 study visits over 
the course of approximately 30 weeks.  Each subject will provide six stool samples and two to four 
blood specimens.   
 
 
Rationale for Intervention 
8.2.1 
Rationale for Frozen, Freeze-dried Stool 
Recent studies have shown that frozen stool FMT works as well as fresh stool41, 42 and 
may be stored for up to 12 months.  
8.2.2 
Rationale for Universal Donors 
The choices for a donor for FMT include a household or non-household member or 
other individual known to and selected by the recipient versus a universal anonymous or 
non-anonymous donor. There are pros and cons to each of these options but the main 
limitation of the approach where the donor selected by the recipient is logistical. Many of 
our patients that have undergone FMT have not been able to identify a donor. Even for 
those that have selected a donor, it has taken several weeks to get the donor tested and 
the procedure scheduled due to issues of transportation, challenges in taking time off 
from work, etc. Compare this to the universal donor, where testing is performed 
frequently and stool is collected and frozen until such time as it may be used. Recent 
studies have shown that frozen stool is perfectly adequate for FMT compared with fresh 
stool. This study will utilize universal donors that are screened and tested. More than 
one donor may be used for this trial. 
8.2.3 
Rationale for Encapsulated Fecal Microbiota versus Other FMT Delivery Modes 
FMT may be delivered by enema, colonoscopy, nasogastric (NG) tube, and oral 
encapsulation of stool. Encapsulated fecal microbiota was selected for this RCT 
because ingestion of a single dose of encapsulated fecal microbiota (~ 5 x 1011 bacteria) 
is ~ 80% successful in terminating the cycle of recurrent Clostridioides difficile infection 


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(rCDI) in patients who have failed multiple attempts to achieve cure with antibiotics 
alone.29, 30 In addition, encapsulated FMT may be more appealing to potential study 
participants and less invasive than enema FMT, thereby eliminating possible recruitment 
challenges that might be encountered in using enema FMT. Administering oral capsules 
also requires less in-patient care and demand on hospital resources. The encapsulated 
fecal microbiota in this RCT, MTP-101-C, is an investigational drug that has been used 
since 2015 for treatment of rCDI under the 2013 FDA enforcement discretion policy, 
which allows FMT for treatment of rCDI that failed standard therapies. 
 
 
 
Study Risk/Benefit Assessment 
8.3.1 
Known Potential Risks & Risk Minimization 
 
Vancomycin:  Oral vancomycin is the standard of care treatment for recurrent CDI.  
When administered orally, vancomycin is poorly absorbed, and ingestion does not 
result in significant levels of drug in the body.  The most common side effects 
associated with oral vancomycin are nausea, stomach pain, and low potassium 
levels in the blood.  Less common side effects include peripheral edema, tiredness, 
fever, headache, diarrhea, gas, vomiting, urinary tract infection, and back pain.  
Rare but serious side effects include kidney failure, decrease in platelets, hearing 
problems, and vasculitis.  Additionally, there is risk of developing antibiotic 
resistance including vancomycin resistant enterococcus (VRE). Risk minimization 
will include surveillance for VRE colonization at study visits and communication 
between subjects and study staff; and specimen collection and analysis.  
 
 
Vancomycin Matching Placebo:  The vancomycin matching placebo capsules 
used in this study will be composed of Microcrystalline Cellulose (MCC), NF. MCC is 
a purified, partially depolymerized cellulose, obtained as a pulp from fibrous plant 
material. It is widely used in vitamin supplements and tablets, and the likelihood for 
adverse reaction is virtually none. There are no obvious foreseeable risks 
associated with the ingestion of the placebo capsules. 
 
 
Fecal Microbiota Transplantation (FMT):  The most common risk associated with 
FMT’s is abdominal discomfort (e.g., nausea, bloating, cramping, diarrhea).  There is 
also a risk of inadvertent transmission of infectious organisms (bacteria, viruses, fungi, 
parasites) or MDRO contained in the stool as well as allergic reactions to constituents 
(antigens) contained in the donor stool. There is also a risk of transmission of non-
infectious disease, e.g., immune dysregulation, energy metabolism dysregulation, 
malignancy, neurologic disease, and psychiatric disorder. It is unknown if FMT will 
impact the risk of rejection, organ function, malignancy, hospitalizations, and 
emergency department visits.  The potential long-term effects of alterations in gut 
microbiome are unclear.  
 
Subjects suspected of developing acute organ rejection while on study will receive a 
clinical hand-off to the clinical transplant team and will continue to be monitored for 
the duration of the study. 
 
 
MTP-101-C: While there have been no adverse events linked to MTP-101-C, a 
number of risks exist. These include: 
o Risk of infectious disease transmission: FMT has been associated with 
pathogen transmission, including Shiga-toxin producing Escherichia coli 
(STEC), Enteropathogenic E. coli (EPEC), norovirus. Although the donor 
material is tested for these pathogens, tests may be false negative. In addition, 
the current testing may not capture all important pathogens that could be 


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transmitted. Similarly, although the donor screening and testing protocol is 
designed to mitigate risk of SARS-CoV-2 transmission, this risk cannot be 
eliminated with 100% certainty given the possibility of false negative tests. 
o Risk of transmitting multi-drug resistant organisms: FMT has been associated 
with 
transferring 
Extended 
Spectrum 
Beta-Lactamase 
(ESBL) 
Enterobacteraceae.8 This risk is mitigated by excluding health care workers 
who have contact with patients as donors and donor material that tests 
posititive for ESBL, carbopenem-resistant Enterobacteraceae, vancomycin-
resistant Enterococcus, methicillin-resistant Staphylococcus aureus. 
o Risk of transferring risk of non-infectious diseases: Intestinal microbiota is 
integral to human physiology and its composition can affect the functions of 
the immune system, energy metabolism, and nervous system. Therefore, 
there is a theoretical risk that the new intestinal microbiota formed in part with 
the donor microbes can increase risks for autoimmunity, allergies, obesity, 
cancer, neurologic and psychiatric disorders. This risk is mitigated by 
excluding donors with these conditions. There is also a screening and testing 
protocol for SARS-CoV-2 in donors.  
o •It is possible that healthy, asymptomatic stool donors may potentially shed 
two specific viruses called BK virus and CMV in the stool.  There is an 
increased risk of CMV infection in SOT recipients who have a positive blood 
test for CMV infection and who receive FMT from stool donors who may have 
an active CMV infection. To prevent transmission of CMV, we use only donors 
who have tested negative for CMV as a way to reduce the risk of CMV 
transmission. For BK, we test the donor urine to evaluate for BK virus shedding 
in the urine and if that test was positive, we would not use that donor specimen 
for FMT. It is important to recognize that tests for CMV and BK have limitations 
and no test can guarantee 100% accuracy. However, the actions described 
above can reduce the risk to very low. 
 
 
MTP-101-C Matching Placebo: The MTP-101-C matching placebo is prepared 
using identical capsules and contain the equivalent amount of trehalose 
lyoprotectant. The rest of the content is made up with carboxymethylcellulose. There 
are no known risks for the placebo capsules.  
 
 
Blood Draw:  The risks of drawing blood from a vein include discomfort at the site of 
puncture; possible bruising and swelling around the puncture site; rarely an 
infection; and, uncommonly, faintness from the procedure. 
 
 
Completing Study Visits at Home (at sites where applicable): When study visits 
are completed at home, it is possible that any of the risks described above will be 
treated differently. This is most relevant for the risks associated with study 
procedures such as completing a blood draw in a non-hospital setting and 
administration of the FMT capsule. Participants will be asked to consider this when 
scheduling visits away from a healthcare setting with lesser access to immediate 
care.  
 
 
8.3.2 
Potential Benefits to the Subjects 
The potential benefits to research subjects associated with this study include the 
possible treatment of recurrent CDI.  
 


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If this study is able to show a therapeutic benefit of FMT in SOT patients, the community 
at large would benefit by the availability of a non-antibiotic based management option 
for CDI. 
 
 
End of Study Definition 
A subject is considered to have completed the study if he or she has completed all phases of the 
study including the last visit (Visit 7) as outlined in Section 11.13, Study Calendar. 
 
 


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9.0 
SUBJECT SELECTION 
 
 
Inclusion/Exclusion Criteria 
Eligibility will be determined by inclusion and exclusion criteria below and confirmed by medical 
record review as necessary. 
 
Inclusion Criteria  
1. Willing to provide written informed consent. 
2. Willing to comply with all study procedures and be available for the duration of the study. 
3. Ability to take oral medication. 
4. Male or female, at least 18 years of age. 
5. Solid organ transplant recipient. 
6. Has recurrent C. difficile infection.  A C. difficile recurrence is defined as: 
 
Positive C. difficile testing in stool (confirmed via medial record review) AND 
 
Diarrhea (≥ 3 loose stools over 24 hours) during the 180-day period following completion of 
treatment for prior CDI episode. 
7. History of positive IgG testing to cytomegalovirus (CMV) and Epstein Barr Virus (EBV) for  subject 
or donor.  
8. Clinical response to 4-14 days of C. difficile treatment for the current CDI episode. Clinical 
response is defined as ≥25% reduction of diarrhea. 
9. Females of childbearing potential must have a negative urine or serum pregnancy test at 
baseline and prior to randomization. A female of child-bearing potential is any woman 
(regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by 
choice) who meets the following criteria: 
 
Has not undergone a hysterectomy or bilateral oophorectomy; or 
 
Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had 
menses at any time in the preceding 12 consecutive months). 
10. Women of childbearing potential in sexual relationships with men must use an acceptable 
method of contraception§ from 30 days prior to enrollment until 4 weeks after completing study 
treatment.  Males must agree to avoid impregnation of women during and for four weeks after 
completing study treatment through use of an acceptable method of contraception. 
§Note: Acceptable method of contraception is defined as those, alone or in combination, that 
result in a low failure rate [i.e. less than 1% per year] or in conjunction with their sexual 
partner(s), use 2 forms of medically acceptable contraceptive methods that have a reported 
failure rate of >1% per year. Includes, but is not limited to, barrier with additional spermicidal 
foam or jelly, intrauterine device, hormonal contraception (started at least 30 days prior to study 
enrollment), intercourse with men who underwent vasectomy. 
 
Exclusion Criteria 
1. Major bowel resection surgery within 90 days of randomization.  
2. Active chronic intestinal disease (e.g. Crohn's disease, ulcerative colitis). 
3. History of total colectomy or bariatric surgery. 
4. Known or suspected toxic megacolon and/or known small bowel ileus. 
5. Presence of colostomy or ileostomy. 
6. Concomitant antibiotic use within 48 hours of Visit 2.  Topical antibiotics and SOT 
prophylaxis (e.g., trimethoprim-sulfamethoxazole) are permitted. 
7. Dysphagia: oropharyngeal, esophageal, functional, neuromuscular (e.g. stroke, multiple 
sclerosis, ALS), or patient shows evidence of dysphagia when the ‘safety test’ capsule is 
administered. 
8. Currently receiving medication for treatment of acute rejection and/or develop acute 
rejection prior to administration of FMT 
9. Active, severe gastroparesis 


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10. Unwilling to withhold probiotics for duration of study. Probiotics include supplements, 
prescriptions, and non-prescriptions. Foods (like yogurt) are permitted. 
11. Neutropenia, ≤500 neutrophils/mL [abstracted from the medical record and resulted within 
7 days of Visit 2]. 
12. Symptomatic co-infection with another intestinal pathogen as determined by chart review. 
13. Concurrent intensive induction chemotherapy, radiation therapy or biological treatment for 
active malignancy. Patients on maintenance chemotherapy may be enrolled only after 
consultation with medical monitor. 
14. Any severe food allergy, defined as a history of anaphylaxis, systemic urticarial or 
angioedema attributed to a food and requiring current avoidance precautions. 
15. Expected life expectancy <6 months. 
16. Use of investigational drugs, biologics, or devices within 30 days prior to randomization. 
17. Women who are pregnant, lactating or planning on becoming pregnant during the study.   
18. Not suitable for study participation due to other reasons at the discretion of the 
investigators. 
 
 
 
Recruitment  
Prospective subjects will be identified through routine surveillance of electronic medical records 
using patient census and infection control lists.  Providers will also be asked to refer patients from 
outpatient clinics (e.g., transplant clinic).  Inpatient subjects will first be approached in person by 
someone involved in their clinical care. This is also true for those patients approached in a clinic 
setting. 
 
Upon approaching potentially eligible participants, study team may present study advertisements, 
FMT explanation documents, comics, and information sheet as part of initial discussion.  
 
Advertisements will be posted in public locations and on the internet. Letters will be sent to 
potentially eligible subjects identified through electronic medical records. 
 
Study teams will follow institutional guidelines that allow for study team to communicate with 
potential participants via Electronic Medical Record (eg Patient Portal, Mychart, etc), and will utilize 
approved language/letters. 
 
 
Retention Strategies 
Strategies for retention include:  
 
Frequent phone contact throughout the 6 month follow-up study period.  Subjects will 
receive a call 1-3 days after randomization (Visit 2) to assess for AEs, review concomitant 
mediations and remind them to complete daily stool diaries.  Between Visit 3 and Visit 7, 
study staff will attempt weekly phone contacts for the aforementioned purposes as well as 
to assist with subject retention (e.g., study visit and stool collection reminders). 
 
Flexible study visit windows (i.e. +/- 7 days) to accommodate subject schedules.   
 
Offering subjects the option to complete Visits 4, 5, 6, and 7 over the phone or in person. 
 
Subjects will receive reimbursement for each completed study visit, a maximum total of 
$590. 
 
Sites will offer travel reimbursement/parking reimbursement per site guidelines 
 
Sites may offer in person visits in clinic or in home, where locally approved. Home visits will 
be completed by qualified study team members who have documented training in 
completing all study procedures 
 
 
 
Early Termination and Withdrawal 
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with a CDI recurrence after randomization will be terminated early. 
 
The Principal Investigator (PI) may discontinue or withdraw a subject from the study for the 
following reasons: 
● Pregnancy 
● 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 subject 
● Disease progression which requires discontinuation of the study intervention 
● If the subject is no longer an appropriate candidate for participation 
● Any Grade 3 AE or SAE that is assessed as possibly, probably or definitely related to study 
product. 
 
Subjects who sign the informed consent form and are randomized but do not receive the study 
intervention may be replaced by randomizing a new subject to meet the accrual goal. Replacement 
participants will be assigned a new study ID. Subjects who sign the informed consent form, are 
randomized and receive the study intervention, then subsequently withdraw, or are withdrawn or 
discontinued from the study, will not be replaced. 
 


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10.0 STUDY INTERVENTION 
 
 
Study Intervention Description 
10.1.1 
MTP-101-C 
The U.S. Food & Drug Administration (FDA) requires an investigational new drug (IND) 
for the use ofMTP-101-C ) to treat C. difficile infection not responding to standard 
therapies.   
 
MTP-101-C is prepared from stool of healthy human donors, who are screened and tested 
for infectious and non-infectious diseases. Raw stool is homogenized and filtered to 
separate the microbiota, which is then frozen in the presence of a lyoprotectant 
(trehalose), freeze-dried and encapsulated in hypromellose capsules. Each capsule 
contains ~ 1 x 1011 bacteria. The capsules are acid-resistant and likely dissolve > 2 hours 
following ingestion in the small bowel or proximal colon.  
 
MTP-101-C will be provided by the University of Minnesota Microbiota Therapeutics 
Program, and will be shipped on dry ice directly to study sites. MTP-101-C capsules 
should be stored frozen at -80°C. 
10.1.2 
MTP-101-C Matching Placebo  
The MTP-101-C matching placebo is prepared using identical capsules and contain the 
equivalent amount of trehalose lyoprotectant. The rest of the content is made up of 
carboxymethylcellulose. Placebo capsules will be provided by University of Minnesota 
Microbiota Therapeutics Program and shipped on dry ice directly to study sites.  
10.1.3 
Vancomycin 
Vancomycin is a tricyclic glycopeptide antibiotic that inhibits bacterial cell wall formation.  
Oral vancomycin is FDA-approved as first line treatment for CDI and is recommended 
for severe and recurrent CDI.  Commercially available vancomycin capsules will be 
procured and over-encapsulated to look similar to placebo by an FDA-registered 
pharmaceutical manufacturing facility.   
10.1.4 
Vancomycin Matching Placebo 
The vancomycin matching placebo will be composed of Microcrystalline Cellulose 
(MCC), NF. Placebo capsules will be procured and/or prepared by an FDA-registered 
pharmaceutical manufacturing facility. 
 
 
Source 
10.2.1 
MTP-101-C/Matching Placebo Capsules 
The University of Minnesota Microbiota Therapeutics Program will distribute MTP-101-C 
and matching placebo capsules to the study sites directly. Each shipment will include a 
temperature-monitoring device to verify maintenance of the cold chain during transit, as 
well as a packing slip. On delivery of the investigational product to the site, the person in 
charge of investigational product receipt will follow the instructions given in the Manual 
of Procedures, including checking that the cold chain was maintained during shipment 
(i.e., verification of the temperature indicator). The contents of the shipment will then be 
reviewed and verified against the packing slip, and will be documented as instructed by 
the Clinical Coordinating Center (CCC).  
 
If the temperature-monitoring indicator reflects that the cold chain has been broken, the 
entire shipment must be immediately quarantined, the investigational product must not 
be administered, and the site investigator or responsible person should contact the CCC 
for instructions on how to properly discard the product. See the Manual of Procedures 
for further information on processing temperature deviations during shipment.  
 


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Sites will be responsible for ensuring appropriate receipt, use, disposition and 
reconciliation of the investigational product as outlined in the Manual of Procedures. 
10.2.2 
Vancomycin/Matching Placebo 
As noted in sections 10.1.3 and 10.1.4, an FDA-registered pharmaceutical 
manufacturing facility will be responsible for procuring and over-encapsulating oral 
vancomycin and matching placebo, and subsequently shipping drug to each clinical site 
 
 
Packaging and Labeling 
10.3.1 
Labeling of MTP-101-C and Matching Placebo Capsules 
Each dose of MTP-101-C and matching placebo is packaged in an individual 
sealed container. The label lists the following information: 
 Microbiota Transplant or Matching Placebo 
 # capsules 
 Bottle # xxxx  
 Store refrigerated 
 
Caution: New Drug-Limited by Federal Law to Investigational Use 
10.3.2 
Vancomycin/Matching Placebo 
Vancomycin and matching placebo capsules will be shipped to sites from an FDA-
registered pharmaceutical manufacturing facility, and subsequently packaged by each 
site’s investigational drug pharmacy into prescription bottles, containing the appropriate 
number of capsules indicated for the subject.  Bottles will be labeled with subject name, 
study ID, date dispensed, and dosage instructions (Figure 4).  Labels will reflect each 
site’s local context information (e.g., site PI, phone number).     
 
Figure 4:  Vancomycin/Matching Placebo Capsules Label Example 
 
Name __________________________ Date _________ 
Subject ID# _______________             RPh: ______________ 
Vancomycin/Matching Placebo 125 mg Capsules     #50 Capsules 
Directions:  
Take one capsule by mouth as instructed on the Medication Diary. Swallow capsules whole.  
FOR INVESTIGATIONAL USE ONLY     IND# 27262 
Fecal  Microbiota  transplantation  for  C.  difficile  Infection  (CDI_  in  Solid  Organ  Transplant 
Recipients. 
Nasia Safdar, MD PhD 
*** 
Site # __________________ 
Site PI and  Location:  
______________________________________ 
______________________________________ 
______________________________________ 
Site Contact Phone# _________________ 
 
 
 
Preparation 
10.4.1 
MTP-101-C/Matching Placebo Capsules 
The investigational drug pharmacy or designees at each site will prepare MTP-
101-C and matching placebo as follows: 
 
Check product for tampering and/or exposure to high temperatures 
 
Thaw prior to administration, taking care to avoid freeze-thaw cycles and 
excessive humidity, using one of the following methods: A) Transfer to 4°C 
refrigerator until thawed, and store up to 30 days; B) Place at room temperature 
until thawed, and store up to 4 days. 


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Warning: Capsules should never be refrozen, or exposed to excessive humidity. If 
thawed, and not used within the prescribed amount of time based on storage 
temperature, the material should be disposed of. Freeze-thaw cycles may 
compromise stability or viability of the product. 
 
10.4.2 
Vancomycin/Matching Placebo 
After receiving oral vancomycin and matching placebo from an FDA-registered 
pharmaceutical manufacturing facility, drug will be further prepared by each site’s 
investigational drug pharmacy as detailed in section 10.3.2. 
 
 
Storage and Stability 
Investigational product must be stored separately from normal hospital stocks and must be stored 
in a securely locked area accessible only to authorized trial personnel until dispensed. The 
temperature must be monitored and documented on the appropriate form for the entire time that 
the investigational product is at the trial site. If the storage temperature deviates from the permitted 
range, the investigational product must not be administered, and the site investigator or responsible 
person should contact the CCC for further instructions.  
10.5.1 
MTP-101-C/Matching Placebo Capsules 
Thus far, stable integrity of bacteria in MTP-101-C has been demonstrated following:  
 
 
20 months of storage at -80oC 
 
12 months of storage at -20oC (laboratory freezer, no auto-defrost feature)  
 
One month at 4oC 
 
Four days at 25oC (room temperature) 
 
Importantly, the microbiota experienced no interim freeze-thaw cycles in the stability 
experiments and remains at the steady indicated temperature for the stated period of time. 
Theoretically, humidity represents the greatest threat to the integrity of the product. MTP-
101-C and matching placebo capsules should be stored at -80°C for up to 20 months 
whenever possible, but may also be stored for 12 months at -20°C in a laboratory freezer 
without an auto-defrost feature. 
10.5.2 
Vancomycin/Matching Placebo 
Store at controlled room temperature, 59° to 86°F (15° to 30°C). 
 
 
Accountability 
The person in charge of product management at the site will maintain records of product delivery, 
site inventory, and product disposal or return.  The DMC/study monitors will verify each site’s 
product accountability records against the record of administered doses in the eCRFs, the source 
documents, and the communication from the online randomization program. 
 
In case of any expected or potential shortage of product during the trial, the investigator or an 
authorized designee should alert the CCC as soon as possible, so that a shipment can be 
arranged. In the event of a quality issue, the site should quarantine the investigational product and 
contact CCC for further instructions. 
 
 
Dosing and Administration 
10.7.1 
MTP-101-C/Matching Placebo Capsules 
 
C. difficile treatment will be stopped at least 48 hours prior to randomization.  
 
 
Blinded nurse will administer MTP-101-C and matching placebo. 
 
Administration of MTP-101-C should not coincide with concurrent treatment with 
antibiotics. 


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 
If possible, do not take proton pump inhibitors or H2 blocker medications that 
block or diminish stomach acid production for 12 hours prior to MTP-101-C.  
 
No solid food should be present in the stomach at the time of treatment. Solid 
food should be avoided for at least 4 hours prior to ingestion of capsules and can 
be resumed 2 hours after ingestion of capsules. Clear liquids are allowed at all 
times. 
 
Drink at least one glass of water or another clear liquid after taking the capsules. 
 
Remain upright for at least 2 hours after taking the capsules. 
10.7.2 
Vancomycin/Matching Placebo 
Subjects will receive one 125 mg vancomycin capsule or one matching placebo every 6 
hours for a total of 14 days (inclusive of the 4-14 days of C. difficile treatment taken prior 
to visit 2), followed by 125 mg oral vancomycin or placebo every 12 hours for 7 days, 
followed by 125 mg oral vancomycin or placebo once daily for 7 days, followed by 125 
mg oral vancomycin or placebo every 3 days for 14 days.   
 
 
Randomization and Blinding 
This will be a randomized, double-blind, doubly placebo-controlled trial. Eligible subjects will be 
randomized in a 1:1 ratio stratified by site. Study staff will randomize subjects through a web-based 
program that assigns the subject an identification number and treatment arm. 
 
To maintain the blind, the MTP-101-C matching placebo capsules will mimic the MTP-101-C 
capsules in appearance, and the vancomycin matching placebo capsules will mimic the 
vancomycin capsules in appearance.  
 
 
Unblinding Procedures 
Unblinding will be done in emergent circumstances where the identity of the study medication 
needs to be known. All efforts will be made to maintain blinding except in the case of urgent 
medical necessity. If a subject needs to be unblinded, the study staff should contact the medical 
monitor prior to any unblinding procedures and refer to the Manual of Procedures for further 
instruction.  
 
 Study Intervention Compliance 
The MTP-101-C/matching placebo capsules will be taken under direct supervision by research 
staff; thus adherence is not a concern.  
 
Several measures will be used to assess oral vancomycin adherence, including: 
 
Drug accountability by study staff at Visit 3. 
 
Subjects will be provided a dose diary to record administration of vancomycin/matching 
placebo capsules according to prescribed schedule. 
 
For reporting non-compliance, refer to section 14.4 (Protocol Deviations). 
 
 Concomitant Therapy 
No other drugs potentially useful in the treatment of CDI should be given during the study unless 
they are specifically given because of a primary treatment failure or recurrence.  Drugs to control 
diarrhea (e.g., loperamide) must also be withheld.  Subjects may continue to take transplant-related 
medications, provided they are not for acute rejection.   
 


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11.0 STUDY VISITS AND PROCEDURES 
 
 
Screening and Enrollment 
The Screening and Enrollment visits and procedures are described in detail below. 
11.1.1 
Prescreening 
Prescreening activities may include medical record review to verify limited inclusion 
criteria (e.g., adult SOT recipient prescribed C. difficile treatment for a CDI recurrence).  
Potentially eligible outpatients will be contacted by letter or phone to inform them of the 
study.  Potentially eligible inpatients will be asked by member of their clinical care team 
if they would be interested in learning about a research study. Outpatient telephone 
recruitment will be preceded by a recruitment letter, unless a patient is fully eligible to 
enroll in the study. If a patient is fully eligible, they may be contacted without first 
sending a recruitment letter in order to enroll a patient within the required timeframe. 
Upon approaching potentially eligible participants, study team may present study 
advertisements, FMT explanation documents, comics, and information sheet as part of 
initial discussion. 
 
11.1.2 
Informed Consent 
The informed consent process will be conducted following all federal and institutional 
regulations relating to informed consent. Participants may also be provided with an 
information sheet prior to completing the entire informed consent, as part of the study 
discussion and to provide them with a succinct description of study activities. Informed 
consent will be obtained prior to conducting any study related activities. The consent 
process will occur in-person or via telephone.  
 
The informed consent process will be performed as follows: 
1. The investigator or designee will review the consent form and discuss the study 
in detail with the potential research subject. 
2. The study team member will explain the study, its risks and benefits, and what 
would be required of the research subject 
3. The research subject will be given the opportunity to take the consent form home 
so that he or she may discuss it with family members, friends, clergy, or others 
when possible.   
4. The subject will have the opportunity to ask questions and have all questions 
answered by the study coordinator and/or PI. 
5. The informed consent document must be signed and dated by the research 
subject. 
6. The study team member will review the informed consent document to ensure 
that all fields that require a response are complete (i.e. checkbox marked yes or 
no, etc.) as applicable. 
7. The person obtaining consent (POC) must sign and date the informed consent 
document. 
8. The research subject will be given a copy of the signed and dated informed 
consent. The original signed informed consent is kept in the subject’s research 
Table 1: Concomitant Medications Not Permitted During the Study 
Antibiotics/Antivirals# Anti-Diarrheals  
Other 
 
 Nitazoxanide 
 
Atropine/diphenoxylate  
Probiotics 
 
≥80 mg of prednisone or 
other treatment for acute 
transplant rejection 
 
 Rifampin 
 
Bismuth subsalicylate 
 
 
Loperamide 
 
 
 
 
 
#Topical antibiotics/antivirals are allowed. 
   


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chart or medical record in accordance with each site’s institutional 
policy/practice.  
 
Additionally, an alternative method obtaining consent remotely will be through the 
use of mail or email correspondence. When approaching patients, either in person 
or via telephone, study staff will ask patients if it is acceptable to email 
correspondence with patients. This correspondence and subject approval will be 
documented in study Redcap database. If subjects are unable to return to clinic in a 
timely manner to meet to sign study consent, study team will mail or email the 
consent to the patient to assist in coordinating within study timeframes. Study team 
may complete the full consent process over the telephone and participants will 
provide a signature via a Part 11 compliant e-signature manner (e.g. DocuSign) and 
confirm participant’s identity through an attached picture or copy of a photo ID. 
11.1.3 
Screen Failure and Re-enrollment 
Not applicable.  
 
 
Visit 1 (Baseline) – May be completed in person (in clinic or at home where approved) or via 
phone 
 
Obtain written informed consent  
 
Obtain demographics and contact information 
 
Review concomitant medications  
 
Review medical history 
 
Social history: smoking status 
 
Perform chart abstraction 
 
Perform targeted physical examination 
 
Measure height, weight and vital signs (temperature, respiratory rate, heart rate, and blood 
pressure) 
 
Blood draw (if necessary) 
 
Urine or serum pregnancy testing in women of childbearing potential 
 
Assess inclusion/exclusion criteria  
 
Administer Quality of Life Questionnaire (Cdiff32) 
 
Dietary history (may be collected at Visit 2) 
 
Dispense stool collection kit and instructions 
 
Schedule visit 2.  
 
Instruct subject to hold C. difficile treatment for at least 48 hours prior to the scheduled 
randomization appointment. 
 
Instruct subject to avoid eating solid food for at least 4 hours prior to visit 2. 
 
 
Visit 2 (Randomization/Subject Enrollment) In person (in clinic or at home where approved) 
 
Confirm subject withheld SOC C. difficile treatment for at least 48 hours 
 
Confirm subject has been taking SOC C. difficile for ≤14 days 
 
Confirm subject has not eaten solid food for at least 4 hours 
 
Review concomitant medications, changes in medical history, assess AEs 
 
Perform chart abstraction 
 
Urine or serum pregnancy testing in women of childbearing potential 
 
Blood draw (if necessary) 
 
Retrieve subject-collected stool specimen (if necessary) 
 
Administer safety capsule 
 
Confirm eligibility   
 
Randomize subject via the internet using Stars (Statistical Registration & Randomization 
System)  


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 
Blinded nurse administers MTP-101-C/matching placebo capsules and monitors subject for 
30 minutes following administration 
 
Dispense oral vancomycin/matching placebo and instruct subject on use 
 
Dispense stool collection kit and instructions 
 
Dispense stool diary  
 
Schedule follow-up phone call and visit 3 
 
Subjects will be asked to complete a specific stool diary, for 7 days post-FMT, that in 
addition to recording every bowel movement, they will also be asked to record if they 
experience any of the following adverse events: fever, vomiting, abdominal pain, bloating, 
flatulence, diarrhea, constipation, and (for 7 days post-FMT). Subjects will be asked to 
return this completed diary at Visit 3.  
 
 
Study Drug Administration Follow-up Call 
 
Subjects will be contacted by phone 1-3 days after randomization (Visit 2) to assess for AEs, 
review concomitant medications, and remind subjects to complete daily stool diaries.  
 
 
Visit 3 In person (in clinic or at home where approved) 
 
 
Review concomitant medications, changes in medical history, assess AEs  
 
Perform chart abstraction 
 
Perform targeted physical examination 
 
Measure weight and vital signs (temperature, respiratory rate, heart rate, and blood 
pressure) 
 
Blood draw 
 
Renal function tests, (if abnormal, check vancomycin levels for patients dependent on 
hemodialysis or per investigator’s discretion) 
 
Retrieve subject-collected stool specimen (if necessary) 
 
Collect and review daily stool dairies 
 
Collect unused study medication and perform accountability  
 
Administer Quality of Life Questionnaire (Cdiff32) 
 
Dispense stool collection kit and instructions 
 
Dispense additional stool diaries  
 
Schedule visit 4 
 
 
Visit 4 (in-person or phone call) 
 
Review concomitant medications, changes in medical history, assess AEs  
 
Perform chart abstraction  
 
Retrieve subject-collected stool specimen (if necessary) 
 
Collect and review daily stool dairies (if phone call, participants may provide at next visit or 
mail to study coordinators) 
 
Collect unused study medication and perform accountability if not collected at Visit 3 
 
Dispense stool collection kit and instructions 
 
Dispense additional stool diaries as necessary  
 
Schedule visit 5 
 
 
Visit 5 (in-person or phone call) 
 
Review concomitant medications, changes in medical history, assess AEs  
 
Perform chart abstraction 
 
Retrieve subject-collected stool specimen (if necessary) 
 
Collect and review daily stool dairies (if phone call, participants may provide at next visit or 
mail to study coordinators) 
 
Dispense stool collection kit and instructions 


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 
Dispense additional stool diaries as necessary  
 
Schedule visit 6 
 
 
Visit 6 (in-person or phone call) 
 
Review concomitant medications, changes in medical history, assess AEs  
 
Perform chart abstraction 
 
Retrieve subject-collected stool specimen (if necessary) 
 
Collect and review daily stool dairies (if phone call, participants may provide at next visit or 
mail to study coordinators) 
 
Dispense stool collection kit and instructions 
 
Dispense additional stool diaries as necessary  
 
Schedule visit 7 
 
 
Visit 7 (in-person or phone call) 
 
Review concomitant medications, changes in medical history, assess AEs  
 
Perform chart abstraction 
 
Retrieve subject-collected stool specimen (if necessary) 
 
Collect and review daily stool dairies 
 
Administer Quality of Life Questionnaire (Cdiff32) 
 
 Telephone Contact 
Between Visit 3 and Visit 7, study staff will attempt weekly phone contacts to assess for AEs, review 
concomitant medications, and remind subjects to complete daily stool diaries. If contact with the 
patient is unsuccessful, study staff must document their attempt(s) to contact the participant. 
  
 Unscheduled Visit 
Unscheduled Visits occur at the time of diarrhea or suspected CDI recurrence (≥3 loose stools that 
take the shape of the container in a 24-hour period). Data collection for unscheduled visits will be 
collected in addition to early termination visit if recurrence is confirmed. Study staff will complete a 
recurrence CRF for each episode of CDI. This CRF will be used to track duration of the episode, 
type, dosage, and duration of antibiotics. Data points for infectious episode: 
 
Date 
 
Preliminary diagnosis 
 
Antibiotic/s 
o Name 
o Formulation (IV, suspension, capsules) 
o Dosage 
o Prescribed duration 
o Final (actual) duration of antibiotics 
o Change in antibiotics regimen 
 
Concomitant medication (name, dose, route of administration, duration) 
 
Hospital admission (yes/no) 
o Name of facility 
o Department where participant was admitted (ward / step down/ ICU) 
o Relevant Medical Procedures 
 
Colonoscopy (including preparation) 
 
Intestinal surgery 
 
Dialysis 
 
Other 
 
Final diagnosis 
 
 Early Termination and Withdrawal 
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subject decides to end his or her participation, the PI and study staff will invite the subject to 
complete the Early Termination Visit. Participants who meet the primary endpoint of recurrence will 
complete the early termination visit.   
 
At this visit, the following procedures will occur: 
 
Review concomitant medications, changes in medical history, assess AEs  
 
Perform chart abstraction 
 
Retrieve subject-collected stool specimen (if necessary) 
 
Collect and review daily stool dairies 
 
Administer Quality of Life Questionnaire (Cdiff32) 
 
Collect unused study medication and perform accountability if not collected previously 
 
The following actions must be taken if a subject fails to return to the clinic for a required study visit: 
 
Before a subject is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the subject where possible, 3 telephone calls and, if necessary, 
a certified letter to the subject’s last known mailing address or local equivalent methods. 
These contact attempts should be documented in the subject’s study file.  
 
If the subject continues to be unreachable, he or she will be considered to have withdrawn 
from the study with a primary reason of lost to follow-up. The withdrawn date is the last day 
of attempted contact.  
 
 
 


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 Study Calendar 
 
 
Baseline 
Study Treatment 
Follow-up 
Procedure 
(Visit Window) 
Visit 113 
(Day -7 to  
Day -1) 
Visit 213 
(Day 0) 
Study 
Drug 
Admin. 
Follow-up 
Call  
(Day 1 to 
Day 3) 
Visit 3 
(Day 31 to  
Day 38) 
Visit 411 
(Week 9  
 7 days) 
Visit 511 
(Week 13  
 7 days) 
Visit 611 
(Week 17  
 7 days) 
Visit 711 
(Week 29  
 7 days) 
Unsched. 
Early 
Term. 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medical History1 
X 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
Physical Examination, Height, 
Weight & Vital Signs2 
X 
 
 
X 
 
 
 
 
 
 
Urine or Serum Pregnancy 
Test (if applicable) 
X 
X 
 
 
 
 
 
 
 
 
Stool Collection3 
- - - - - - - - X - - - - - - - 
 
X 
X 
X 
X 
X 
X 
X 
Stool Assessments4 
- - - - - - - - X - - - - - - - 
 
X 
X 
X 
X 
X 
X 
X 
CBC w/ diff Blood Draw5 
X5 
X5 
 
X5 
 
 
 
 
 
 
CMP6 
X6 
 
 
x6 
 
 
 
 
 
 
CMV/EBV Antibodies Blood 
Draw 
X7 
 
 
 
 
 
 
 
 
 
Safety Vancomycin Serum 
Level8 
 
 
 
X13 
 
 
 
 
 
 
Quality of Life Questionnaire 
(Cdiff32) 
X 
 
 
X 
 
 
 
X 
 
X 
Safety Capsule 
 
X 
 
 
 
 
 
 
 
 
Adverse Event Monitoring 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Daily Stool Diary12 
 
 
- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - X - - - - - - - - - - - - - - -- - - - - - - - - - - - - - - - - - - - - - - - - -  
Discontinue Standard of Care 
C. difficile treatment  
 
X 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
Oral Vancomycin/ Matching 
Placebo 
 
 
- - - - - - - - - - - - - - - X - - - - - - - - - - - - - - - 
 
 
 
 
 
MTP-101-C/Matching Placebo  
 
X 
 
 
 
 
 
 
 
 
Telephone Contact9 
 
 
X 
- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - X- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -  
Drug Collection & 
Accountability 
 
 
 
- - - - - - - - - - X - - - - - - - - - - 
 
 
 
 
X 
Chart Abstraction10 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CDI Recurrence 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 


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1. 
Baseline medical history to include type of transplant, date of transplant, donor characteristics, cytomegalovirus status, Epstein Barr Virus status, rejection episodes, 
induction immunosuppression, probiotic use, social history (smoking status).  Confirm positive stool C difficile toxin test.   
2. 
Targeted physical exam to include assessment of heart, lung and abdomen. Height will be measured at Visit 1 only. Weight will be measured at Visit 1 and Visit 4. Vital 
signs to include temperature, respiratory rate, heart rate, and blood pressure.   
3. 
Subject to collect stool sample within specified window.  Specimen may be brought to study visit or shipped.   
4. 
Stool will be processed at UW-Madison research laboratory for microbiology analysis, toxin assays and microbiome analysis. 
5. 
CBC with differential will be drawn as part of study visit if not completed clinically within seven days prior to visit 2 or within study visit window for visit 3 
6. 
CMP will be drawn as part of study visit if not completed clinically within 30 days prior to visit 2 or within study visit window for visit 3 
7. 
Antibodies to CMV and EBV will be assessed at Visit 1 if not previously documented.    
8. 
Serum vancomycin concentrations will be drawn on patients currently undergoing hemodialysis with abnormal Kidney Function Levels (CMP) at Visit 3  
9. 
Between Visit 3 and Visit 7, study staff will attempt weekly phone contacts to assess for AEs, review concomitant medications and remind subjects to complete daily stool 
diaries as well as to assist with subject retention.     
10. The following variables will be abstracted from the medical record at each study visit:  rejection episodes, maintenance immunosuppression, nutritional status, bowel habits, 
organ function assessment, metabolic parameters, bloodstream infections, viral and fungal infections, hospitalizations, emergency department visits, gastric acid 
suppression, antibiotic use, FMT history, concomitant medications, and safety endpoints. 
11. Visits may be conducted in-person or via telephone call.   
12. Dispense 7-day post-FMT Stool Diary and Stool Diary at visit 2 for subject to complete at home.  
13. Visits 1 and 2 may occur on the same day. Visit 2 must be scheduled ≤ 14 days after SOC C. difficile treatment has started. 
 
 


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 Study Procedures 
11.14.1 
Physical Examination and Vital Signs 
At visits 1 and 3, a targeted physical exam including heart, lung, abdomen, and 
weight. Height will be measured at Visit 1 only.   Vital signs to include temperature, 
respiratory rate, heart rate, and blood pressure.   
11.14.2 
Urine or Serum Pregnancy Test 
Females of childbearing potential must have a negative urine or serum pregnancy 
test at baseline (Visit 1) and prior to randomization (Visit 2). Samples should be 
processed by each sites’ clinical laboratory or research staff.   
11.14.3 
Stool Collection 
A total of 6 stool samples will be self-collected by participants or perirectal swabs 
collected by study staff if stool sample(s) cannot be produced.  Subjects may choose 
to:  A) collect samples within the 24 hours proceeding their scheduled visits and 
bring to their appointment; or B) collect samples within the allotted visit window and 
ship directly to the UW infectious disease research laboratory.  Reference MOP for 
additional detail.   
11.14.4 
Stool Assessments 
Stool specimens collected to coincide with visits 2-7 will be processed at the UW 
Infectious Disease Research Lab for microbiology, toxin (TechLab C. difficile TOX 
A/B II) and microbiome analysis.  Note:  the positive C. difficile test required for 
eligibility will be assessed from medical record review.  Reference MOP for additional 
detail. 
11.14.5 
Blood Assessments  
A total volume of approximately 25 ml (4 teaspoons) of blood will be collected during 
the study.   
 
 
 IgG Antibodies to CMV and EBV 
If historical laboratory results for antibodies to CMV and EBV are not 
available, approximately 5 ml of blood will be drawn at visit 1.   
 
 Complete Blood Count (CBC) with differential 
Approximately 5 ml of blood will be drawn during screening if not clinically 
completed within window at visit 2 and visit 3 and processed at each 
site’s clinical laboratory. Reference MOP for additional detail.   
 
 Comprehensive Metabolic Panel (CMP) 
Approximately 5 ml of blood will be drawn during Screening (Visit 1) if not 
clinically completed within window and within window for Visit 3 and 
processed at each site’s clinical laboratory. Reference MOP for additional 
detail. 
 
 Safety Serum Vancomycin Level 
Patients currently on Hemodialysis with abnormal kidney function levels 
based on CMP at Visit 3 will have Serum Vancomycin Levels. Reference 
MOP for additional detail 
 
11.14.6 
Quality of Life Questionnaire (Cdiff32) 
Health-related quality of life will be assessed at visits 1, 3 and 7 using Cdiff32, a 
validated instrument specific for patients with CDI.  
 


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11.14.7 
Safety Capsule Administration 
Subjects will ingest one inert ‘safety’ capsule under direct supervision of the study 
nurse at visit 2. The safety capsule is identical to the MTP-101-C matching placebo 
and will minimize risk to study participation by determining subjects’ tolerance for 
consuming capsules. 
 
11.14.8 
MTP-101-C/Matching Placebo and Vancomycin/Matching Placebo at Visit 2 
 
At visit 2, subjects will receive a single dose of MTP-101-C or matching placebo.  A 
single dose consists of 5 capsules, each swallowed individually with water. 
Reference section 10.7.1 and MOP for additional detail.    
  
At visit 2, subjects will also receive oral vancomycin or matching placebo capsules to 
be taken according to the prescribed schedule. Reference section 10.7.2 and MOP for 
additional detail.  
11.14.9 
Daily Stool Diary 
Subjects will complete a daily stool diary starting at visit 2 through the end of the 
study (visit 7).  The modified Bristol stool consistency scale will be used for diarrhea 
assessment. At visit 2, subjects will be asked to complete a specific stool diary for 7 
days post FMT that will assess the following adverse events:  fever, vomiting, 
abdominal pain, bloating, flatulence, diarrhea, constipation, and rectal bleeding. 
11.14.10 Chart Abstraction 
The following data will be abstracted at baseline: transplant, date of transplant, donor 
characteristics, cytomegalovirus status, Epstein Barr Virus status, rejection episodes, 
induction immunosuppression.  The following variables will be abstracted at each 
study visit:  rejection episodes, maintenance immunosuppression, nutritional status, 
bowel habits, organ function assessment, metabolic parameters, bloodstream 
infections, viral and fungal infections, hospitalizations, emergency department visits, 
gastric acid suppression, antibiotic use, FMT history, concomitant medications, and 
safety endpoints. 
 
 


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12.0 DATA COLLECTION, HANDLING AND RECORD KEEPING 
 
The PI will be responsible to ensure the accuracy, completeness, legibility, and timeliness of the data 
reported.  All source documents will be completed in a neat, legible manner to ensure accurate 
interpretation of data.  Black or blue ink is required to ensure clarity of reproduced copies.  When 
making changes or corrections, cross out the original entry with a single line, and initial and date the 
change.   
 
Copies of the electronic CRF (eCRF) will be provided for use as source documents and maintained for 
recording data for each subject enrolled in the study.  Data reported in the eCRF derived from source 
documents should be consistent with the source documents or the discrepancies should be explained. 
Frontier Science, a not-for profit clinical research organization that has extensive experience on data 
management and quality control, will be responsible for these activities to support the study.  
 
 
Types of Data 
 
Data for this study will include safety, laboratory, and endpoint measures: diarrhea, 
demographics, comorbidity, medications, transplant related factors, C. difficile lab results, other 
multidrug-resistant organism results and fecal microbiome assessment.  
 
 
Data Collection  
12.2.1 
Source Documents and Access to Source Data/Documents  
Most data will be recorded on structured electronic case report forms (eCRFs) at 
clinical sites; other data will be sent electronically to the DCC from the lab.  Drafts of 
the study eCRFs will be prepared by the DMC and reviewed and approved by the 
study team.  
 
The information collected on eCRFs will be self-coding whenever possible. Brief 
instructions for completing the form will be given for each eCRF. Additional 
instructions, including those for standard data formats (e.g., dates, justification, and 
zero-filling), will be included in the MOP.  All of the data collected on CRFs will be 
visit-driven. At scheduled protocol-defined visits (screening, baseline, and weeks12 
and 24) and protocol-specific data (e.g., clinical, laboratory, medication, adherence, 
adverse effects) will be recorded.  Protocol-specified clinical events (e.g., adverse 
events or deaths) will be reported as they occur.  
 
The lab will send data files to the DCC, which then logs the data into the central 
repository. The data management will be coordinated by Frontier Science.  
 
The DCC will be located in the Department of Biostatistics and Medical Informatics of 
the University of Wisconsin-Madison, with a subcontract at Frontier Science & 
Technology Research Foundation office (Amherst NY). UW-Madison will be 
responsible for oversight of the DCC activities with specific responsibilities for 
statistical methods, and FSTRF will be responsible for data management, quality 
control and trial monitoring support. 
12.2.2 
Data Collection Forms 
Standardized data collection forms (e.g., source documents, case report forms, 
standardized assessment forms, etc.) are used to ensure data collected are 
consistent and compliant with the protocol and IRB application.  
Data collection is the responsibility of study team members under the supervision of 
the principal investigator. The principal investigator is responsible for ensuring the 
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All data collection forms must be completed in a legible manner; any missing data 
will be explained. Data entry errors will be corrected with a single line through the 
incorrect entry and the correct data is entered above/near the correction. All changes 
will be initialed and dated. 
 
Data collection forms are maintained in the subject files and retained as described in 
the Record Retention section. 
12.2.3 
Data Management Responsibilities  
All source documents and laboratory reports must be reviewed by the clinical team 
and data entry staff, who will ensure that they are accurate and complete.  Adverse 
events must be graded, assessed for severity and causality, and reviewed by the site 
PI or designee. 
 
Data collection is the responsibility of the clinical trial staff at the site under the 
supervision of the site PI.  During the study, the investigator must maintain complete 
and accurate documentation for the study.   
 
Data Capture Methods 
Clinical data (including AEs, concomitant medications, and reactogenicity data) and clinical 
laboratory data will be entered into a 21 CFR Part 11-compliant Internet Data Entry System 
(IDES) provided by Frontier Science.  The data system includes password protection and 
internal quality checks, such as automatic range checks, to identify data that appear 
inconsistent, incomplete, or inaccurate.  Clinical data will be entered directly from the source 
documents. 
12.3.1 
Data Management Software System(s) 
OpenClinica will be the clinical trial data management system (CTDMS) for this trial.  
It is a web-based CTDMS thus it can be accessed from most locations in the world to 
support multi-center studies. OpenClinica is FDA 21 CFR Part 11 compliant and 
supports Good Clinical Practice (GCP) via differentiated user roles and privileges, 
password and user authentication security, electronic signatures, secure sockets 
layer (SSL) encryption, and a comprehensive auditing record and monitoring of 
access and data changes. 
 
Based on the differentiated roles and privileges, subject data will only be available to 
the specific site which has enrolled the subject and entered data. All clinical data 
required by the protocol is entered using a unique subject assigned number and no 
personal identifying information is entered or stored other than dates of birth and 
service. 
 
All data entered through OpenClinica will be stored on servers provided by 
OpenClinica, LLC which maintains all data in a SAS 70 Type II audit certification and 
meets ISO 17799 standards for information security. Access to OpenClinica on their 
servers is limited, via login credentials, to authorized users for the web interface only. 
Customers have no access to the server itself.  All OpenClinica employees are 
granted access only to computer and networking areas necessary to perform their 
duties. Each installation is separate, and cannot be accessed from any other 
installation. Connection to a hosted instance is encrypted by means of secure socket 
layer. The application server and database server are secured via firewall, hardened 
to remove nonessential access credentials, and strong password compliance. 
Hosted systems are constantly monitored for latencies and intrusion. 
 


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Data Confidentiality 
12.4.1 
Confidentiality of Subject Records 
Participant confidentiality and privacy is strictly held in trust by the participating 
investigators, their staff, and the sponsor(s) and their interventions. This 
confidentiality is extended to cover testing of biological samples 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. 
 
All the staff participating in this project must complete human subjects protections, 
Good Clinical Practice (GCP), and HIPAA training. 
 
Information about study subjects will be kept confidential and managed according to 
the requirements of the Health Insurance Portability and Accountability Act (HIPAA). 
All subjects will sign an informed consent document and HIPAA authorization that 
includes specific privacy and confidentiality rights. Study data will be maintained per 
federal, state, and institutional data policies. 
 
The investigator(s) will ensure that the identities of subjects are protected by using 
coded subject information. The subject log with identifying information, linking 
subjects to their study-specific identification number, will be maintained electronically 
on a secure network server that is password-protected with access provided only to 
authorized study personnel. 
 
Authorized representatives of the following groups may need to review this research 
as part of their responsibilities to protect research subjects: authorized 
representatives of the NIAID, representatives of the IRB, DMC, DCC staff, regulatory 
agencies or study product suppliers. The clinical study site will permit access to such 
records. 
 
To protect privacy, the NIH has provided a Certificate of Confidentiality, CoC.  With 
this CoC, the participating sites cannot be forced to release information that may 
identify the participant, even by a court subpoena, in any federal, state, or local civil, 
criminal, administrative, legislative, or other proceedings.  The participating sites will 
use the CoC to resist any demands for information that would identify the participant, 
except as explained below. 
 
The CoC cannot be used to resist a demand for information from personnel of the 
United States Government that is used for auditing or evaluation of federally funded 
projects, like this study or local laws, such as for reporting of communicable 
diseases. 
 
 
 
Records Retention 
Study records will be retained for a minimum of 7 years after study completion.   
 
 
Specimen Banking 
All samples collected from this study will be labeled with a subject ID and maintained in secure 
freezer space located UW Infectious Disease Research Lab. Laboratory and freezer access is 
limited to authorized personnel.  
 


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Subjects will be given the option to allow their tissue to be stored for future research and may 
withdraw their tissue at any time. Subjects may withdraw their tissue by contacting the PI. If the 
patient withdraws consent, the subject’s data will be excluded from future distributions, but data 
that have already been distributed for approved research use will not be able to be retrieved. 
 
 


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13.0 ASSESSMENT OF SAFETY 
 
 
Adventitious Findings 
Not applicable.  
 
 
Adverse Event (AE) Definition 
Per the Code of Federal Regulations 21CFR312.32, adverse event (AE) means any untoward 
or unfavorable medical occurrence in a human subject or others that happens during or after 
participation in a research study. 
 
An abnormal laboratory value will not be assessed as an AE unless that value leads to 
discontinuation or delay in treatment, dose modification, therapeutic intervention, or is 
considered by the investigator to be a clinically significant change from baseline. These AEs will 
be entered into the electronic data capture system (EDC). 
 
For the purposes of this study, baseline symptoms will be collected prior to the administration of 
the study intervention. Only those symptoms identified as new or worsened compared to the 
baseline assessment will be recorded as an AE. In addition, only those abnormal laboratory 
values or physical examination assessments that are considered clinically significant will be 
recorded in the study documents. 
 
 
Serious Adverse Event (SAE) Definition 
 Per the Code of Federal Regulations 21CFR312.32, an adverse event is considered "serious" if, 
in the view of either the investigator or sponsor, meets any of the following criteria: 
● Results in death 
● Are life-threatening (Refers to an AE in which the subject was at risk of death at the time 
of the event. It does not refer to an event, which hypothetically, might have caused death 
if it were more severe.) 
● Requires an inpatient hospitalization or prolongation of an existing hospitalization  
● Results in persistent or significant disability or incapacity. (Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions.) 
● Results in a congenital anomaly/birth defect, constitute, based upon appropriate medical 
judgment, an event that may jeopardize the subject’s health and may require medical or 
surgical intervention to prevent one of the other outcomes listed above. 
● Important medical events that may not result in death, be life-threatening, or require 
hospitalization and that 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. (Examples of 
such medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse”) 
 
 
Unanticipated Problem (UP) Definition 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving 
risks to subjects or others to include, in general, any incident, experience, or outcome that 
meets all of the following criteria:  
 
The incidence, experience, or outcome is unexpected given the research procedures 
described in protocol-related documents (e.g., the study protocol, the consent documents, 
the Investigator’s Drug Brochure) and the characteristics of the subject population being 
studied. An event may be considered unexpected if it exceeds the nature, severity, or 
frequency described in the study-related documents, Investigator’s Drug Brochure, product 
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 
The incidence, experience, or outcome is related or probably related to participation in the 
research study. Probably related means the incidence, experience, or outcome is more likely 
than not to be caused by the research study procedures. 
 
The occurrence of the incidence, experience, or outcome suggests that the research places 
subjects or others at a greater risk of harm (physical, psychological, economic, or social) 
than was previously known or recognized. 
 
 
Classification of an Adverse Event 
13.5.1 
Severity of Event 
All AEs will be assessed by the clinician using the Common Terminology Criteria for 
Adverse Events (CTCAE) Version 5. For AEs not included in the protocol defined 
grading system, the following guidelines will be used to describe severity. All grade 4 
and 5 AEs must be reported as SAEs. 
 
Mild (grade 1) – Events require minimal or no treatment and do not interfere 
with the subject’s daily activities.  
 
Moderate (grade 2) – Events result in a low level of inconvenience or 
concern with the therapeutic measures. Moderate events may cause some 
interference with functioning.  
 
Severe (grade 3) – Events interrupt a subject’s usual daily activity and may 
require systemic drug therapy or other treatment. Severe events are usually 
potentially life-threatening or incapacitating. 
 
Life threatening (grade 4) - The patient was at risk of death at the time of 
the event. Must be reported as an SAE. 
 
Fatal (grade 5) - The event caused death. Must be reported as an SAE. 
13.5.2 
Relationship to Study Intervention 
For all collected AEs, the clinician who examines and evaluates the subject will 
determine the AE’s causality based on temporal relationship and his/her clinical 
judgment. The degree of certainty about causality will be graded using the categories 
below; for safety purposes, all AEs considered Definitely, Probably, and Possibly 
Related will be evaluated as Related. 
 
Definitely Related – Clearly related to the study procedures and other 
possible contributing factors can be ruled out. 
 
Probably Related – Likely related to the study procedures and the influence 
of other factors is unlikely.  
 
Possibly Related – Possibly related to the study procedures and there are 
other factors that could be equally likely. 
 
Unlikely to be related – Doubtfully related to the study procedures and there 
is another likely cause. 
 
Unrelated – Clearly not related to the study procedures and/or evidence 
exists that the event is definitely related to another cause. 
13.5.3 
Expectedness to Study Intervention 
The PI will be responsible for determining whether an AE is expected or unexpected 
in relation to the intervention, based on information in the Investigator’s Brochure, 
and any prior reports related to the investigational product.  
 
For investigational drug and device studies, an AE will be considered unexpected if 
the nature, severity, or frequency of the event is not consistent with the risk 
information previously described in the clinical protocol, device manual, investigator’s 
brochure, investigational drug brochure, the package insert(s), the IRB application, or 
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Collection and Reporting of AEs, SAEs & UPs 
Study subjects will be instructed to contact the study staff if any serious or unexpected adverse 
event occurs. Reported AE’s will be recorded in detail in an AE case report form. 
 
Adverse events will be identified with subjects on weekly telephone calls and study visits. Any 
adverse events will be discussed with the PI and will be reviewed to determine whether a 
change in protocol is necessary.   
 
Of note, subjects suspected of developing acute organ rejection while on study will receive a 
clinical hand-off to the clinical transplant team and will continue to be monitored for the duration 
of the study. 
 
All adverse events and serious adverse events should be recorded on the Adverse Event Log, 
Serious Adverse Event Log, and in OpenClinica, within 24 hours. 
 
Investigators must immediately report any SAE to the sponsor, whether or not the investigator 
considers the event to be related to the investigational product. 
 
SAEs should also be reported to NIH Division of Microbiology and Infectious Diseases (DMID) 
within 24h of site awareness. Report to Pharmacovigilance Group (PVG) via: 
 
DMID Pharmacovigilance Group 
Clinical Research Operations and Management Support (CROMS) 
6500 Rock Spring Dr., Suite 650 
Bethesda, MD 20817 
SAE Hot Line: 1-800-537-9979 (US) 
SAE Fax: 800-275-7619 (US) 
SAE Email: PVG@dmidcroms.com 
 
PVG will forward SAE to DMID Medical Monitor who will review and contact PI if any questions. 
PI holds the responsibility of assessment and reporting to FDA per the grant responsibilities, 
DMID’s role is consultative. 
 
 
 
AE/SAEs that meet the definition of an unanticipated problem will be reported to the IRB & DMC 
within 14 business days. Events that are immediately life threatening, severely debilitating to 
other current subjects or resulted in a death will be reported to the IRB Chair or IRB Director 
and the DMC Chair via telephone or email within 24 hours (1 business day) of site awareness. 
 
13.6.1 
AE/SAEs that meet the definition of suspected, unexpected serious adverse 
reactions will be reported to the FDA no later than 15 calendar days after 
determining the information qualifies for reporting or within 7 calendar days 
for any unexpected fatal or life-threatening suspected adverse reactions as 
outlined in 21 CFR 312.32Adverse Events of Special Interest 
Adverse Events of Special Interest (AESIs) are defined as Adverse Events of scientific and 
medical concern specific to the sponsor’s product or program, for which ongoing monitoring and 
rapid communication by the investigator to the sponsor can be appropriate. 
 
Several AESIs have been identified which will require reporting to study sponsor: 
 
New onset obesity 
 
Glucose intolerance 
 
Metabolic syndrome 
 
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 
Any infection that is not reported in the past or that is not commonly transmitted 
by FMT 
 
13.6.2 
Additional Adverse Event and Outcome Reporting 
Given lack of substantial data on any adverse effects from FMT, the following will be collected for 
the duration of the study 
 
New onset chronic medical conditions 
 
Outcomes on all pregnancies that occur during study 
 
 
 
Stopping Rules 
13.7.1 
Study Stopping Rules 
This study may be suspended or prematurely terminated 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 sites, 
funding agency, and regulatory authorities. If the study is prematurely terminated or 
suspended, the PI will promptly inform the IRB, FDA and NIH, and will provide the 
reason(s) for the termination or suspension.  
 
   
 
Circumstances that may warrant termination or suspension include, but are not 
limited to:  
 
One or more subjects experience an infection that is considered at least 
possibly related to the FMT product. 
 
Determination of unexpected, significant, or unacceptable risk to subjects 
when a causal relationship with the study treatment is probable 
 
Any serious adverse event (SAE) that is assessed to be at least possibly 
related to the FMT product 
 
Insufficient compliance to protocol requirements  
 
.  
 
Study may resume once concerns about safety, protocol compliance, data quality 
are addressed and satisfy the DMC and applicable federal and institutional 
regulatory authorities. 
 
 


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14.0 STUDY ANALYSIS 
 
 
Statistical Hypothesis 
This  multi-site randomized active-controlled trial in solid organ transplant recipients with at least 
a first recurrence of CDI is designed to test the hypothesis that FMT will result in less recurrence 
of CDI compared with oral vancomycin. 
 
 
Primary Efficacy Objective 
The primary efficacy objective is to compare the effects of FMT and oral vancomycin on the 
recurrence of CDI in SOT recipients. The primary analysis will be performed according to the 
intention-to-treat principle. The primary efficacy analysis will be based on the primary endpoint 
of CDI recurrence in a 60-day period as a dichotomous variable. The primary comparison 
between the two treatment arms will be based on a Cochran-Mantel-Haenszel chi-square test 
accounting for stratification by clinical site at a significance level of 0.05.  A log binomial model 
with treatment as model term while adjusting for potential confounders such as age, sex, 
race/ethnicity, comorbidities, exposure to healthcare system, clinical site, and type of transplant 
organ as per NIH Rigor and Reproducibility standards will be used to estimate the relative risk 
or risk ratio of CDI recurrence with 95% confidence interval. As a secondary analysis, time to 
recurrence of CDI as time to event data will be compared using log-rank test stratified by clinical 
site, and its survival distribution estimated using Kaplan-Meier method.21 A Cox proportional 
hazards regression model stratified by clinical site will be used to estimate a hazard ratio with 
95% confidence interval.57 
 
 
Primary Safety Objective 
The primary safety objective is to evaluate the short- and medium-term safety of FMT. The 
frequency and proportion of short- and medium-term adverse outcomes will be summarized and 
compared using chi-square test for dichotomous and Jonckheere-Terpstra test for ordinal data.  
 
 
Secondary Objectives 
 
14.4.1 
Secondary Objective 1 
The Secondary Objective 1 is to compare the CDI-related quality of life of SOT 
recipients.  The CDI-related quality of life (QoL), as measured using Cdiff32, will be 
compared using longitudinal mixed effects regression model with treatment and time, 
and treatment by time interaction as model terms while adjusting for potential 
confounders. 
14.4.2 
Secondary Objective 2 
The secondary objective 2 is to compare the change in gut microbiota using multiple 
metrics of microbiota structure and function and 2) to evaluate the association 
between the change in gut microbiota and recurrence of CDI. 
 
The change in diversity indices between the treatment groups will be compared 
using t-test and analysis of covariance. With the effective sample size of 158, there is 
0.80-0.90 power to detect the treatment effect size of 0.51-0.59, where the treatment 
effect size is defined as the difference in mean change in diversity indices between 
the two groups divided by the standard deviation.  Cytokines and levels of lactoferrin 
will also be compared between the treatment groups. As a secondary analysis, the 
longitudinally measured diversity indices will be analyzed using linear mixed models 
with treatment and time and treatment by time interactions as model terms, while 
adjusting for potential confounders.  Depending on the distribution of the diversity 
index, a normalizing transformation may be necessary or a nonparametric test such 
as Wilcoxon rank sum test used instead. Association between clinical outcome of 
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and metagenomics) will be assessed using the Cox regression model for time to CDI 
recurrence with treatment and gut diversity as a time-varying covariate as model 
terms, while adjusting for potential confounders and using either Bray-Curtis 
dissimilarity with ANOSIM (16S rRNA) or chi-square test (metagenomics). 
14.4.3 
Secondary Objective 3 
The third secondary objective is to compare the effects of FMT and oral vancomycin 
on intestinal colonization by multidrug-resistant organisms other than C. difficile in 
SOT recipients.  The primary analysis will compare the prevalence of colonization by 
each multidrug-resistant organism at 24 weeks between the two groups, using 
Mantel-Haenszel chi-square test accounting for stratification by clinical site at a 
significance level of 0.05. The longitudinally measured prevalence of colonization 
over time will be analyzed using generalized linear mixed models with treatment and 
time, and treatment by time interactions as model terms while adjusting for potential 
confounders. Although Specific Aim 3 is exploratory, a power of > 0.90 for detecting 
the prevalence of 0.1 vs 0.3, 0.05 vs 0.25, and 0.05 vs 0.3, is expected for FMT and 
vancomycin given the sample size of 158. 
 
 
Sample Size Justification 
The primary endpoint of the study is the recurrence of CDI over 60 days from randomization 
defined as a dichotomous outcome.  With the probability of 60-day recurrence denoted by pV 
and pF, respectively, for the SOC vancomycin (V) arm and the FMT (F) arm, the primary 
objective of the study will be evaluated by testing the null hypothesis H0:pV=pF using a two-tailed 
two-sample test at a significance level α=0.05 against the alternative hypothesis H1:pV≠pF with 
power 1-β=0.9 to detect the decrease in the probability of 60-day recurrence (Δp=pV-pF) of 0.3.  
The table below gives the sample size estimates under different drop-out rates. Assuming a 
random drop-out rate of 20%, we propose a sample size of 158 based on pV=0.60-0.70 and 
pF=0.30-0.40.  If the probability of 60-day recurrence on vancomycin (pV) is <0.60 or >0.70, the 
study will have a slightly higher power than 0.90. 
 
 
Subject Population(s) for Analysis 
The study will enroll 158 subjects who meet the inclusion and exclusion criteria over the course 
of 4 years from five domestic clinical sites. 
 
14.6.1 
ITT analysis set 
The intent-to-treat analysis set will include all randomized participants. 
14.6.2 
Per-protocol analysis set 
The per-protocol analysis set will include those who complete the study without 
major protocol deviations. Major protocol deviations are defined in section 15.4. 
14.6.3 
Safety analysis set 
The safety analysis set will include those who receive at least one dose of protocol 
treatment, either MTP-101-C or oral vancomycin. 
 
 
The efficacy analyses of the 
trial will be based on the 
intention-to-treat principle, 
to include all participants 
who are randomized as 
defined in section 14.6.1.  
For those subjects who fail to return for evaluation of the primary and secondary efficacy 
endpoints, a method of multiple imputation will be used to impute the missing endpoints26 or 
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outcomes. See also section 14.9 for handling of missing data. Multiple imputation will follow the 
standard approach: 1) generate complete datasets multiple times using a log-binomial 
regression model based on the available data; 2) analyze the multiply imputed datasets using 
the same model; 3) and combined the results for statistical inference. A supportive analysis of 
the efficacy endpoints will be performed using the per-protocol analysis set defined in section 
14.6.2. 
 
All randomized subjects who underwent the protocol treatment of either MTP-101-C or oral 
vancomycin in the safety analysis set defined in section 14.6.3 will be included in all safety 
analyses.  
 
 
Statistical Methods 
Statistical methods will follow the established good statistical practice adopted by a wider 
community of statisticians in clinical research.  All statistical data analyses will be performed 
using the latest version of SAS (SAS Institute, Inc., Cary NC) and R (The R Foundation, Vienna, 
Austria) to provide validation of all analyses as per NIH Rigor and Reproducibility standards. 
14.7.1 
Demographics and Baseline Characteristics  
Summary tables and graphs of all randomized subjects, subject disposition and 
reasons for withdrawal, demographics, and baseline CDI characteristics will be 
produced. Baseline subject characteristics will be summarized using descriptive 
statistics such as mean and standard deviation, or median and interquartile range for 
quantitative measurements, frequency and proportion for binary or categorical 
measurements, graphics such as box plots and empirical distribution functions, and 
assessed for balance between the two dose groups.   
 
Appropriate categorical data analysis methods such as chi-square test or Jonckeere-
Terpstra test will be used to determine if the two treatment groups are balanced and 
comparable with respect to demographic and baseline characteristics.7 Student’s t-
test or Wilcoxon rank-sum tests will be used to determine if the two treatment groups 
are balanced with respect to baseline continuous covariates. 
14.7.2 
Efficacy Analysis 
Primary Efficacy Analysis: The primary analysis will be performed according to the 
intention-to treat principle. The primary efficacy analysis will be based on the primary 
endpoint of CDI recurrence in a 60-day period as a dichotomous variable. The 
primary comparison will be based on a Mantel-Haenszel chi-square test accounting 
for stratification by clinical site at a significance level of 0.05.  A log-binomial 
regression model with treatment as model term while adjusting for potential 
confounders such as age, sex, comorbidities, exposure to healthcare system, clinical 
site, and type of transplant organ will be used to estimate the relative risk or risk ratio 
of CDI recurrence with 95% confidence interval. As a secondary analysis, time to 
recurrence of CDI as time to event data will be compared using log-rank test 
stratified by clinical site, and its survival distribution estimated using Kaplan-Meier 
method. A Cox proportional hazards regression model stratified by clinical site will be 
used to estimate the hazard ratio of recurrence of CDI with 95% confidence interval. 
 
Secondary Efficacy Analyses: The CDI-related quality of life (QoL), as measured 
using Cdiff32, will be compared using longitudinal mixed effects regression model 
with treatment and time and treatment by time interaction as model terms while 
adjusting for potential confounders. 
 
The prevalence of colonization by each of three multidrug-resistant organisms, VRE, 
MRSA and FRGNB, at 24 weeks will be compared between the FMT and 
vancomycin groups using a Mandel-Haenszel chi-square test accounting for 


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stratification by clinical site. Although this analysis is exploratory, a power of >0.90 
for detecting the prevalence of 0.1 vs 0.3, 0.05 vs 0.25, and 0.05 vs 0.3, is expected 
for FMT and vancomycin, given the sample size of 158. In addition, the prevalence of 
colonization over time will be analyzed using generalized linear mixed models with 
treatment and time and treatment by time interactions as model terms while adjusting 
for potential confounders. 
 
14.7.3 
Safety Analysis 
The frequency and proportion of short- and medium-term adverse outcomes will be 
summarized by tables and graphs and compared using chi-square test for 
dichotomous and Jonckheere-Terpstra test for ordinal data.  
 
All inferential statistical tests of safety data will use two-sided statistical tests with a 
significance level at 0.05 without adjustment for multiplicity.  The format and content 
of all tables and graphs summarizing adverse event, vital signs and laboratory data 
will adhere to standard good statistical practice. 
 
Adverse events will be summarized in multiple tables and graphs by treatment group: 
• 
Incidence Table:  summary of the incidence of any adverse event, 
• 
Serious Adverse Event Table:  summary of the incidence of serious adverse 
events 
 
Shifts in laboratory tests are compared between treatments in terms of numbers of 
subjects showing an increase, decrease, and no change, with respect to the normal 
range.  Changes from baseline to week 24 (calculated as final value minus baseline 
value) will also be compared between treatments.  Inferential analyses will use 
Wilcoxon rank-sum tests for continuous variables and chi-square test for categorical 
variables. All early termination laboratory results will be considered final laboratory 
results. 
 
The percent of subjects showing clinically relevant changes from baseline in 
laboratory tests will be compared between the two treatment groups. Significant 
laboratory changes from baseline within treatment group as determined by Student t-
test will be listed. 
14.7.4 
Analysis of Correlative Endpoints 
The change in diversity indices between the treatment groups will be compared 
using t-test and analysis of covariance. Depending on the distribution of the diversity 
index, a normalizing transformation may be necessary or a nonparametric test such 
as Wilcoxon rank sum test used instead. With the sample size of 158, there is 0.80-
0.90 power to detect the treatment effect size of 0.51-0.59, where the treatment 
effect size is defined as the difference in mean change in diversity indices between 
the two groups divided by the standard deviation.  Metagenomic data as well as 
cytokines, CXCL-5/ENA-78 and CXCL-8/IL-8, and levels of quantitative lactoferrin 
will also be compared between the FMT and vancomycin groups using appropriate 
two-sample tests depending on the statistical distributions for these endpoints.  
 
As a secondary analysis, diversity indices over time will be analyzed using linear 
mixed models with treatment and time and treatment by time interactions as model 
terms, while adjusting for potential confounders. Association between clinical 
outcome of CDI recurrence and the change in gut diversity and microbiota data (both 
16S rRNA and metagenomics) will be assessed using the Cox regression model for 
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as model terms, while adjusting for potential confounders and using either Bray-
Curtis dissimilarity with ANOSIM (16S rRNA) or chi-square test (metagenomics). 
 
 
Subgroup Analysis 
Many baseline characteristics are known to be prognostic or suspected confounders for the 
clinical outcomes in the CDI study population, including age, sex, race/ethnicity, status of 
hospital stay, clinical site, and type of transplant organ. Internal consistency of the primary 
efficacy analysis will be assessed in subgroups defined by these covariates. Heterogeneity will 
be assessed using interaction tests of treatment by these baseline covariates. Any interaction 
test resulting in a heterogeneity p-value < 0.15 will be further evaluated for clinical plausibility. 
 
 
Handling Missing Data 
Not all subjects will have their stool samples, stool diaries, and QoL data available for analysis, 
and there will inevitably be missing data.  Most methods for handling missing data assume that 
the data are missing at random, which may not be a valid assumption. Reasons for missing data 
will be documented and evaluated. If the missing data are extensive, model-based approaches 
will estimate their effects under various assumptions regarding missingness.  For longitudinal 
data, principal stratification will be used for missing data. Missing data analysis will follow the 
guideline promulgated in the National Research Council report.28  
 
 Exploratory Analysis 
Marginal analyses, separately, of the clinical outcomes for the primary objective and the change 
in diversity of the gut microbiota for the secondary objective may not fully capture the effects of 
FMT treatment. In order to better understand the effects of FMT clinically and biologically, joint 
statistical models for the gut microbiota diversity index at baseline and weeks 1, 4, 8 and 12 and 
time to recurrence of CDI will be developed.  
 
In addition, mediation analysis will be performed to understand whether the effects of FMT is 
directly on the clinical outcomes without mediation of the gut microbiota diversity or indirectly 
through modulation of the gut microbiota diversity index instead (Figure 5). A publicly available 
R package, mediation, will be used to perform the required mediation analysis (http://cran.r-
roject.org/web/packages/mediation/index.html). 
 
Figure 5:   Direct and indirect effects of treatment with 
gut microbiota modulation and association between the 
change in diversity index and clinical outcomes. 
 
 
 Interim Analysis 
No interim analysis for efficacy is planned.  
 
 Multiplicity of Endpoints and Multiple Testing 
Considering the nature of the study, observed significance level, the so-called p-value, less than 
0.05 will be taken to indicate statistical significance without adjustment for multiple testing 
involved with subgroup analysis.  Statistical significance will be assessed in a hierarchical 


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manner starting with the primary endpoint followed by the secondary endpoints in the order of 
appearance in Section 6.4. 
 
 


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15.0 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
 
Quality Management 
All sites will have a plan in place for assuring the quality of the research being conducted and 
will have SOPs in place for quality management. Frontier Science will be responsible for data 
management which includes quality control. Relative to quality control, their role will be the 
following: 
● On an ongoing basis, perform QA/QC of submitted clinical and laboratory data, primarily 
through automated facilities. 
● On an ongoing basis, collect data from other instruments and/or other sources 
collaborating in the study. 
● On a daily basis, monitor computer processes and the database to ensure that all 
systems are operating correctly. These include data transmission and update 
operations, and the operations of the system software supporting and managing the 
study database. 
● Monitor the registration & randomization system on a daily basis. Monitor accruals and, 
working with the study statistician, ensure that the study dosing schema is executed 
properly. 
● Provide 24X7 user support for the data management systems. Provide backup to the 
registration & randomization system if there is a failure or if a site is temporarily unable 
to directly enter a subject. 
● Provide training in data management issues and software to staff as needed 
● Assist the project statistician with database retrievals and resolve any data 
inconsistencies identified by the statistician, querying sites as necessary. 
● Produce periodic reports for the PI, study sites, and other study collaborators as 
requested.  Generally, sites will receive operational reports, the PI and designees will 
receive administrative and site performance reports, while others will receive function-
specific reports. 
● Generate reports on schedules and as needed; develop additional reports as required. 
 
 
Safety Oversight 
UW ICTR has established a Data Monitoring Committee (DMC) to provide a key resource for 
UW-Madison investigators conducting clinical research.  This DMC will provide investigators 
services to ensure appropriate measures are in place to promote subject safety, research 
integrity and compliance with federal regulations and local policies for individual clinical 
research protocols in need of DMC review (as determined by the Principal Investigator (PI), the 
funding agency, the local Scientific Review Committee, or the local IRB, and for which no DMC 
exists). For these studies, the UW ICTR DMC will be the primary data and safety advisory group 
for the Principal Investigator.  
 
The DMC is supported in its mission of safety and compliance by experienced ICTR staff to 
provide administrative assistance, experienced members representing a diversity of 
backgrounds, skills and knowledge, and the use of the UW Department of Medicine instance 
Research Electronic Data Capture (REDCap) tool which provides data management 
functionality by allowing the development of eCRFs and surveys to support data capture. In 
providing oversight for the conduct of this study, the ICTR DMC will approximately meet every 
12 months during the 5-year study. Additional meetings may be scheduled as determined by the 
DMC or as requested by the PI. The DMC members will review protocol-specific reports created 
by statisticians that serve a non-voting member role on the DMC using data pulled from 
REDCap. These standard reports will include an overview of study objectives, a review of actual 
and projected accrual rates, an evaluation of patient demographics for balance of 
randomization, and a summary of the number and seriousness of adverse events. An interim 
analysis of study results may be requested, and source documents may be reviewed to allow 


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the DMC to independently judge whether the overall integrity and conduct of the protocol remain 
acceptable based on data provided and reported by the Principal Investigator. The DMC will 
make recommendations to the Principal Investigator that could include actions of continuation, 
modification, suspension, or termination. 
 
 
 
 
 
 
Study Monitoring  
The DMC/Frontier Science monitors will be responsible for implementing and maintaining 
quality control and quality assurance systems with written standard operating procedures 
(SOPs) to ensure that trial is conducted and data are generated, documented, and reported in 
compliance with the protocol, accepted standards of Good Clinical Practice (ICH E6), and all 
applicable federal, state, provincial, and local laws, rules, and regulations relating to the conduct 
of the clinical trial.  
 
During the trial, the DMC and Frontier Science monitors will utilize on-site, remote and risk-
based monitoring to ensure that the protocol and good clinical practices (GCPs) are being 
followed as described in detail in a separate quality assurance document/monitoring plan.  
At regular intervals during the clinical trial, each site will be contacted, through on-site 
monitoring visits, webinars or telephone calls, by a Frontier Science monitor to review trial 
progress, Investigator and patient compliance with protocol requirements and any emergent 
problems. These monitoring visits will include but not be limited to review of the following 
aspects: patient Informed consent for 100% of patients, source data verification, patient 
recruitment and follow-up, adverse event documentation and reporting (including timeliness), 
trial treatment administration, patient compliance with the regimens, pharmacy 
review/accountability, concomitant therapy use and quality of data. 
 
The DCC will determine data accuracy using several statistical-based approaches to identify 
potential data errors. Source documents, such as documentation of entry criteria, may be 
queried and reviewed by members of the DMC to identify data irregularities and to confirm that 
the data recorded on the case report forms is accurate. Any site found to be Unacceptable or 
Acceptable/Needs Follow-up on monitoring is required to submit a written response and/or 
corrective action plan to the DMC within 21 days of the receipt of the final monitor findings. Sites 
that fail to meet the standards for acceptable performance will undergo follow-up action, which 
will be determined by the severity of the discrepancies and may include repeat on-site 
monitoring, probation, or suspension. For-cause monitoring will occur if irregularities are 
identified, and if necessary will be supplemented by site visits by members of the DMC. The 
Investigator and the clinical site will allow the monitors and appropriate regulatory authorities 
direct access to source documents to perform this verification.  
 
The Clinical Site may be subject to review and/or inspection by the Institutional Review Board 
(IRB), the US Food and Drug Administration (FDA), and/or to quality assurance audits 
performed by the NIAID or the DMC. 
 
It is important that the Investigator(s) and the relevant clinical site personnel be available during 
the monitoring period and possible audits or inspections, and that sufficient time is devoted to 
the process. 
 
 
Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol or investigational plan 
requirements. The noncompliance may be either on the part of the subject, the investigator, or 
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implemented promptly.  
 
It is the responsibility of the Principal Investigator/site investigator/study staff to use continuous 
vigilance to identify and report deviations. The Principal Investigator is responsible for assessing 
whether the deviation constitutes noncompliance as defined by the reviewing IRB and if so, 
reporting it within the required time frame(s).The site investigator is responsible for knowing and 
adhering to the reviewing IRB requirements.  
 
For this trial, subject non-compliance with MTP-101-C/matching placebo or oral 
vancomycin/matching placebo (e.g., missed dose) is considered a protocol deviation. 
Incomplete 7-Day Post-FMT Stool Diaries are deviations. Incomplete Stool Diaries after the 7-
days post-FMT are not deviations but study staff must reeducate subjects on completion and 
use of the diary and document reeducation. 
 
 
Publication Plan 
Publication of the results of this trial will be governed by policies and procedures developed by 
the Steering Committee.  No results will be released publicly before completion of the final 
analysis regarding the primary endpoint of this study without the approval of the NIAID, and the 
Steering Committee. Any presentation, abstract, or manuscript will be made available for review 
by the principal investigators and the NIAID prior to submission. 
 
This study will comply with the NIH Public Access Policy, which requires submission of final 
peer-reviewed journal manuscripts that arise from NIH funds to the digital archive PubMed 
Central. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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16.0 MULTISITE RESEARCH COMMUNICATION PLAN 
 
Statement of Compliance with NIH Single IRB Policy 
In accordance with the NIH Policy on the use of a single IRB for multisite research, a single IRB 
will provide IRB review under 45 CFR 46 of all human subjects’ research at all collaborating 
sites. 
 
UW-Madison Health Sciences IRB 
The UW-Madison Health Sciences IRB will serve as the single IRB of record for all sites. 
 
Participating Sites Agreement to Rely on sIRB 
Only sites who agree to rely on UW-Madison Health Sciences IRBs Office as the single IRB will 
participate. 
 
Communication between Sites and the sIRB 
16.4.1 
Roles 
 
Reviewing IRB: Responsible for addressing questions related to the 
Reviewing IRB’s policies and procedures and review status for a ceded study 
 
Clinical Coordinating Center (CCC): Main entity responsible for 
communication with the Reviewing IRB and facilitating communication 
between relying-site study teams and the Reviewing IRB regarding the ceded 
study 
 
Relying Site Reliance Point of Contact (POC): Main person or entity 
responsible for communication with the Reviewing IRB and local study 
team regarding the ceded study (e.g., personnel in the local IRB office 
or local human research protection program personnel) 
 
Relying Site Study Team POC: Main person responsible for communication 
with the Clinical Coordinating Center regarding the ceded study 
16.4.2 
Lead Study Team POC (or CCC) Responsibilities 
The Lead Study Team will be the primary POC for communication to and from the 
Reviewing IRB. Site-specific information from the relying sites will be provided to the 
lead study team and then submitted to the Reviewing IRB. All communication from 
the Reviewing IRB will flow from the Reviewing IRB to the Lead Study Team POC to 
the CCC to the Relying Study Team POC. This includes (but is not limited to) the 
following: 
 
 
Preparing and submitting the study-wide application for initial IRB review and 
study- wide amendments to the Reviewing IRB 
 
Preparing and submitting the site-specific applications and site-specific 
amendments to the Reviewing IRB that address site variations in study 
conduct, informed consent language, HIPAA Privacy Rule requirements (if 
applicable), subject identification and recruitment processes (including 
recruitment materials), and any other applicable components of the research 
 
Providing documentation of IRB determinations to relying site study teams 
 
Providing copies of IRB-approved materials to the lead study team 
 
Providing copies of the most current versions of IRB-approved materials to 
relying site study teams in a timely manner 
 
Providing the consent form template to relying site study teams 
 
Providing relevant Reviewing IRB policies to the study teams 
 
Obtaining and collating study-wide information for continuing review to the 
Reviewing IRB 
 
Submitting continuing review progress report to the Reviewing IRB 


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 
Reporting reportable events to the Reviewing IRB (e.g., unanticipated 
problems, noncompliance, subject complaints) 
 
Providing the Reviewing IRB with required information when a study is closed 
16.4.3 
Relying Study Team Responsibilities 
Relying Study Team POC will be responsible for communicating with the Relying 
Site POC for: 
 
Site-specific research applications (if any) 
 
Obtaining site-specific approvals (if any) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Origuen J, Fernandez-Ruiz M, Lumbreras C, et al. Potential role of post-transplant hypogammaglobulinemia in 
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Munoz P, Giannella M, Alcala L, et al. Clostridium difficile-associated diarrhea in heart transplant recipients: is 
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Carbone J, Sarmiento E, Palomo J, et al. The potential impact of substitutive therapy with intravenous 
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van Nood E, Vrieze A, Nieuwdorp M, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N. 
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Khoruts A, Dicksved J, Jansson JK, Sadowsky MJ. Changes in the composition of the human fecal microbiome 
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Hamilton MJ, Weingarden AR, Unno T, Khoruts A, Sadowsky MJ. High-throughput DNA sequence analysis 
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Peterfreund GL, Vandivier LE, Sinha R, et al. Succession in the Gut Microbiome following Antibiotic and Antibody 
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Russell DL, Flood A, Zaroda TE, et al. Outcomes of colonization with MRSA and VRE among liver transplant 
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Singh N, Wagener MM, Obman A, Cacciarelli TV, de Vera ME, Gayowski T. Bacteremias in liver transplant 
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Said A, Safdar N, Lucey MR, et al. Infected bilomas in liver transplant recipients, incidence, risk factors and 
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29. 
Staley C, Hamilton MJ, Vaughn BP, et al. Successful resolution of recurrent Clostridium difficile infection using 
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17.0 APPENDICES 
 
Quality of Life Questionnaire (Cdiff-32) 


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Stool Diary 
17.2.1 
7-Day Post-FMT Stool Diary 
 


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17.2.2 
Stool Diary 


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Subject Instructions for Stool Collection 
 
 
 


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Medication Diary 
 


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Data Safety Monitoring Board Charter and Membership  
 


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