Phase II Randomized, Double Blind, Placebo-controlled, Parallel Group Trial of Encapsulated Fecal Microbiota Transplantation for Vancomycin Resistant Enterococcus Decolonization
Phase: PHASE2
Conditions: Antibiotic Resistant Strain
Sponsor: Microbiome Health Research Institute

 
1
APPENDIX C. PROTOCOL 
 
A Randomized Controlled Trial of Encapsulated Fecal Microbiota for 
Vancomycin Resistant Enterococcus Decolonization  
 
 
Full title: Phase II randomized, double blind, placebo-controlled, parallel group 
trial of encapsulated fecal microbiota transplantation for vancomycin resistant 
enterococcus decolonization  
 
Sponsor: Microbiome Health Research Institute, d/b/a OpenBiome  
 
OpenBiome Sponsor Representative Principal Clinician: 
Majdi Osman, MD, MPH 
Co-Principal Investigators: 
Monika Fischer MD, MSc 
Nasia Safdar MD, PhD 
 
Funding Source: Centers for Disease Control and Prevention (BAA 
2016-N-17812) 
 
IND Number: 17312 
ClinicalTrials.gov Identifier: NCT03063437 
Privileged and Confidential 
Not for distribution 
 
September 9, 2019 

 
 
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STATEMENT OF COMPLIANCE 
 
The study will be carried out in accordance with Good Clinical Practices (GCP) 
as required by the following: 
 United States Code of Federal Regulations (CFR) applicable to clinical 
studies (45 CFR Part 46; 21 CFR Part 50, 21 CFR Part 54, 21 CFR Part 56, 
and 21 CFR Part 312); 
 International Conference on Harmonization (ICH) E6; 62 Federal 
Register 25691 (1997); 
 
Compliance with these standards provides public assurance that the rights, 
safety and well-being of study subjects are protected, consistent with the 
principles that have their origin in the Declaration of Helsinki. 
All key personnel (all individuals responsible for the design and conduct of this 
study) have completed Human Subjects Protection Training. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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PRINCIPAL CLINICIAN SIGNATURE PAGE 
 
 
 
Protocol Title:  
Phase II randomized, double blind, placebo-
controlled, parallel group trial of encapsulated 
fecal microbiota transplantation for 
vancomycin resistant enterococcus 
decolonization 
 
 
Version Date:  
September 9, 2019 
 
 
I acknowledge that I have read and understand the protocol named above and 
agree to conduct the study according to the protocol named above. I also agree and 
will adhere to terms and procedures in accordance with United States Food and Drug 
Administration (FDA)/International Council for Harmonisation (ICH) guidelines, including 
all federal and locally applicable regulations and laws. 
 
I assure that the study drug supplied by OpenBiome will be used only as described in 
the protocol named above. 
 
 
 
 ____________________________________________  
 _________________________  
 
 
Signature  
Date 
 
 
 

 
 
4
APPENDIX C. TABLE OF CONTENTS 
STATEMENT OF COMPLIANCE ....................................................................................... 2 
SIGNATURE PAGE .......................................................................................................... 3 
APPENDIX C. TABLE OF CONTENTS............................................................................... 4 
LIST OF ABBREVIATIONS ................................................................................................. 7 
PROTOCOL SUMMARY .................................................................................................. 9 
C.1.  KEY ROLES............................................................................................................ 18 
C. 2. BACKGROUND AND SCIENTIFIC RATIONALE .................................................... 19 
C.2.1 
Background ........................................................................................................ 19 
C.2.2  
Scientific Rationale ............................................................................................. 20 
C.2.3  
Potential Risks and Benefits ................................................................................ 22 
C.2.3.1 
Potential Risks ...............................................................................................22 
C.2.3.2 
Potential Benefits .........................................................................................23 
C.3. OBJECTIVES .......................................................................................................... 23 
C.3.1 
Study Objectives ................................................................................................ 23 
C.3.2 
Study Outcome Measures ................................................................................. 24 
C. 3.2.1 
Efficacy Outcome Measures ......................................................................24 
C.3.2.2 
Safety Outcome Measures .........................................................................25 
C.3.2.3 
Exploratory Outcome Measures .................................................................26 
C.4. STUDY DESIGN ...................................................................................................... 26 
C.5. STUDY ENROLLMENT AND WITHDRAWAL ........................................................... 27 
C.5.1  
Participant Inclusion Criteria .............................................................................. 27 
C.5.2  
Participant Exclusion Criteria ............................................................................. 27 
C.5.3  
Treatment Assignment Procedures ................................................................... 28 
C.5.3.1 
Randomization Procedures .........................................................................29 
C.5.3.2 
Masking Procedures ....................................................................................29 
C.5.3.3 
Reasons for Withdrawal ...............................................................................29 
C.5.3.4 
Handling Withdrawals .................................................................................30 
C.5.3.5 
Termination of Study ....................................................................................30 
C.6. STUDY INTERVENTION/INVESTIGATIONAL PRODUCT ......................................... 30 
C.6.1  
Study Product Description .................................................................................. 30 
C.6.2  
Formulation ......................................................................................................... 30 
C.6.2.1 
Encapsulated fecal microbiota preparation (formulation FMP-402) ......30 
C.6.2.2 
Placebo ........................................................................................................31 
C.6.3.  
Product Storage and Stability ............................................................................ 31 
C.6.4  
Dosage, Preparation and Administration of Study Intervention/Investigational  
Product 32 
C.6.5  
Accountability Procedures for the Study Intervention/Investigational Product
 
32 
C.6.6  
Modification of Study Intervention/Investigational Product for a Participant 32 
C.6.7  
Assessment of Participant Compliance with Study 
Intervention/Investigational  Product ............................................................................... 33 

 
 
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C.6.8  
Concomitant Medications/Treatments ............................................................. 33 
C.7. STUDY SCHEDULE ................................................................................................. 33 
C.7.1  
Screening (Visit 1) ............................................................................................... 33 
C.7.2  
Enrollment and Intervention Administration (Visit 2) ........................................ 34 
C.7.2.1 
Enrollment .....................................................................................................34 
C.7.2.2 
Intervention Administration (Day 0) ............................................................35 
C.7.3  
Follow-Up (Visit 3, 4, 5, 6) ................................................................................... 36 
C.7.3.1 
Visit 3 - Day 3 (±2 days) ................................................................................36 
C.7.3.2 
Visit 4 - Day 10 (±3 days) ..............................................................................37 
C.7.3.3 
Visit 5 – Week 4 (±5 days) ............................................................................38 
C.7.3.4 
Visit 6 - Month 6 (±14 days) ..........................................................................38 
C.7.4  
Early Termination Visit ......................................................................................... 39 
C.7.5  
Unscheduled Visit ............................................................................................... 40 
C.7.6  
Stool Collection .................................................................................................. 41 
C.8. ASSESSMENT OF SAFETY ....................................................................................... 41 
C.8.1  
Definition of an Adverse Event (AE) .................................................................. 41 
C.8.2 
NIH Grading of Severity of the Event ................................................................. 42 
C.8.3 
Relatedness ......................................................................................................... 42 
C.8.4 
Solicited Adverse Events after FMT .................................................................... 43 
C.8.5  
Serious Adverse Events ...................................................................................... 44 
C.8.6 
Unsolicited Adverse Events ................................................................................ 45 
C.8.7  
Reporting of Adverse Events .............................................................................. 45 
C.8.8 
Follow-up of Participants after Adverse Events ................................................ 47 
C.8.9. Halting Rules ............................................................................................................ 47 
C.8.9.1 
Study Halting Rules .......................................................................................47 
C.8.9.2 
Individual’s Halting Rules .............................................................................47 
C.8.10 
Safety Oversight.................................................................................................. 48 
C.8.10.1 
Data and Safety Monitoring Board (DSMB) ...............................................48 
C.9. CLINICAL MONITORING ...................................................................................... 48 
C.9.1 
Site Monitoring Plan ............................................................................................ 48 
C.10. STATISTICAL CONSIDERATIONS ......................................................................... 48 
C.10.1 
Sample Size ......................................................................................................... 49 
C.10.2 
Final Analysis Plan .............................................................................................. 49 
C.11. SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ........ 49 
C.12. QUALITY CONTROL AND QUALITY ASSURANCE .............................................. 49 
C.12.1 
Database QC ...................................................................................................... 50 
C.13. ETHICS/PROTECTION OF HUMAN PARTICIPANTS ............................................. 50 
C.13.1 
Ethical Standard ................................................................................................. 50 
C.13.2 
Institutional Review Board .................................................................................. 50 
C.13.3 
Informed Consent Process ................................................................................. 50 
C.13.4 
Exclusion of Women, Minorities, and Children (Special Populations) ............ 52 
C.13.5 
Participant Confidentiality ................................................................................. 52 
C.13.6  
Study Discontinuation ..................................................................................... 52 
C.13.7 
Future Use of Stored Specimens ........................................................................ 53 

 
 
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C.14. DATA HANDLING AND RECORD KEEPING ....................................................... 53 
C.14.1 
Data Management Responsibilities .................................................................. 54 
C.14.2 
Data Capture Methods ...................................................................................... 54 
C.14.3 
Types of Data ...................................................................................................... 54 
C.14.4 
Timing/Reports .................................................................................................... 54 
C.14.5 
Study Records Retention .................................................................................... 55 
C.14.6 
Protocol Deviations ............................................................................................ 55 
C.15. PROTOCOL REFERENCES ................................................................................... 56 
C.16. PROTOCOL ABSTRACTS ..................................................................................... 59 
C.16.1 
Eysenbach et al. ID Week 2016 ......................................................................... 59 
C.16.2 
Osman et al. ID Week 2016 ............................................................................... 60 
C.16.3 
Dubois et al. ID Week 2015 ................................................................................ 62 
C.17. STUDY DESIGN .................................................................................................... 65 
C.17.1 
Study Schematic ................................................................................................. 65 
C.17.2 
Study Visit Table .................................................................................................. 66 
C.17.3 
NIH Common Terminology Criteria for Adverse Events (CTCAE) .................... 67 
C.17.4 
Adverse Event Assessment Flow Chart ............................................................. 68 
 
 
 
 

 
 
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LIST OF ABBREVIATIONS 
 
AE 
Adverse Event/Adverse Experience 
CDAD 
Clostridium difficile Associated Diarrhea 
CFR 
Code of Federal Regulations 
CONSORT 
Consolidated Standards of Reporting Trials 
CFR 
Code of Federal Regulations 
CRE 
Carbapenem-Resistant Enterobacteriaceae 
CRF 
Case Report Form 
DSMB 
Data and Safety Monitoring Board 
eCRF 
Electronic Case Report Form 
ESBL 
Extended-Spectrum Beta-Lactamases 
FMT 
Fecal Microbiota Transplantation 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
Independent or Institutional Ethics Committee 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
MOP 
Manual of Procedures 
N 
Number (typically refers to participants) 
PHI 
Protected Health Information 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SMC 
Safety Monitoring Committee 
SOP 
Standard Operating Procedure 
VRE 
Vancomycin Resistant Enterococcus 
 
 
 
 
 
 
 
 
 
 

 
 
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9
PROTOCOL SUMMARY 
Title: 
A Randomized Controlled Trial of Encapsulated Fecal 
Microbiota for Vancomycin Resistant Enterococcus 
Decolonization  
Phase: 
II 
Population: 
Vancomycin resistant enterococcus (VRE) identified 
by stool culture in the past 14 days among adults. 
Sample size  
46 (1:1 randomization) - 23 in the treatment group 
and 23 in the placebo group). 
Number of sites: 
Multi-center study at 2 tertiary academic medical 
centers (Indiana University and University of 
Wisconsin). 
Study duration: 
Approximately 1 year. 
Description of Agent: 
Encapsulated fecal microbiota preparation 
(formulation FMP-402). Please refer to OpenBiome 
BBMF # 17300, Section I, H. 
Sourced from human-derived microbes. Please 
refer to OpenBiome BBMF # 15543, Section F. 
 
 

 
 
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Study Objectives: 
 
To investigate the efficacy and safety of FMP-402 to 
decolonize VRE. 
Primary Objectives: 
 To determine the VRE decolonization rate of 
FMP-402 versus placebo.  
 To evaluate the safety profile for FMP-402 versus 
placebo.  
Secondary Objectives: 
 To determine the VRE infection rate of FMP-402 
versus placebo.  
 To evaluate the decolonization rate of 
antibiotic resistant bacteria (ARB) for FMP-402 
versus placebo. 
 To determine the composite ARB infection rate 
for FMP-402 versus placebo.  
 To evaluate the time to VRE colonization and 
infection. 
 To evaluate the VRE decolonization rate for 
FMP-402 versus placebo among 
immunocompromised patients. 
 To evaluate VRE decolonization rate for FMP-
402 versus placebo among those 65 years and 
older. 
 
Exploratory Objectives: 
 To evaluate the microbiome disruption index 
(MDI) by 16s rRNA sequencing): MDI-community 
and MDI-species (day 3, day 10, week 4). 
 To evaluate the trends in VRE type/strain-level 
engraftment using whole genome sequencing 
among those colonized. 
 
 
 
 

 
 
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Study 
Endpoints/Outcome 
Measures:  
 
 
 
 
 
 
Primary Efficacy Outcome Measure: 
 Proportion of participants with VRE 
decolonization at day 10 (±3 days) after 
randomization.   
o VRE decolonization is defined by 
absence of VRE on stool culture using 
standard clinical laboratory 
techniques.  
Secondary Efficacy Outcome Measures: 
 Proportion of participants with VRE infection at 
day 3 (±2), day 10 (± 3), week 4 (±5 days) after 
randomization.    
 VRE infection will be defined as an 
associated bacteremia, urinary tract 
infection, or wound-related infection.    
 Proportion of participants with other antibiotic 
resistant bacteria (ARB) colonization at day 10 
(± 3) after randomization. ARB testing will be 
conducted with AcuitasTM MDRO test (OpGen) 
or similar PCR assay platform. 
  ARB will be defined as: a) carbapenem-
resistant enterobacteriaceae (CRE) by PCR; 
b) extended-spectrum beta-lactamase 
(ESBL) producing organism by PCR; c) C. 
difficile by PCR. 
 Proportion of participants with antibiotic 
resistant bacteria (ARB) colonization at day 10 
(± 3) after randomization. ARB testing will be 
conducted with AcuitasTM MDRO test (OpGen) 
or similar PCR assay platform. 
  ARB will be defined as: a) carbapenem-
resisant enterobacteriaceae (CRE) by PCR; 
b) extended-spectrum beta-lactamase 
(ESBL) producing organism by PCR; c) C. 
difficile by PCR; d) VRE  

 
 
12
 Proportion of participants with composite ARB 
infection at day 3 (±2), day 10 (± 3), week 4 (±5 
days) after randomization and time (in days) 
when ARB infection occurs. 
o ARB infection will be defined as VRE, CRE, 
ESBL or C. difficile-associated clinical 
infection in keeping with standard clinical 
practices.   
 Time (in days) from randomization until the 
study day when VRE colonization and infection 
occurs. 
 Proportion of participants with VRE 
decolonization among immunocompromised 
patients at day 10 (± 3) after randomization.  
 Proportion of participants with VRE 
decolonization among 65 years or older at day 
10 (± 3) after randomization.      
Primary Safety Outcome Measures: 
 Proportion of participants with an adverse 
event (AE) through day 10 (±3 days) after 
randomization. 
 Proportion of participants with a severe adverse 
event (SAE) through day 10 (±3 days) after 
randomization. 
 Proportion of participants with newly acquired 
transmissible infectious diseases which are 
considered adverse events of special interest 
(AESI) through day 10 (±3 days) after 
randomization.     
Secondary Safety Outcome Measures: 
 Proportion of participants with an AE through 
week 4 (±5 days) after randomization. 
 Proportion of participants with an SAE through 
week 4 (±5 days) after randomization. 

 
 
13
 Proportion of participants with newly acquired 
transmissible infectious diseases which are 
considered adverse events of special interest 
(AESI) through week 4 (±5 days) after 
randomization. 
 Proportion of participants with a SAE at month 6 
(±14 days) phone safety assessment after 
randomization. 
 
Exploratory Outcome Measures: 
 Proportion of participants with microbial 
engraftment assessed by MDI (MDI-community 
and MDI-species) measured by 16s ribosomal 
RNA at day 3, day 10, week 4 after 
randomization. 
 
 To evaluate the trends in VRE type/strain-level 
engraftment using whole genome sequencing 
among those colonized. 
 
 Description of 
Study Design: 
 
This multi-center, randomized, double blind, placebo-
controlled, parallel group trial will compare the 
efficacy and safety of oral FMP-402 to decolonize 
VRE. Participants will be 18 years of age or older with 
VRE on stool assessment within the last 14 days before 
randomization. Participants must meet inclusion 
criteria and have no exclusion criteria prior to 
randomization.  
Participants will then be randomized in a 1:1 ratio to 1 
of 2 treatment groups:  
 FMP-402: Encapsulated fecal microbiota sourced 
from human-derived microbes generated by 
healthy, screened donors. Dosing regimen will be 
a single 30 capsule dose. Patients will be nil per os 
(NPO) for a minimum of 2 hours prior to 
administration, and 1 hour post-administration.  

 
 
14
  Placebo: Oral placebo will be identical to the 
investigational product but will not contain 
product microbes. Placebo capsules will consist of 
glycerol and saline. Dosing regimen will be a single 
30 capsules dose. Patients will be NPO for a 
minimum of 2 hours prior to administration, and 1 
hour post-administration.  
Participants will be assessed for: 
a) Clinical and safety assessment will occur at day 
3 (±2) after randomization. This will use a 
structured case report form (CRF) at an in-
hospital assessment or telephone assessment if 
the patient is discharged.  
b) Clinical and safety assessment will occur at day 
10 (±3 days) after randomization. This will use a 
structured CRF at an in-hospital assessment or 
clinic assessment if the patient is discharged.  
c) Clinical and safety assessment will occur at 
week 4 (±5 days) after randomization. This will 
use a structured CRF at an in-hospital 
assessment or a telephone assessment if the 
patient is discharged.  
d) Safety follow-up will occur at month 6 (±14 
days) (structured telephone questionnaire) 
after randomization. All attempts will be made 
to complete safety follow-up for participants 
who received the study product, but 
discontinued participation in other study 
procedures, for the duration of the planned 
follow-up period.  
e) Unscheduled visit: At the time of a VRE infection 
(for participants who experience an infection) 
or a serious AE, an unscheduled visit will be 
attempted (optional). If this is not possible, 
clinical data will be collected from the 
patient’s most responsible physician, allied 
healthcare team and medical records. 

 
 
15
 
Stool samples will be collected at: 
a) Screening 
b) Enrollment  
c) Day 3 (±2) after randomization 
d) Day 10 (±3) after randomization 
e) Week 4 (±5) after randomization 
f) Unscheduled visit: At the time of VRE infection 
(for participants who experience an infection) 
or a serious AE. Stool samples will attempt to be 
collected (optional). Additionally, VRE isolates 
from the site of associated VRE infection 
(blood, urine, wound) will attempt to be 
collected (optional) during a suspected VRE 
infection if no residual sample that was 
obtained clinically is available.  
Information regarding the co-administration of any 
oral or parenteral antimicrobial agents or probiotics, 
any acid blockers (H2 blockers and PPIs) or any 
antiperistaltics will be recorded through follow-up. 
 
 

 
 
16
Estimated Time to 
Complete Enrollment: 
11 months 
Participant Inclusion Criteria 
Participants eligible to participate in this study must 
meet the following inclusion criteria: 
1. 
Adults 18 years or older at the time of 
enrollment. 
2. 
Able to provide signed and dated informed 
consent. 
3. 
Identified as VRE-positive by a stool culture 
within last 14 days.  
4. 
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. 
5. 
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: 
§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.  
*Includes, but is not limited to, barrier with additional 
spermicidal foam or jelly and vasectomy.  
 
Participant Exclusion Criteria 
Participants will not be able to participate if they 
meet any of the following exclusion criteria: 
 
1. Female patient who are pregnant, lactating or 
planning on becoming pregnant during study. 

 
 
17
Female patients of childbearing potential will 
undergo a pregnancy test, and be excluded 
from the study if positive.  
2. Inability (e.g. dysphagia) to or unwilling to 
swallow capsules.  
3. Active antibiotic-resistant bacteria (ARB) or 
gastrointestinal infection at time of enrollment. 
4. Patient received antibiotics or probiotics in the 
last 48 hours. Patients will be eligible to enroll if 
antibiotic therapy is discontinued for at 
minimum 48 hours prior to randomization. Does 
not include antibiotics used for prophylaxis or 
topical antibiotics.  
5. Requires continued antibiotic use or anticipates 
antibiotic use in the upcoming 4 weeks.  Does 
not include antibiotics used for prophylaxis or 
topical antibiotics. 
6. Unwilling to withhold probiotics for a minimum 
of 48 hours prior to providing a screening stool 
sample. 
7. Known or suspected toxic megacolon and/or 
known small bowel ileus. 
8. Major gastrointestinal surgery (e.g. significant 
bowel resection) within 3 months before 
enrollment. This does not include 
appendectomy or cholecystectomy.  
9. History of total colectomy or bariatric surgery. 
10. Admitted to or expected to an intensive care 
unit for medical reasons (not just boarding). 
Patients residing in a nursing home, long-term 
care facility or rehabilitation center may be 
enrolled. 
11. 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.        
12. Unable or unwilling to comply with protocol 
requirements. 
13. Expected life expectancy < 6 months  
14. Previous FMT or microbiome-based products at 
any time excluding this study. 
15. Patients with a history of severe anaphylactic or 
anaphylactoid food allergy. 

 
 
18
16. Solid organ transplant recipients  90 days post-
transplant or on active treatment for rejection. 
17. Neutropenia (500 neutrophils/mL) or other 
severe immunosuppression. Anti-TNF will be 
permitted. Patients on monoclonal antibodies 
to B and T cells. glucocorticoids, 
antimetabolites (azathioprine, 6-
mercaptopurine, methotrexate), calcineurin 
inhibitors (tacrolimus, cyclosporine) and 
mycophenolate mofetil may be enrolled only 
after consultation with the medical monitor.  
18. If at risk for CMV/EBV associated disease (at 
investigator’s discretion, e.g. 
immunocompromised), negative IgG testing for 
cytomegalovirus (CMV) or Epstein Barr Virus 
(EBV).  
19. A condition that would jeopardize the safety or 
rights of the subject, would make it unlikely for 
the subject to complete the study, or would 
confound the results of the study. 
 
 
 
 
 
C.1.  KEY ROLES  
 
OpenBiome Sponsor Representative: 
Majdi Osman, MD, MPH 
 
 
 
 
OpenBiome  
 
 
 
 
2067 Massachusetts Avenue, 3rd Floor 
 
 
 
 
Cambridge, MA 02140 
 
 
 
 
majdi@openbiome.org 
 
Principal Clinician:  
Monika Fischer MD, MSc (Co-PI; Site Lead) 
Indiana University, Department of Gastroenterology 
550 N. University Blvd., Suite 1710, Indianapolis, IN, 46202 
Email: mofische@iu.edu   
 
Nasia Safdar MD, PhD (Co-PI; Site Lead) 
University of Wisconsin, Department of Infectious 
Diseases  
 
 
 
 
UW Medicine Foundation Centennial Building 
 
 
 
 
1685 Highland Ave, Madison, WI, 53705 

 
 
19
Email: ns2@medicine.wisc.edu  
 
Medical Monitor:  
Majdi Osman MD, MPH 
 
 
 
 
2067 Massachusetts Avenue, 3rd Floor 
 
 
 
 
Cambridge, MA 02140 
Email: majdi@openbiome.org 
 
Scientific Leads 
 
Mark Smith PhD 
 
 
 
 
Finch Therapeutics Group 
 
 
 
 
200 Innerbelt Rd, Suite 400, Somerville, MA, 02143 
Email: mark@finchtherapeutics.com 
 
Eric Alm PhD 
MIT, Department of Biological Engineering  
Center for Microbiome Informatics & Therapeutics 
77 Massachusetts Ave, NE 47-379 
Cambridge, MA, 02139 
 
 
 
 
Email: ejalm@mit.edu 
 
 
 
 
 
Data Coordinating Center 
 
OpenBiome 
 
 
 
 
2067 Massachusetts Avenue, 3rd Floor 
 
 
 
 
Cambridge, MA 02140 
 
 
 
 
Chair: Scott Olesen, PhD 
 
 
 
 
Email: solesen@openbiome.org 
 
 
C. 2. BACKGROUND AND SCIENTIFIC RATIONALE 
 
C.2.1 Background  
 
VRE colonization as a public health threat  
Antibiotic-resistant organisms are a major public health threat with over 2 million 
Americans infected each year.1 Over half of these infections are transmitted in 
healthcare settings, where the widespread use of antibiotics selects for 
resistance and creates a stable pool of vectors, enabling the transmission of 
resistant organisms. Among resistant organisms, Vancomycin resistant 
enterococcus (VRE) is designated as a “serious threat” by the CDC and a major 
public health challenge both clinically and economically.1 There are an 
estimated 20,000 VRE cases and 1,300 associated deaths annually, which 
account for approximately 30% of all healthcare-acquired infections.1 Beyond 
the poor clinical outcomes among patients with VRE, there is a significant 
economic burden rooted in hospitalization costs driven by an increased length 

 
 
20
of stay and the use of more costly antimicrobial agents.2,3 Evidence suggests 
that a VRE infection increases a patient’s length of stay by 17 days, increases 
healthcare costs by $81,208 per patient and carries a median hospital mortality 
of 75% versus 29% in an otherwise matched control group.3  
The gastrointestinal tract is the reservoir for VRE, where it persists for a mean 
duration of 26 weeks.4 VRE colonization is a significant and growing problem in 
healthcare settings. A National Healthcare Safety Network survey (2006-2007) 
identified 33% of enterococci in US healthcare settings that were vancomycin 
resistant.5 A recent study suggested 8.8% (95% CI: 7.1-10.6%) of patients 
admitted to the ICU were VRE colonized and an additional 8.8% (95% CI: 6.9-
11.0%) will become colonized during their admission.6 Transplant patients are at 
higher risk of VRE colonization with up to 13.3% of liver transplant patients 
colonized.7,8  
VRE colonization is a prerequisite for VRE infection. A 2013 meta-analysis reports 
10.2% of VRE colonized patients will develop VRE infections compared to less 
than 2% of non-colonized patients.6,9 Additionally, VRE colonization is associated 
with higher mortality rates (24.6% versus 17.1%), a 25% increase in total admission 
days, and a 22% increase in hospital costs compared to matched controls.10 In 
addition to direct patient outcomes, patients colonized with VRE serve as a 
vector for VRE transmission, posing a risk to other vulnerable hospitalized patients 
and healthcare workers.11  
Current approaches to preventing transmission of VRE are both expensive and 
ineffective. Current standard of care does not include any intervention or 
technology to eliminate VRE in colonized patients. While contact precautions 
and isolation procedures are used to reduce transmission, lack of routine 
screening in many settings means that colonized patients may not be identified. 
Furthermore, such protocols can be costly to implement and challenging to 
ensure compliance, resulting in limited success. While reducing carriage of 
antibiotic-resistant bacteria (ARB) by prevention measures alone is possible, the 
CDC has reported that "nearly all studies reporting successful [multi-drug 
resistant organism] MDRO control employed a median of 7 to 8 different 
interventions concurrently or sequentially."12 Indeed, at high levels of 
colonization, prevention methods such as adhering to hand-washing protocols 
and antibiotic stewardship have been shown to have very limited, if any, impact 
on infection rates.11 For these reasons, there is a significant need for an 
inexpensive, safe intervention that can rapidly eliminate colonization and 
thereby interrupt the chain of transmission.  
C.2.2  Scientific Rationale  
 
Scientific principles support FMT for elimination of VRE colonization  

 
 
21
FMT, has been shown to be a highly effective and safe intervention for 
treatment of recurrent C. difficile infection (CDI). A recent systematic review and 
pooled analysis reports FMT was 83% effective in the treatment of recurrent CDI, 
with few reported adverse events.13 Although not fully elucidated, the 
hypothesized mechanism of FMT for CDI is that normal colonic microbiota 
outcompete and competitively exclude C. difficile.14  
In a recent commentary, Halpin and McDonald from the CDC highlighted the 
ecological principles and preliminary research suggesting that FMT may also be 
effective for eliminating enteric colonization with VRE.15 Similar to CDI, VRE 
colonization is known to be induced by microbial dysbiosis.16 Furthermore, 
vancomycin-resistance is known to carry a fitness defect for the organism 
carrying this gene, making it a prime target for a microbial intervention such as 
FMT, a procedure which infuses microbiota that will competitively exclude VRE. 
In vitro competition assays with enterococci have demonstrated a 4% fitness 
defect of VanA relative to sensitive enterococci.17 Similarly, expression of VanB-
type resistance results in reduced fitness in vitro, as well as reduced colonization 
ability and dissemination in gnotobiotic mice.18 More recently, genetic analyses 
identified two distinct evolutionary clades within E. faecium: Clade A, which 
includes subclade A1, commonly associated with hospital-acquired infections, 
and Clade B, associated with healthy human microbiota.19 When strains from 
clade A and clade B were co- introduced in a murine gastrointestinal tract, 
Clade B strains were better able to persist.20 Introduction of commensal 
microbiota may also help to eliminate VRE infection through direct effects such 
as nutrient depletion, or immune-mediated factors such as stimulation of TLR 
signaling and restoration of intestinal REGIIIγ expression.14,21  
Importantly, the role of FMT in eradicating VRE is also supported by FMT 
administration in murine models. Transfer of healthy colonic microbiota from 
antibiotic-naive mice to animals that have been treated with antibiotics and 
colonized with VRE reversed dysbiosis and eliminated VRE infection within 14 
days.22  
Clinical data supports FMT for elimination of ARB  
A number of case reports suggest that FMT may be able to decolonize patients 
colonized with ARB, including VRE. In a case report of FMT performed on a 
patient suffering from CDI along with high levels of VRE colonization and a 
history of VRE infection, Stripling and colleagues reported a reduction in 
Enterococcus along with dramatic clinical improvement, including no further 
VRE infections.23 Three case reports and a case series also reported 
decolonization of other ARB following FMT, including Carbapenem-resistant 
enterobacteriaceae (CRE), Extended-spectrum beta-lactamases (ESBL) and 
Methicillin-resistant Staphylococcus aureus (MRSA) enteritis.24–27 A recent study of 

 
 
22
20 patients with recurrent CDI treated with FMT by colonoscopy demonstrated a 
reduction in the overall abundance and diversity of resistance genes (resistome) 
in the gut microbiota post-FMT.28 Finally, among 8 recurrent CDI patients, VRE 
colonization density decreased by 2-6 logs 8 weeks after receiving a microbial 
therapeutic.29  
Evidence from a multi-center retrospective analysis  
Our group performed a multicenter retrospective analysis was performed using 
stool samples from recurrent CDI patients treated with FMT (n=31) or autologous 
FMT as a control from a previous trial (n=18). VRE was assessed using a PCR-
based assay targeting VanA (Acuitas® MDRO Gene Test). Colonization was 
defined as positive result at any dilution. VRE decolonization was defined as 
absence of VRE colonization post-FMT among a patient colonized with VRE pre-
FMT. Among this cohort, 16 patients were VRE colonized; 9/9 (100%) in the FMT 
group tested VRE-negative compared to 3/7 (43%) in the control group (p=0.02, 
Fisher's Exact Test). Two of these patients were treated with a single dose of 30 
FMT capsules, while the rest received FMT via traditional modalities (Appendix 
16.1). 
 
C.2.3  Potential Risks and Benefits  
 
There are risks associated with conducting this study; however, OpenBiome and 
its clinical affiliates possess a unique set of resources and expertise to mitigate 
these risks.  To clarify, the risks described below are generalized to FMT therapies 
that are delivered endoscopically.  There is no data available that is specific to 
FMT therapies that are delivered orally, with is the case for FMP-402.  It is 
expected that the risks of oral FMT therapy will be significantly reduced because 
many of the risks of FMT therapy delivered via endoscope are due to the 
procedure itself, not the drug that is delivered. 
 
 
C.2.3.1 
Potential Risks 
In the first randomized controlled trial on FMT, mild diarrhea (94%), abdominal 
cramping (31%) and belching (19%) were observed on the day of colonoscopic 
infusion; however, these symptoms resolved within 3 hours. Of note, in follow-up 
three patients who were treated with donor feces (19%) had constipation. No 
other adverse events related to the study treatment were reported.36 Recently, 
Osman et al presented effectiveness and safety data from a 2,050 patient 
cohort among OpenBiome recipients. The data suggests that among the 42 
suspected adverse events, 0 were definitely related to FMT material based on 
NIH criteria after a comprehensive investigation (Appendix 16.2). 
 
There is a paucity of data on long-term follow-up related to FMT. Brandt et al 
conducted a retrospective multi-center study (n=77) with a follow up varying 

 
 
23
between 3 to 68 months and reported 7 deaths. However, none related to 
FMT.37 A recent systematic review on the safety of FMT, suggests there are risk 
including: infectious (fever, bacteremia), autoimmune disease (peripheral 
neuropathy, Sjogren’s syndrome, idiopathic thrombocytopenic purpura and 
rheumatoid arthritis, inflammatory bowel disease flare among patients with 
ulcerative colitis) and other studies have suggested a link to metabolic 
syndrome.38, 39 However, comprehensive screening of donors should decrease 
any potential future risk. Donors are highly selected with only 2.8% of candidate 
donors qualifying to donate after screening both infectious disease and 
microbiome-mediated disease (Appendix 16.3). 
 
 
C.2.3.2 
Potential Benefits 
Studies have suggested that FMT may be able to decolonize patients colonized 
with VRE, and in turn, the prevention of VRE associated infection. As described 
previously, our group has demonstrated in a retrospective study that allogenic 
FMT is able to decolonize VRE significantly more than autologous FMT (Appendix 
16.1). Additionally, a number of case reports have reported decolonization of 
ARB following FMT, including carbapenem-resistant Enterobacteraciae (CRE), 
extended spectrum beta-lactamase (ESBL)-producing Escherichia coli and 
methicillin-resistant Staphylococcus aureus (MRSA) enteritis.23-29 
 
 
C.3. OBJECTIVES 
 
C.3.1 Study Objectives 
To investigate the efficacy and safety of FMP-402 to decolonize VRE. 
Primary Objectives: 
 To determine the VRE decolonization rate of FMP-402 versus placebo.  
 To evaluate the safety profile for FMP-402 versus placebo.  
 
Secondary Objectives: 
 To determine the VRE infection rate of FMP-402 versus placebo.  
 To evaluate the decolonization rate of antibiotic resistant bacteria (ARB) 
for FMP-402 versus placebo. 
 To determine the composite ARB infection rate for FMP-402 versus 
placebo.  
 To evaluate the time to VRE colonization and infection. 
 To evaluate the VRE decolonization rate for FMP-402 versus placebo 
among immunocompromised patients. 
 To evaluate VRE decolonization rate for FMP-402 versus placebo among 
those 65 years and older. 
 

 
 
24
Exploratory Objectives: 
 To evaluate the microbiome disruption index (MDI) by 16s rRNA 
sequencing): MDI-community and MDI-species (day 3, day 10, week 4). 
 To evaluate the trends in VRE type/strain-level engraftment using whole 
genome sequencing among those colonized. 
 
C.3.2 Study Outcome Measures 
 
 
C. 3.2.1 
Efficacy Outcome Measures 
 
 
Primary Efficacy Outcome Measure: 
 Proportion of participants with VRE decolonization at day 10 (±3 days) 
after randomization.   
o VRE decolonization is defined by absence of VRE on stool 
culture using standard clincal laboratory techniques.  
Secondary Efficacy Outcome Measures: 
 Proportion of participants with VRE infection at day 3 (±2), day 10 (± 3), 
week 4 (±5 days) after randomization.    
 VRE infection will be defined as an associated bacteremia, urinary 
tract infection, or wound-related infection.    
 Proportion of participants with other antibiotic resistant bacteria (ARB) 
colonization at day 10 (± 3) after randomization. ARB testing will be 
conducted with AcuitasTM MDRO test (OpGen) or similar PCR assay 
platform. 
  ARB will be defined as: a) carbapenem-resisant 
enterobacteriaceae (CRE) by PCR; b) extended-spectrum beta-
lactamase (ESBL) producing organism by PCR; c) C. difficile by PCR. 
 Proportion of participants with antibiotic resistant bacteria (ARB) 
colonization at day 10 (± 3) after randomization. ARB testing will be 
conducted with AcuitasTM MDRO test (OpGen) or similar PCR assay 
platform. 
  ARB will be defined as: a) carbapenem-resisant 
enterobacteriaceae (CRE) by PCR; b) extended-spectrum beta-
lactamase (ESBL) producing organism by PCR; c) C. difficile by PCR; 
d) VRE  

 
 
25
 Proportion of participants with composite ARB infection at day 3 (±2), 
day 10 (± 3), week 4 (±5 days) after randomization and time (in days) 
when ARB infection occurs. 
o ARB infection will be defined as VRE, CRE, ESBL or C. difficile-
associated clinical infection in keeping with standard clinical 
practices.   
 Time (in days) from randomization until the study day when VRE 
colonization and infection occurs. 
 Proportion of participants with VRE decolonization among 
immunocompromised patients at day 10 (± 3) after randomization.  
 Proportion of participants with VRE decolonization among 65 years or 
older at day 10 (± 3) after randomization.      
 
 
C.3.2.2 
Safety Outcome Measures 
Primary Safety Outcome Measures: 
 Proportion of participants with an AE through day 10 (±3 days) after 
randomization. 
 Proportion of participants with a SAE through day 10 (±3 days) after 
randomization. 
 Proportion of participants with newly acquired transmissible infectious 
diseases which are considered adverse events of special interest (AESI) 
through day 10 (±3 days) after randomization.     
Secondary Safety Outcome Measures: 
 Proportion of participants with an AE through week 4 (±5 days) after 
randomization. 
 Proportion of participants with an SAE through week 4 (±5 days) after 
randomization. 
 Proportion of participants with newly acquired transmissible infectious 
diseases which are considered adverse events of special interest (AESI) 
through week 4 (±5 days) after randomization. 
 Proportion of participants with a SAE at month 6 (±14 days) phone safety 
assessment after randomization. 

 
 
26
 
 
C.3.2.3 
Exploratory Outcome Measures 
 Proportion of participants with microbial engraftment assessed by MDI 
(MDI-community and MDI-species) measured by 16s ribosomal RNA at 
day 3, day 10, week 4 after randomization. 
 To evaluate the trends in VRE type/strain-level engraftment using whole 
genome sequencing among those colonized. 
 
C.4. STUDY DESIGN 
 
This multi-center, randomized, double blind, placebo-controlled, parallel group 
trial will compare the efficacy and safety of oral FMP-402 to decolonize VRE. It 
will be performed in collaboration with Indiana University and the University of 
Wisconsin. A study schematic can be found in the Appendix 17.1.   
 
Study Population: Participants will be 18 years of age or older with VRE on stool 
assessment within the last 14 days before randomization. Participants must meet 
inclusion criteria (Section 5.1) and have no exclusion criteria (Section 4.2) prior to 
randomization.  
Subjects will then be randomized in a 1:1 ratio with random permuted blocks 
(size of 2 or 4) at each site to either the intervention or control group. 
Intervention: FMP-402 - Encapsulated fecal microbiota sourced from human-
derived microbes generated by healthy, screened donors. Dosing regimen will 
be a single 30 capsule dose. Patients will be nil per os (NPO) for a minimum of 2 
hours prior to administration, and 1 hour post-administration.  Patients may 
consume water during capsule administration. 
 
Dosing Rationale 
The dosing rationale is driven by the successful VRE decolonization of 2 patients 
with recurrent CDI following a single dose of 30 OpenBiome FMT capsules and 
the success of this dose among recurrent CDI patients presented by our group 
(Appendix 16.1). 
 
Capsule Tolerability 
Clinically, there have been no reported concerns regarding the number of 
administered capsules among >300 recurrent CDI patients treated, even among 
elderly and medically complex patients. Specifically, elderly patients who 
commonly manage polypharmacy find tolerability of 30 capsules easier than 
younger patients without experience administering pills. Overall, mean time of 
30 capsule administration is approximately 20 minutes (range 10-30 minute) 
(Allegretti, unpublished data). To mitigate safety risks with capsules, in an eligible 

 
 
27
patient thought to be a capsule candidate, a single inert ‘test capsule’ is 
administered at screening under direct observation, and any evidence of 
dysphagia is a contraindication for capsule administration. 
 
Control: Placebo - Oral placebo will be identical to the investigational product 
but will not contain product microbes. Placebo capsules will consist of glycerol 
and saline. Dosing regimen will be a single 30 capsules dose. Patients will be 
NPO for a minimum of 2 hours prior to administration, and 1 hour post-
administration. 
 
C.5. STUDY ENROLLMENT AND WITHDRAWAL  
 
C.5.1  Participant Inclusion Criteria  
Participants eligible to participate in this study must meet the following inclusion 
criteria: 
1. Adults 18 years or older at the time of enrollment. 
2. Able to provide signed and dated informed consent. 
3. Identified as VRE-positive by a stool culture within last 14 days.  
4. 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. 
5. 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: §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. 
 
C.5.2  Participant Exclusion Criteria  
Participants will not be able to participate if they meet any of the following 
exclusion criteria: 
 
1. Female patient who are pregnant, lactating or planning on becoming 
pregnant during study. Female patients of childbearing potential will 
undergo a pregnancy test, and be excluded from the study if positive. 
2. Inability (e.g. dysphagia) to or unwilling to swallow capsules.  

 
 
28
3. Active antibiotic-resistant bacteria (ARB) or gastrointestinal infection at 
time of enrollment. 
4. Patient received antibiotics in the last 48 hours. Patients will be eligible to 
enroll if antibiotic therapy is discontinued for at minimum 48 hours prior to 
randomization. Does not include antibiotics used for prophylaxis or topical 
antibiotics.  
5. Requires continued antibiotic use or anticipates antibiotic use in the 
upcoming 4 weeks.  Does not include antibiotics used for prophylaxis or 
topical antibiotics.  
6. Unwilling to withhold probiotics for a minimum of 48 hours prior to 
providing a screening stool sample. 
7. Known or suspected toxic megacolon and/or known small bowel ileus. 
8. Major gastrointestinal surgery (e.g. significant bowel resection) within 3 
months before enrollment. This does not include appendectomy or 
cholecystectomy.  
9. History of total colectomy or bariatric surgery. 
10. Admitted to or expected to an intensive care unit for medical reasons 
(not just boarding). Patients residing in a nursing home, long-term care 
facility or rehabilitation center may be enrolled. 
11. 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.        
12. Unable or unwilling to comply with protocol requirements. 
13. Expected life expectancy < 6 months  
14. Previous FMT or microbiome-based products at any time excluding this 
study. 
15. Patients with a history of severe anaphylactic or anaphylactoid food 
allergy. 
16. Solid organ transplant recipients  90 days post-transplant or on active 
treatment for rejection. 
17. Neutropenia (500 neutrophils/mL) or other severe immunosuppression. 
Anti-TNF will be permitted. Patients on monoclonal antibodies to B and T 
cells. glucocorticoids, antimetabolites (azathioprine, 6-mercaptopurine, 
methotrexate), calcineurin inhibitors (tacrolimus, cyclosporine) and 
mycophenolate mofetil may be enrolled only after consultation with the 
medical monitor. 
18. If at risk for CMV/EBV associated disease (e.g immunocompromised), 
negative IgG testing for cytomegalovirus (CMV) or Epstein Barr Virus (EBV).  
19. A condition that would jeopardize the safety or rights of the subject, 
would make it unlikely for the participant to complete the study, or would 
confound the results of the study. 
 
C.5.3  Treatment Assignment Procedures  

 
 
29
 
 
C.5.3.1 
Randomization Procedures  
 
 
Participants who fulfill the criteria for randomization, will be randomized on a 1:1 
basis with a with random permuted blocks (size of 2 or 4) to receive FMP-402 or 
placebo. Participant’s randomization will be carried out by a bioinformatician 
based at OpenBiome using random number generation software to create a 
randomization schedule. 
 
 
C.5.3.2 
Masking Procedures  
 
This is a double blinded placebo controlled trial where both the participant and 
treating physicians will be blinded. FMP-402 or placebo will be dispensed by 
OpenBiome thereby maintaining blinding of study clinician. Packaging will be 
identical and consist of the same saline and glycerol buffer used in FMT 
processing without the addition of microbiota. 
 
Under normal circumstances, the blind should not be broken. The blind should 
be broken only if specific emergency treatment would be dictated by providing 
the treatment the participant was receiving.  In such cases, the site PI must 
contact the Medical Monitor to request that the blind be broken. For 
participants who require unblinding, this information will be captured in the case 
report form (CRF). 
The randomization schedule will be maintained by OpenBiome. Study 
participants or legal guardians will remain blinded and not be provided any 
information until all participants have completed the trial. 
 
 
C.5.3.3 
Reasons for Withdrawal  
A participant may withdraw from the study at any time for any reason, without 
any consequence. A participant may be withdrawn from the study by the site PI 
for the following reasons: 
Adverse event that may make it no longer in the best interest of the subject to 
continue participation in the study 
Participant choice (withdrawal of consent) 
Protocol violation/non-compliance 
Pregnancy 
Lost to follow up 
Other (must be noted) 
  

 
 
30
 
C.5.3.4 
Handling Withdrawals  
The primary reason for withdrawal from the study will be recorded on the Study 
Status CRF page. Participants will be encouraged to complete the Early 
Termination Visit. The Early Termination Visit procedures are listed. Although 
participants are free to withdraw at any time, participants will be encouraged 
to remain in the study for follow-up safety evaluation. Every attempt should be 
made to follow all AEs and SAEs ongoing at the time of early withdrawal to 
resolution or until stabilized. If possible, a final stool sample will be collected at 
the Early Termination Visit. Intention-to-treat analysis will be utilized according to 
best practices in clinical trials. Attempts will be made to complete safety follow-
up for all subjects who have received the study product, including those who 
have discontinued participation in other study procedures, for the duration of 
the planned follow-up period. 
Participants who are withdrawn from the study after randomization but before 
intervention or placebo will be replaced. Possible reasons for participant 
withdrawal after randomization include but are not limited to: 
 Participants who are started on a new course of antibiotics after 
randomization and before intervention/placebo 
 Unrelated participant death  
 
 
C.5.3.5 
Termination of Study  
 
In the unlikely event that significant safety concerns arise, the PIs can terminate 
or halt the study pending review by the DSMB. In addition, this study may be 
halted early based on the DSMB charter or FDA recommendations. 
 
C.6. STUDY INTERVENTION/INVESTIGATIONAL PRODUCT 
 
C.6.1  Study Product Description   
 
FMP-402 is encapsulated fecal microbiota sourced from human-derived 
microbes. The human source generating the fecal microbes has been 
extensively screened for infectious pathogens and microbiome mediated 
diseases using a standardized process (found in OpenBiome’s BBMF # 15543, 
Section F). Additionally, the capsule delivery vehicle enables targeted 
deposition of the investigational active pharmaceutical ingredient into the 
colon.  
 
C.6.2  Formulation  
 
C.6.2.1 
Encapsulated fecal microbiota preparation (formulation FMP-
402) 

 
 
31
This formulation is encapsulated fecal microbiota sourced from human-derived 
microbes generated by healthy, screened donors, as described in OpenBiome’s 
 
 
 
 
 
 
 
 
 
 
 
 
 
BBMF # 17300
 
. 
 
 
C.6.2.2 
Placebo 
Placebo capsules will be identical in appearance to FMP-402 capsules but will 
not have human feces, 
 
 
 
 
processed as described in OpenBiome’s BBMF # 
17300
 
. 
 
C.6.3.  
Product Storage and Stability  
 
Produced material will be stored at -80°C and each unit will have a date of 
production printed on it for tracking purposes. Studies have been conducted to 
ensure long-term bacterial viability following the freezing process based on 
studies conducted by Hamilton et. al and Youngster et. al.40,41 Local site storage 
at -20°C will be permitted for up to 6 months.  
 
FMP-402 is currently undergoing stability testing, therefore expiration dates will 
not be provided with each unit. Instead, storage requirements will be provided 
via correspondence from the manufacturing company, Finch Therapeutics. 
Results from ongoing stability testing will be provided by Finch Therapeutics to 
partner sites, through OpenBiome, on an anticipated monthly basis. If units are 
determined to be unstable, Finch Therapeutics will communicate with 
OpenBiome to destroy the relevant units. 
 

 
 
32
C.6.4  Dosage, Preparation and Administration of Study 
Intervention/Investigational  Product 
Participants will receive a single dose of 30 FMP-402 or placebo capsules. The 
dosing rationale is driven by the successful VRE decolonization for 2 patients with 
recurrent CDI and co-colonization of VRE following a single dose of 30 
OpenBiome FMT capsules. Participants will undergo capsule administration by 
the following process: 
 Document Review: Confirmation/review of exclusion 
criteria/contraindications as previously described. 
 Safety Capsules: Direct observed capsule test, where participants will 
ingest one inert, size 00 ‘safety’ capsule under direct supervision of the 
study physician/nurse. 
 Dietary instructions: Patients should maintain a clear liquid diet the day of 
administration and should fast (NPO) for a minimum of 2 hours prior to 
administration 
 Capsule administration:  
a. Patient should ingest 30 capsules (FMP-402 or placebo) under the 
direct observation of a physician/nurse.  Patients may have water 
during capsule administration. 
b. Patient should ingest capsules after extraction from freezer, and no 
longer than 60 minutes after removal. 
c. Patients should remain fasting (NPO) for 1 hour following ingestion 
but may then return to a full diet.  
 
C.6.5  Accountability Procedures for the Study Intervention/Investigational 
Product 
 
The site principal investigator (PI) (or designee) will maintain an accurate record 
of the receipt of the investigational materials as shipped, including the date 
received. One copy of this receipt will be returned to OpenBiome when the 
contents of the investigational materials shipment have been verified. In 
addition, the unblinded laboratory technician based at OpenBiome will 
maintain a log of all clinical trial materials (FMP-402 and placebo) dispensed. 
This clinical trial material accountability record will be available for inspection at 
any time.  
 
C.6.6  Modification of Study Intervention/Investigational Product for a Participant 
 
If the participant is unable to complete the full dose of FMP-402 or placebo, the 
following modification will take place. The dose will be recorded and the 
remainder of capsules will be offered to participant the same day at the 
discretion of the treating physician. Intention-to-treat analysis will be utilized 
according to best practices in clinical trials. 

 
 
33
 
C.6.7  Assessment of Participant Compliance with Study 
Intervention/Investigational Product 
 
FMP-402 or placebo capsules will be consumed under direct supervision of study 
staff. 
 
C.6.8  Concomitant Medications/Treatments  
 
Given the participants with VRE colonization and who are most at risk for VRE 
infection are patients with multiple comorbidities, all medications will be 
accepted in this study, at the discretion of the treating physician. This includes, 
but is not limited to: 
1. Anti-hypertensive therapies  
2. Heart failure medications 
3. Diuretics 
4. Laxatives 
5. Topical medications 
6. Anti-depressants 
7. Statins 
8. Diabetic medication 
9. NSAID 
10. Acid-blockers 
11. Anticoagulants 
12. Opioids 
13. Iron supplementation 
14. Anti-TNF will be permitted. Patients on monoclonal antibodies to B and T 
cells. glucocorticoids, antimetabolites (azathioprine, 6-mercaptopurine, 
methotrexate), calcineurin inhibitors (tacrolimus, cyclosporine) and 
mycophenolate mofetil may be enrolled only after consultation with the 
medical monitor. 
 
Participants will be eligible to enroll 48 hours after their last dose of antibiotics; 
however, topical and prophylactic antibiotics will be permitted. Participants are 
also eligible to enroll 48 hours after their last dose of probiotics.    
 
C.7. STUDY SCHEDULE 
 
A schematic representation of the study schedule can be found in Appendix 
17.2.  
 
C.7.1  Screening (Visit 1)  
Screening will take place with both passive and active systems. From a passive 
system perspective, VRE positive stool samples will be identified by each sites 

 
 
34
laboratory and compiled lists of candidate participants distributed for study 
evaluation. Patients previously marked VRE positive in the medical records will 
also be approached for study evaluation. From an active system perspective, 
individuals at high-risk for VRE colonization including but not limited to those 
discharged from ICU to ward after a greater than 3 days stay, undergoing 
chronic dialysis, have an oncology or stable organ transplant history will be 
approached for consent to screen for VRE.42 Awareness about the study will be 
raised by standard, approved recruitment techniques and discussions with key 
stakeholdes including clinical microbiology, infectious diseases and laboratory 
medicine teams.  Past VRE positive patients in the health system may also be 
eligible to participate, provided that they fulfill eligibility criteria, and will be 
contacted by the research staff and invited to participate via an invitation 
letter/telephone follow-up call (UW) or with an invitation via telephone call (IU).  
 
If patients are interested in participating in the study, and have been 
discharged from the hospital, stool samples can be submitted for screening for 
VRE colonization with a waiver of consent documentation. Patients being seen 
in any ambulatory setting in the health system are eligible if they are known to 
be VRE or at risk of having VRE. 
 
If on probiotics at time of screening then patients will be advised to withhold 
probiotics for 48 hours prior to providing a sample. 
 
C.7.2  Enrollment and Intervention Administration (Visit 2) 
 
 
C.7.2.1 
Enrollment  
All VRE positive individuals will be equally eligible for enrollment into this study, 
provided they fulfill the eligibility criteria.  A detailed consent process will be 
administered by study staff who are trained in consenting procedures. Potential 
participants who fulfill the eligibility criteria will undergo a detailed clinical 
assessment by study staff which will include demographics, medical history, 
dietary information and current medication. Data from this assessment may be 
from the participant/substitute decision maker, healthcare team and/or 
medical record.  
 
 Data points at enrollment study visit: 
o General parameters: 
▪ Date of birth 
▪ Sex 
▪ Smoking status 
▪ Race  
▪ Ethnicity 
o Past medical history and allergies  

 
 
35
▪ A focused collection of past medical history (including 
common infections) 
▪ Charlson’s Comorbidity Index 
o Current medication list 
o Antibiotic history  
o Dietary history 
o Social history 
▪ Country of birth, duration living in the U.S. 
o Travel history 
o Examination findings 
▪ Vital signs: temperature, height (measured or abstracted 
from medical records), weight (measured or abstracted from 
medical records), heart rate, blood pressure, waist 
circumference, respiration rate, oxygen saturation 
▪ Relevant review of systems 
o Overall assessment of current health 
 Sample collection 
o Positive VRE stool sample collected within the previous 14 days to 
the Enrollment visit using a stool collection kit/hat or a rectal swab 
 Formal aspects 
o Informed consent procedure 
o Verification of inclusion and exclusion criteria including 
administering ‘test’ capsule and documenting: 
▪ Safe to receive intervention (yes/no) 
▪ Able to swallow test capsule (yes/no) 
- 
Participants that are at risk for EBV/CMV associated disease (at 
investigator’s discretion, e.g. immunocompromised) will undergo EBV and 
CMV IgG testing, if double positive status (EBV+/CMV+) not already 
documented. If CMV/EBV testing cannot be conducted at the university 
hospital, non-university hospitals may be used to perform the testing.  Any 
costs associated with CMV/EBV testing to determine eligibility for this study 
will be paid by study funds; the patient will not incur any charges.  The 
research team will send results from outside laboratories via mail or secure 
fax from outside laboratories and will store the results in the patients’ study 
chart, if applicable. If either is negative, the patient will be excluded. 
CMV/EBV testing may occur at the screening or enrollment visit. 
 
 
C.7.2.2 
Intervention Administration (Day 0) 
 

 
 
36
After baseline clinical asssessment, stool sample has been collected and female 
participants of childbearing potential have been administered a urine 
pregnancy test and reported negative, the participant is eligible to undergo 
adminstration of the intervention (FMP-402 or placebo) in accordance with the 
randomization schedule. The intervention will be administered by the blinded 
study staff and the participant observed for 30 minutes following administration. 
In addition to the previously described baseline clinical assessment, pre-
intervention vital signs (temperature, blood pressure, heart rate) and immediate 
post-intervention assessment will take place including any overt safety concerns 
and post-intervention vital signs if clinically indicated at the discretion of the 
study staff. Participants will be provided with information regarding monitoring 
for minor and severe adverse event related to the intervention administration. 
Participants will be encouraged to report any concerning symptoms to staff. 
Oral nutrition may commence 1 hour post-capsules administration. 
 
C.7.3  Follow-Up (Visit 3, 4, 5, 6) 
 
At day 3 and day 10 post-intervention, the study physician/nurse will perform a 
clinical assessment and administer a study questionnaire, which will specifically 
inquire about solicited and unsolicited symptoms of AEs. Access to the medical 
records may be utilized to capture salient changes in healthcare status. 
Participants will have a stool sample within each follow-up window. 
 
At week 4 and month 6 study visits, participants will undergo a similarly 
structured study visit which includes a clinical assessment and AE focused 
questionnaire. 
 
 
C.7.3.1 
Visit 3 - Day 3 (±2 days) 
Clinical and safety assessment will occur at day 3 (±2 days) after randomization. 
This will use a structured CRF at an in-hospital assessment or telephone 
assessment if the patient is discharged and unable to attend clinic. If this 
assessment is done over the phone, participants will be given instructions to mail 
in or drop off their stool sample, depending on their preference. 
 
 Clinical and safety assessment by study nurse / physician, specifically 
evaluating adverse events related to the intervention. 
 Data collection at visit: 
o Interim medical history with focus on infectious diseases  
o Concomitant medication 

 
 
37
o Significant changes in diet 
o Changes in stool consistency (Bristol Stool Scale) and frequency 
o Clinical evaluation using standard, structured assessment 
o Vital signs [if in-patient]: Temperature, heart rate, blood pressure, 
weight (will be obtained from medical record, if available, rather 
than collected specifically for research purposes), waist 
circumference, respiration rate, oxygen saturation 
o General health status 
o Adverse events (NIH criteria)  
 Stool collection for 16S sequencing and ARB PCR 
 
 
C.7.3.2 
Visit 4 - Day 10 (±3 days) 
Clinical and safety assessment will occur at day 10 (±3 days) after 
randomization. This will use a structured CRF at an in-hospital assessment or clinic 
assessment if the patient is discharged and unable to attend clinic.  
 
 Clinical and safety assessment by study nurse / physician, specifically 
evaluating adverse events related to the intervention. 
 Data collection at visit: 
o Interim medical history with focus on infectious diseases  
o Concomitant medication 
o Significant changes in diet 
o Changes in stool consistency (Bristol Stool Scale) and frequency 
o Clinical evaluation using standard, structured assessment 
o Vital signs [if in-patient]: Temperature, heart rate, blood pressure, 
weight (will be obtained from medical record, if available, rather 
than collected specifically for research purposes), waist 
circumference, respiration rate, oxygen saturation 
o General health status 

 
 
38
o Adverse events (NIH criteria)  
 Stool collection for 16S sequencing and ARB PCR 
 
 
C.7.3.3 
Visit 5 – Week 4 (±5 days)  
Clinical and safety assessment will occur at week 4 (±5 days) after 
randomization. This will use a structured CRF at an in-hospital/clinic assessment or 
a telephone assessment if the patient is discharged and unable to attend clinic.  
 
 Clinical and safety assessment by study nurse / physician, specifically 
evaluating adverse events related to the intervention. 
 Data collection at visit: 
o Interim medical history with focus on infectious diseases  
o Concomitant medication 
o Significant changes in diet 
o Changes in stool consistency (Bristol Stool Scale) and frequency 
o Clinical evaluation using standard, structured assessment 
o Vital signs [if in-patient]: Temperature, heart rate, blood pressure, 
weight (will be obtained from medical record, if available, rather 
than collected specifically for research purposes), waist 
circumference, respiration rate, oxygen saturation  
o General health status 
o Adverse events (NIH criteria)  
 Stool collection for 16S sequencing and ARB PCR 
 
 
C.7.3.4 
Visit 6 - Month 6 (±14 days) 
Safety follow-up will occur at month 6 (±14 days) (structured telephone 
questionnaire) after randomization. 
 
 Clinical and safety assessment by study nurse / physician, specifically 
evaluating adverse events related to the intervention. 

 
 
39
 Data collection at visit: 
o Interim medical history with focus on infectious diseases  
o Concomitant medication 
o Significant changes in diet 
o Changes in stool consistency (Bristol Stool Scale) and frequency 
o Clinical evaluation using standard, structured assessment 
o General health status 
o Adverse events (NIH criteria)  
 
C.7.4  Early Termination Visit  
 
In the case of an early termination, study staff will complete an ‘Early 
Termination CRF’, if possible, and the following will be assessed: 
 
 Clinical and safety assessment by study nurse / physician, specifically 
evaluating adverse events related to the intervention. 
 Data collection at visit: 
o Interim medical history with focus on infectious diseases  
o Concomitant medication 
o Significant changes in diet 
o Changes in stool consistency (Bristol Stool Scale) and frequency 
o Clinical evaluation using standard, structured assessment 
o Vital signs [if in-patient]: Temperature, heart rate, blood pressure, 
weight (will be obtained from medical record, if available, rather 
than collected specifically for research purposes), waist 
circumference, respiration rate, oxygen saturation 
o General health status 
o Adverse events (NIH criteria)  
 Stool collection for 16S sequencing and ARB PCR 

 
 
40
 
Participants will be asked if study staff may follow participants passively using 
their medical records if clinical follow-up and/or stool collection is not viable. 
 
All attempts will be made to complete safety follow-up for participants who 
received the study product, but discontinued participation in other study 
procedures, for the duration of the planned follow-up period. 
 
C.7.5  Unscheduled Visit   
At the time of VRE infection (for participants who experience an infection) or 
serious AE. Study staff will attempt to collect a stool sample (optional). 
Additionally, VRE isolates from the site of associated VRE infection (blood, urine, 
wound) will attempt to be collected (optional) for participants suspected to 
have a VRE infection.  
 
x Study staff will complete an infection CRF for each ARB infection episode. 
This CRF will be used to track duration of the episode, type, dosage and 
duration of antibiotics.   
x Data points for infectious episode 
R Date  
R Preliminary diagnosis 
R Antibiotic/s  
⿑ Name 
⿑ Formulation (IV, suspension, capsules) 
⿑ Dosage 
⿑ Prescribed duration 
⿑ Final (actual) duration of antibiotics 
⿑ Change in antibiotics regime  
R Concomitant medication (Name, dose, route of administration, 
duration) 
R Hospital admission (yes/no) 
⿑ Name of facility 
⿑ Department where participant was admitted (ward / step 
down/ ICU) 
⿑ Relevant medical procedures 
 Colonoscopy (including preparation) 
 Intestinal surgery 
 Dialysis 
 Other 
R Final diagnosis 
 

 
 
41
 For a serious AE (section 8.5), the details of reporting are outlined in 
Section 8.7 
 
C.7.6  Stool Collection  
Stool samples will be collected (or rectal swabs in keeping with VRE standard of 
care). If the visit is conducted over the telephone, participants will be given 
instructions on how to mail in or drop off their stool sample, depending on their 
preference: 
a) Screening (only if status of VRE colonization is not already known) 
b) Enrollment – if needed (VRE positive screened sample 14 days prior to 
Enrollment visit is acceptable). 
c) Day 3 (±2) after randomization 
d) Day 10 (±3) after randomization 
e) Week 4 (±5) after randomization 
f) At the time of VRE infection (for subjects who experience an infection) or 
serious AE. Stool samples will attempt to be collected (optional). 
Additionally, VRE isolates from the site of associated VRE infection (blood, 
urine, wound) will attempt to be collected (optional) for participants 
suspected to have a VRE infection. 
 
C.8. ASSESSMENT OF SAFETY  
 
Safety will be assessed by the frequency and severity of adverse events (AE) 
C.8.1  Definition of an Adverse Event (AE) 
 
Adverse events (AEs) will be recorded at each regular scheduled study visit in 
the study patient record (source document) as well as on a specific AE case 
report form (CRF). 
 
An AE is any untoward medical occurrence in a study patient or clinical 
investigation participant administered a pharmaceutical product. An AE does 
not necessarily have a causal relationship with this treatment. An AE can 
therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not related to the medicinal product, e.g.: 
 any new clinical diagnosis 

 
 
42
 any symptom that requires medical clarification or leads to in-patient 
admission (surgery or accident) 
 any suspected adverse drug reaction (ADR) 
 any symptom that appears on the study patient’s medical records 
 any event related in time with the application of the study medication 
and affecting the health of the study patient (including laboratory value 
changes) 
If there is any doubt as to whether a clinical observation is an AE, the event 
should be reported. AEs must be graded for severity and relationship to study 
product. Adverse events of special interest (AESI) will be defined as newly 
acquired transmissible infectious diseases (e.g. newly acquired bacteremia). 
 
C.8.2 NIH Grading of Severity of the Event 
AEs will be assessed by the clinician using the NIH Common Terminology Criteria 
for Adverse Events (CTCAE) defined grading system (Appendix 17.3). Briefly, the 
criteria for estimating adverse event severity grade:  
 Grade 1, Mild: Asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
 Grade 2, Moderate: Minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental activities of daily living (ADL). 
 Grade 3, Severe: Severe or medically significant but not immediately life-
threatening; hospitalization or prolongation of hospitalization indicated; 
disabling; limiting self-care ADL. 
 Grade 4, Life threatening: Places the patient or subject at immediate risk of 
death. It does not include an adverse event that, had it occurred in a more 
severe form, might have caused death. 
 Grade 5, Death 
 
 
C.8.3 Relatedness 
 
All adverse events, regardless of relatedness should be reported. All adverse 
events should be evaluated for relatedness when reporting and documenting on 
the CRF.  
The following guidelines of relatedness are used modified from the NIH guidelines: 
☐ Related:  The adverse event is related to the FMT material – i.e. an event that 
follows a reasonable temporal sequence from administration of the FMT material, 
follows a known or expected response pattern to the FMT material, that is 

 
 
43
confirmed by improvement on stopping and reappearance of the event on 
repeated exposure and that could not be reasonably explained by the known 
characteristics of the patient’s clinical state. 
☐ Not Related:  The adverse event is not related to the FMT material. -  i.e. another 
cause of the event is most plausible; and/or a clinically plausible temporal 
sequence is inconsistent with the onset of the event and the study intervention 
and/or a causal relationship is considered biologically implausible.  
 
C.8.4 Solicited Adverse Events after FMT 
In addition to open-ended questions on adverse events meeting the above 
definitions, specific potential adverse events will be inquired about during the 
follow up period (following intervention through to 6 months after 
randomization): 
Symptom that 
is clinically 
more severe 
than 
participant’s 
baseline 
Severity 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Fever* 
38.0 - 39.0 
degrees C  
(100.4 - 102.2 
degrees F) 
>39.0 - 40.0 
degrees C 
(102.3 - 104.0 
degrees F) 
>40.0 degrees 
C (>104.0 
degrees F) for 
<=24 hrs 
>40.0 degrees 
C (>104.0 
degrees F) for 
>24 hrs 
Death 
Diarrhea 
Increase of 
<4 stools per 
day over 
baseline pre-
FMT; mild 
increase in 
ostomy 
output 
compared to 
baseline 
Increase of 4 
- 6 stools per 
day over 
baseline; 
moderate 
increase in 
ostomy 
output 
compared to 
baseline; 
limiting 
instrumental 
ADL 
Increase of 
>=7 stools per 
day over 
baseline; 
incontinence; 
hospitalization 
indicated; 
severe 
increase in 
ostomy 
output 
compared to 
baseline; 
limiting self-
care ADL 
Life-
threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
Vomiting 
1 - 2 episodes 
(separated 
by 5 minutes) 
in 24 hrs 
3 - 5 episodes 
(separated 
by 5 minutes) 
in 24 hrs 
>=6 episodes 
(separated 
by 5 minutes) 
in 24 hrs; tube 
feeding, TPN 
Life-
threatening 
consequences; 
urgent 
Death 

 
 
44
 
* Participants will be given a digital thermometer at the time of enrollment. 
 
C.8.5  Serious Adverse Events 
 
An adverse event or suspected adverse reaction is considered “serious” if, in the 
view of either the site PI or lead PI, it results in any of the following outcomes: 
 Death 
 Life-threatening adverse event* 
 Inpatient hospitalization or prolongation of existing hospitalization 
 A congenital anomaly/birth defect 
 Persistent or significant disability or incapacity or substantial disruption of 
the ability to conduct normal life function 
 Important medical events that, may not result in death, be life-
threatening, or require hospitalization may be considered when, based 
or 
hospitalization 
indicated 
intervention 
indicated 
Abdominal 
Pain 
 
Mild pain  
Moderate 
pain; limiting 
instrumental 
activities of 
daily life 
Severe pain; 
limiting self 
care activities 
of daily life 
n/a 
n/a 
Bloating 
 
No change in 
bowel 
function or 
oral intake 
Systemic, 
decreased 
oral intake; 
change in 
bowel 
function 
n/a 
n/a 
n/a 
Constipation 
Occasional 
or 
intermittent  
symptoms; 
occasional  
use of stool 
softeners,  
laxatives, 
dietary  
modification, 
or enema  
 
Persistent 
symptoms 
with  
regular use of 
laxatives  
or enemas 
indicated; 
limiting 
instrumental 
activities of 
daily life 
 
Symptoms 
interfering  
with self-care 
activities of 
daily life; 
obstipation  
with manual 
evacuation  
indicated  
 
Life-
threatening 
consequences 
(e.g. 
obstruction, 
toxic 
megacolon); 
urgent 
intervention 
indicated 
Death 

 
 
45
upon appropriate medical judgement, they may jeopardize the patient 
or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition 
*Life-threatening adverse event.  An adverse event is considered “life-
threatening” if, in the view of either the site PI or lead PI, its occurrence places 
the patient or participant at immediate risk of death.  It does not include an 
adverse event which, had it occurred in a more severe form, might have 
caused death. 
Any adverse event or suspected adverse reaction that meets the criteria for 
serious adverse event will be:  
 recorded on the appropriate SAE CRF 
 followed through resolution by a study clinician 
 reviewed and evaluated by a study clinician 
 
C.8.6 Unsolicited Adverse Events 
 
On enrollment in the study, the study participants will be instructed to contact 
the site PI if an AE occurs. These unsolicited, unrelated non-serious adverse 
events occurring from the time of FMT until 6 months following FMT. Patients will 
be given a patient diary with date, , details and action taken to help with data 
collection. This diary be taken to the site PI for evaluation at each follow-up visit 
and patients instructed to seek immediate medical attention if indicated. 
C.8.7  Reporting of Adverse Events 
Study participants will be instructed to contact the study nurse or physician if 
any serious or unexpected adverse event occurs. Study staff will enquire about 
AEs at each study visit. Reported AE’s will be recorded in detail in an AE CRF.  
AE information to be collected in the AE CRF: 
 Nature of the event 
 Time of onset: date, time 
 Concomitant treatment: product (generic name), indication, dosage, 
dosage interval, presentation, mode of administration, administration 
regimen 
 Duration of the AE 
 Severity 
 Seriousness 
 Causality 
 Outcome     

 
 
46
The course and outcome of the adverse event will be commented on as 
follows: 
 Recovered without sequelae 
 Not yet recovered 
 Recovered with sequelae 
 Fatal 
Any SAE (including death, irrespective of the cause) occurring during the study 
will be immediately reviewed by the site PI, i.e. within 24 hours and referred to 
the study medical monitor and lead PI.  
 
If determined to be a SUSAR (suspected unexpected serious adverse reaction – 
SUSAR; Appendix 17.3 and 17.4) by the site PI, study medical monitor and lead 
PI, the event will be reviewed by the DSMB. Regulatory filing to the FDA or local 
IRB as per standard practices will occur.  
 
In case of a SAE (non-SUSAR), the site PI will report the event to the study 
medical monitor and lead PI for review and compilation. The DSMB will review all 
SAE every 6 months or ad hoc depending on the clinical case at the discretion 
of the site PI, study medical monitor and lead PI. A specific SAE CRF will be 
provided similar to Appendix 17.3. The report must contain a detailed 
description of the symptoms observed and the concomitant treatment 
administered. Furthermore, the report must comment on a possible causative 
relationship between the AE and the trial medication. Each SAE must be 
followed until it is resolved or can be explained satisfactorily.  
 
For non-serious adverse reactions (definitely related, possibly related, not 
related) the site PI will complete a report and submit it to the medical monitor 
and lead PI. All non-serious adverse reactions will be reviewed by the DSMB 
every 6 months or ad hoc depending on the clinical case at the discretion of 
the site PI, study medical monitor and lead PI. 
 
In accordance with safety requirements, the site PI will inform the local IRB and 
lead PI and will make sure that the involved persons will obtain adequate 
information. The following instructions must be heeded: 
 In the case of an intolerable SAE, the study patient must, at the 
decision of the site PI, be withdrawn from further treatment/placebo, 
and symptomatic treatment must be administered. The participant 
may opt to voluntarily providing sample for duration of study. 
 The measures taken must be recorded on the CRF. 
 In accordance with local legislation, the site PI will submit copies of the 
final SAE-report to the Regulatory Authorities concerned, if necessary. 
 

 
 
47
 
C.8.8 Follow-up of Participants after Adverse Events 
AEs will be followed until resolution or stability even if this extends beyond the 
study-reporting period. Resolution of an AE is defined as the return to 
pretreatment status or stabilization of the condition with the expectation that it 
will remain chronic. 
Follow-up procedures, evaluations, and outcomes will be recorded on the 
participant's case report forms.  
 
C.8.9. Halting Rules 
C.8.9.1 
Study Halting Rules 
Enrollment and administration of study intervention will be suspended pending a 
safety review by the DSMB to determine whether the study will be terminated or 
re-initiated in the following situations: 
 Three or more of the randomized participants in a study treatment group 
have a Grade 3 AE of the same organ system deemed related to the study 
intervention. 
 Any serious adverse event of an enrolled participant related to the study 
intervention including transmission of a pathogen from donor to recipient. 
 An overall pattern of symptomatic, clinical, or laboratory events that the 
Medical Monitor considers related to study product and that may appear 
minor in terms of individual events, but that may collectively represent a 
serious potential concern for safety. 
 
CBER will be notified of any study halt that occurs as a result of any of the 
above halting criteria. 
 
 
C.8.9.2 
Individual’s Halting Rules 
 
Participants who meet any of the following criteria must be assessed by the site 
PI to determine if it is in the participant’s best interest to stop the study 
product(s): 
  
x Participant choice (withdrawal of consent). 
x Participant’s non-compliance.  
x Development of a significant medical condition and/or participation in 
the study is no longer in the best interest of the participant. 
 

 
 
48
All attempts will be made to complete safety follow-up for participants who 
received the study product, but discontinued participation in other study 
procedures, for the duration of the planned follow-up period.   
  
C.8.10 
Safety Oversight  
 
 
C.8.10.1 
Data and Safety Monitoring Board (DSMB) 
Safety oversight will be under the direction of a DSMB. The DSMB is an 
independent group of experts who will advise the study PIs.  The primary 
responsibilities of the DSMB are to 1) periodically review and evaluate the 
accumulated study data for participant safety, study conduct and progress, 
and, when appropriate, efficacy, and 2) make recommendations to the 
continuation, modification, or termination of the trial. The DSMB will be 
composed of at least 3 voting members. The membership will include a 
chairperson who has prior DSMB experience. One member will be an 
experienced gastroenterologist and one member will be an experienced 
infectious disease specialist. All DSMB members will be separate and 
independent of study personnel participating in this trial and should not have 
scientific, financial or other conflict of interest related to the trial. Procedures for 
DSMB data reviews will be defined in the DSMB Charter that will include DSMB 
membership, responsibilities, and the scope and frequency of data reviews.  The 
DSMB will have access to unblinded treatment assignments during the closed 
session of their meetings. The study should be reviewed by the DSMB at least bi-
annually. The DSMB may conduct a safety interim analysis after 50% of patients 
have enrolled in the treatment arm. 
 
C.9. CLINICAL MONITORING 
 
C.9.1 Site Monitoring Plan 
Site monitoring is conducted to ensure that the human participant protection, 
study and laboratory procedures, study intervention administration, and data 
collection processes are of high quality. The lead PI (or delegate) will conduct a 
site-monitoring visit(s) as detailed in a monitoring plan. The PIs will permit 
authorized representatives of CDC, regulatory agency and/or an auditing body 
to inspect facilities and records relevant to this study, if needed. 
Monitoring visits will include, but are not limited to, review of regulatory files, 
accountability records, eCRFs, informed consent forms, medical and laboratory 
reports, and protocol compliance. Study monitors will meet with site PIs to 
discuss any problems and actions to be taken and document visit findings and 
discussions. 
 
C.10. STATISTICAL CONSIDERATIONS 

 
 
49
This is a randomized double blind, placebo controlled clinical trial to determine 
the safety and efficacy of FMP-402 on the decolonization of VRE. 
 
C.10.1 
Sample Size 
Sample size (n=46) was calculated based on a conservative estimate of 85% 
decolonization in FMT group, 40% in control group with power=0.9 and 
alpha=0.05 in keeping with preliminary data and a conservative 15% drop-out 
rate.  
C.10.2 
Final Analysis Plan 
Categorical data will be described using descriptive statistics (proportions and 
percentages). Continuous data will be described using means and standard 
deviations (normally distributed data) or using medians and interquartile range 
(non-parametric data). Appropriate comparative statistical tests will be chosen 
based in the variable types (categorical, dichotomous, continuous) and 
distribution (parametric, non-parametric) and will be used to describe significant 
differences between intervention and control groups. Where appropriate, point 
estimates and confidence intervals will be reported. The p-value will be two 
tailed with a significance level of 0.05. 
C.11. SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS 
Each participating site will maintain appropriate medical and research records 
for this trial, in compliance with ICH E6 GCP, Section 4.9, and regulatory and 
institutional requirements for the protection of confidentiality of participants. 
Forms for use as source documents will be derived from the electronic CRFs. 
Additional source data include records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the 
trial. Examples of these documents and data records include, but are not limited 
to, hospital records, clinical and office charts, laboratory notes, memoranda, 
pharmacy dispensing records, recorded data from automated instruments, 
copies or transcriptions certified after verification as being accurate and 
complete, microfiches, photographic negatives, microfilm or magnetic media, 
imaging, and participant files and records kept at the pharmacy, laboratories, 
and medico-technical departments involved in the clinical trial. 
 
C.12. QUALITY CONTROL AND QUALITY ASSURANCE 
 
The site PI and delegates based at each site are responsible for conducting 
routine quality assurance (QA) and quality control (QC) activities to internally 
monitor study progress and protocol compliance. The site PI will provide direct 
access to all trial-related sites, source data/documents, and reports for the 

 
 
50
purpose of monitoring and auditing, and inspection by local and regulatory 
authorities. The site PI will ensure all study personnel are appropriately trained 
and applicable documentations are maintained on site.  
The site PI or delegate will verify that the clinical trial is conducted and data are 
generated, documented (recorded), and reported in compliance with the 
protocol, GCP, and the applicable regulatory requirements.  
C.12.1 
Database QC 
QC procedures regarding data entry will be implemented. Regular data quality 
control checks will be run on the database. Any missing data or data anomalies 
will be communicated to the site(s) for clarification and resolution. 
C.13. ETHICS/PROTECTION OF HUMAN PARTICIPANTS 
 
C.13.1 
Ethical Standard 
 
The site PI will ensure that this study is conducted in full conformity with principles 
of the Belmont Report: Ethical Principles and Guidelines for the Protection of 
Human Subjects of Research of the National Commission for the Protection of 
Human Subjects of Biomedical and Behavioral Research (April 18, 1979) and 
codified in 45 CFR 46, 21 CFR 50 and 56, and ICH E6; 62 Federal Regulations 
25691 (1997), if applicable.  
C.13.2 
Institutional Review Board 
 
Each participating institution will provide for the review and approval of this 
protocol and the associated informed consent documents, by an appropriate 
ethics review committee or IRB. Any amendments to the protocol or consent 
materials must also be approved before they are placed into use unless change 
is for the safety of the participant. Only those IRB members who are 
independent of the PIs should provide an opinion on study related matters. 
Verification of IRB approval of the protocol and the written informed consent will 
be transmitted by the site PIs or designee prior to the shipment of clinical trial 
material. No deviations from or changes to the protocol will be initiated without 
prior approval of an appropriate amendment unless change is for the safety of 
the participant. Each participating institution is responsible for ensuring 
Continuing Review at least once a year and for keeping the IRB apprised of the 
progress of the study and any changes to the protocol.  
C.13.3 
Informed Consent Process 
The written consent document will embody the elements of informed consent as 
described in the Declaration of Helsinki and will adhere to the ICH Harmonised 
Tripartite Guideline for Good Clinical Practice.  Informed consent should be 

 
 
51
implemented before any protocol-specified procedures or interventions are 
carried out. Informed consent will be obtained in accordance with 21 CFR 50.25 
and 45 CFR 46. Information should be presented both orally and in written form. 
An site PIs or designee will describe the protocol to potential participants face-
to-face. The Participant Information and Consent Form may be read to the 
participants, but, in any event, the site PIs shall give the participants ample 
opportunity to inquire about details of the study and ask any questions before 
the signing and dating the consent form. 
Study staff must inform participants and/or substitute decision maker/proxy that 
the trial involves research, and explain the purpose of the trial, those aspects of 
the trial that are experimental, any expected benefits, all possible risks (including 
a statement that the particular treatment or procedure may involve risks to the 
participant or to the embryo or fetus, if the participant is or may fathers a child, 
that are currently unforeseeable), the expected duration of the participant’s 
participation in the trial, the procedures of the research study, including all 
invasive procedures, and the probability for random assignment to treatment 
groups. Participants and/or substitute decision maker/proxy will be informed that 
they will be notified in a timely manner if information becomes available that 
may be relevant to their willingness to continue participation in the trial. They 
must also be informed of alternative procedures that may be available, and the 
important potential benefits and risks of these available alternative procedures. 
Participants and/or legal guardian must receive an explanation as to whether 
any compensation and any medical treatments are available if injury occurs, 
and, if so, what they consist of, or where further information may be obtained. 
Participants and/or substitute decision maker/proxy guardian must be informed 
of the anticipated financial expenses, if any, to the participant for participating 
in the trial, as well as any anticipated prorated payments, if any, to the 
participant for participating in the trial. They must be informed of whom to 
contact (e.g., the PI or study physician/nurse practitioner) for answers to any 
questions relating to the research project.  Information will also include the 
foreseeable circumstances and/or reasons under which the participant’s 
participation in the trial may be terminated. The participants and/or substitute 
decision maker/proxy must be informed that participation is voluntary and that 
they are free to withdraw from the study for any reason at any time without 
penalty or loss of benefits to which the participant is otherwise entitled. 
Neither the site PIs, nor the trial staff, should coerce or unduly influence a 
participant to participate or continue to participate in the trial.  The extent of 
the confidentiality of the participants’ records must be defined, and participants 
must be informed that applicable data protection legislation will be followed. 
Participants and/or substitute decision maker/proxy must be informed that the 
monitor(s), auditors(s), IRB and regulatory authority(ies) will be granted direct 
access to the participant’s medical records for verification of clinical trial 

 
 
52
procedures and/or data without violating the confidentiality of the participant, 
to the extent permitted by the applicable laws and regulations, and that, by 
signing a written informed consent form, the participant is authorizing such 
access.  Participants and/or substitute decision maker/proxy must be informed 
that records identifying the participant will be kept confidential, and, to the 
extent permitted by the applicable laws and/or regulations, will not be made 
publicly available and, if the results of the trial are published, the participant’s 
identity will remain confidential. 
Consent forms must be in a language fully comprehensible to the prospective 
participants.  Informed consent shall be documented by the use of a written 
consent form approved by the IRB and signed and dated by the participant or 
substitue decision maker/proxy and the person who conducted the informed 
consent discussion. The signature confirms that the consent is based on 
information that has been provided and all questions have been answered to 
the prospective participant’s satisfaction. Each participant’s signed informed 
consent form must be kept on file by the site PIs for possible inspection. The 
participant should receive a copy of the signed and dated written informed 
consent form and any other written information provided to the participants, 
and should receive copies of any signed and dated consent form updates and 
any amendments to the written information provided to participants. 
 
C.13.4 
Exclusion of Women, Minorities, and Children (Special Populations) 
Children are excluded for safety reasons. 
  
C.13.5 
Participant Confidentiality 
Participant confidentiality is held strictly in trust by the participating PIs, their staff, 
and their agents. This confidentiality is extended to cover testing of biological 
samples in addition to the clinical information relating to participating 
participants. 
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 from the lead PI. 
The lead PI or delegate and the FDA may inspect all documents and records 
required to be maintained by the site PIs, including, but not limited to, medical 
records (office, clinic, or hospital) and pharmacy records for the participants in 
this study. The clinical study site will permit access to such records. 
 
C.13.6  
Study Discontinuation 

 
 
53
The lead PI has the right to terminate this study or an individual site’s 
participation at any time.  Reasons for terminating the study may include, but 
are not limited to, the following: 
 Incidence or severity of adverse events indicates a potential health 
hazard; 
 Data recording is inaccurate or incomplete; 
 Site PI does not adhere to the protocol or applicable regulatory 
guidelines in conducting the study. 
 
C.13.7 
Future Use of Stored Specimens 
 
Any leftover stool specimens will be stored and may be used for future research, 
under a future protocol, to learn more about FMP-402. These specimens will be 
stored indefinitely after the study is completed. In the informed consent 
document, participants will be given an opportunity to choose whether or not 
their de-identified barcoded specimens are stored for future use. For 
participants who choose not to allow storage of their samples for future use, 
these samples will be destroyed at the end of the study.  
 
There are no benefits to participants in the collection, storage and subsequent 
research use of specimens. Reports about future research done with 
participant’s samples will NOT be kept in their health records, but participant’s 
samples may be kept with the study records or in other secure areas. 
Participants can decide if they want their samples to be used for future research 
or have their samples destroyed at the end of the study. A participant’s decision 
can be changed at any time before the end of the study by notifying the study 
doctors or nurses in writing. However, if a participant consents to future use and 
some of their stool has already been used for research purposes, the information 
from that research may still be used. 
Samples may be shared with other investigators at other institutions with the 
consent of the lead PI. Each sample will be encoded (labeled) only with a 
barcode and a unique tracking number to protect participant’s confidentiality. 
 
Research using stored specimens may be conducted by other institutions. Any 
specimens and data provided to the receiving-institution will be coded. 
Unequivocally, neither individual personal identifiers nor the key linking coded 
data to individuals will be released to the receiving-institution. The use of any of 
these specimens for any future studies will only be performed after the lead PI 
has authorized the use of these specimens.  
 
 
C.14. DATA HANDLING AND RECORD KEEPING 

 
 
54
The PIs are responsible to ensure the accuracy, completeness, legibility, and 
timeliness of the data reported. All data collection forms should be completed 
in a neat, legible manner to ensure accurate interpretation of data. Black 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. Do not erase, overwrite, or use correction fluid or tape on the original. 
Copies of the electronic CRF (eCRF) will be provided for use as source 
documents and maintained for recording data for each participant 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. 
 
C.14.1 
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 as outlined above. 
Data collection is the responsibility of the clinical trial staff at the site under the 
supervision of the site PI. During the study, the site PIs must maintain complete 
and accurate documentation for the study. 
 
C.14.2 
Data Capture Methods 
Clinical data (including AEs, concomitant medications, and solicited events 
data) and clinical laboratory data will be entered into a 21CFR11-compliant 
Internet Data Entry System, RedCap.  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. 
 
C.14.3 
Types of Data 
Data for this study will include clinical, safety and microbiological outcome 
measures.   
 
C.14.4 
Timing/Reports 
Interim reports for the DSMB will be prepared when approximately 50% of 
treating participants complete enrollment and every 6 months. Interim statistical 
reports may be generated as deemed necessary and appropriate by the lead 
PI. Other safety summary reports may be generated for the DSMB. A final report 
will be prepared following the availability of all the clinical, safety and efficacy 
data. 

 
 
55
 
C.14.5 
Study Records Retention 
Study files (except for future use consent forms) must be maintained for a 
minimum of two years after the last approval of a marketing application in an 
ICH region and until there are no pending or contemplated marketing 
applications in and ICH region or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These 
documents should be retained for a longer period, however, if required by local 
regulations. No records will be destroyed without the written consent of the lead 
PI or designate, if applicable. It is the responsibility of the lead PI or designate to 
inform the site PIs when these documents no longer need to be retained. 
Consent forms for future use will be maintained as long as the sample exists. 
 
C.14.6 
Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, 
or protocol-specific MOP requirements. The noncompliance may be either on 
the part of the participant, the site PI, or the study site staff. As a result of 
deviations, corrective actions are to be developed by the site and 
implemented promptly. 
These practices are consistent with ICH E6: 
 4.5 
Compliance with Protocol, Sections 4.5.1, 4.5.2, and 4.5.3 
 5.1 
Quality Assurance and Quality Control, Section 5.1.1 
 5.20 Noncompliance, Sections 5.20.1, and 5.20.2. 
It is the responsibility of the site PI/study staff to use continuous vigilance to 
identify and report deviations within five working days of identification of the 
protocol deviation, or within five working days of the scheduled protocol-
required activity.  All deviations must be promptly reported to the lead PI or 
designated personnel. 
All protocol deviations, as defined above, must be addressed in study 
participant source documents.  A completed copy of the Protocol Deviation 
Form must be maintained in the Regulatory File, as well as in the participant's 
source document. Protocol deviations must be sent to the local IRB/IEC per their 
guidelines.  The site PI/study staff is responsible for knowing and adhering to their 
IRB requirements. 
 
 

 
 
56
C.15. PROTOCOL REFERENCES 
 
1. 
CDC. Antibiotic Resistance Threats in the United States, 2013. (CDC, 2013). 
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Song, X., Srinivasan, A., Plaut, D. & Perl, T. M. Effect of nosocomial 
vancomycin-resistant enterococcal bacteremia on mortality, length of stay, and 
costs. Infect. Control Hosp. Epidemiol. 24, 251–256 (2003). 
3. 
Pelz, R. K. et al. Vancomycin-sensitive and vancomycin-resistant 
enterococcal infections in the ICU: attributable costs and outcomes. Intensive 
Care Med. 28, 692–697 (2002). 
4. 
Shenoy, E. S., Paras, M. L., Noubary, F., Walensky, R. P. & Hooper, D. C. 
Natural history of colonization with methicillin-resistant Staphylococcus aureus 
(MRSA) and vancomycin-resistant Enterococcus (VRE): a systematic review. 
BMC Infect. Dis. 14, 177 (2014). 
5. 
Orsi, G. B. & Ciorba, V. Vancomycin resistant enterococci healthcare 
associated infections. Ann. Ig. Med. Prev. E Comunità 25, 485–492 (2013). 
6. 
Ziakas, P. D., Thapa, R., Rice, L. B. & Mylonakis, E. Trends and Significance 
of VRE Colonization in the ICU: A Meta-Analysis of Published Studies. PLoS ONE 8, 
(2013). 
7. 
Patel, R. et al. Natural history of vancomycin-resistant enterococcal 
colonization in liver and kidney transplant recipients. Liver Transpl. 7, 27–31 
(2001). 
8. 
McNeil, S. A. et al. Vancomycin-Resistant Enterococcal Colonization and 
Infection in Liver Transplant Candidates and Recipients: A Prospective 
Surveillance Study. Clin. Infect. Dis. 42, 195–203 (2006). 
9. 
Hendrix, C. W. et al. Surveillance strategies and impact of vancomycin-
resistant enterococcal colonization and infection in critically ill patients. Ann. 
Surg. 233, 259–265 (2001). 
10. 
Jung, E., Byun, S., Lee, H., Moon, S. Y. & Lee, H. Vancomycin-resistant 
Enterococcus colonization in the intensive care unit: clinical outcomes and 
attributable costs of hospitalization. Am. J. Infect. Control 42, 1062–1066 (2014). 
11. 
Bonten, M. J. et al. The role of ‘colonization pressure’ in the spread of 
vancomycin-resistant enterococci: an important infection control variable. Arch. 
Intern. Med. 158, 1127–1132 (1998). 
12. 
Siegel, J. D., Rhinehart, E., Jackson, M. & Chiarello, L. Management of 
Multidrug-Resistant Organisms In Healthcare Settings, 2006. (Centers for Disease 
Control and Prevention, 2006). 
13. 
Drekonja, D. et al. Fecal Microbiota Transplantation for Clostridium difficile 
Infection: A Systematic Review. Ann. Intern. Med. 162, 630–638 (2015). 
14. 
Pamer, E. G. Resurrecting the intestinal microbiota to combat antibiotic-
resistant pathogens. Science 352, 535–538 (2016). 
15. 
Halpin, A. L. & McDonald, L. C. The Dawning of Microbiome Remediation 
for Addressing Antibiotic Resistance. Clin. Infect. Dis. ciw187 (2016). 
doi:10.1093/cid/ciw187 

 
 
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16. 
Donskey, C. J. et al. Effect of antibiotic therapy on the density of 
vancomycin-resistant enterococci in the stool of colonized patients. N. Engl. J. 
Med. 343, 1925–1932 (2000). 
17. 
Johnsen, P. J., Simonsen, G. S., Olsvik, O., Midtvedt, T. & Sundsfjord, A. 
Stability, persistence, and evolution of plasmid-encoded VanA glycopeptide 
resistance in enterococci in the absence of antibiotic selection in vitro and in 
gnotobiotic mice. Microb. Drug Resist. Larchmt. N 8, 161–170 (2002). 
18. 
Foucault, M.-L., Depardieu, F., Courvalin, P. & Grillot-Courvalin, C. 
Inducible expression eliminates the fitness cost of vancomycin resistance in 
enterococci. Proc. Natl. Acad. Sci. U. S. A. 107, 16964–16969 (2010). 
19. 
Galloway-Peña, J., Roh, J. H., Latorre, M., Qin, X. & Murray, B. E. Genomic 
and SNP Analyses Demonstrate a Distant Separation of the Hospital and 
Community-Associated Clades of Enterococcus faecium. PLOS ONE 7, e30187 
(2012). 
20. 
Montealegre, M. C., Singh, K. V. & Murray, B. E. Gastrointestinal Tract 
Colonization Dynamics by Different Enterococcus faecium Clades. J. Infect. Dis. 
213, 1914–1922 (2016). 
21. 
Buffie, C. G. & Pamer, E. G. Microbiota-mediated colonization resistance 
against intestinal pathogens. Nat. Rev. Immunol. 13, 790–801 (2013). 
22. 
Ubeda, C. et al. Intestinal microbiota containing Barnesiella species cures 
vancomycin-resistant Enterococcus faecium colonization. Infect. Immun. 81, 
965–973 (2013). 
23. 
Stripling, J. et al. Loss of Vancomycin-Resistant Enterococcus Fecal 
Dominance in an Organ Transplant Patient With Clostridium difficile Colitis After 
Fecal Microbiota Transplant. Open Forum Infect. Dis. 2, (2015). 
24. 
Crum-Cianflone, N. F., Sullivan, E. & Ballon-Landa, G. Fecal microbiota 
transplantation and successful resolution of multidrug-resistant-organism 
colonization. J. Clin. Microbiol. 53, 1986–1989 (2015). 
25. 
Freedman, A. Use of Stool Transplant to Clear Fecal Colonization with 
Carbapenem-Resistant Enterobacteraciae (CRE): Proof of Concept. in (Idsa, 
2014). 
26. 
Singh, R. et al. Donor feces infusion for eradication of Extended Spectrum 
beta-Lactamase producing Escherichia coli in a patient with end stage renal 
disease. Clin. Microbiol. Infect. 20, O977–O978 (2014). 
27. 
Wei, Y. et al. Fecal microbiota transplantation restores dysbiosis in patients 
with methicillin resistant Staphylococcus aureus enterocolitis. BMC Infect. Dis. 15, 
265 (2015). 
28. 
Millan, B. et al. Fecal Microbial Transplants Reduce Antibiotic-resistant 
Genes in Patients With Recurrent Clostridium difficile Infection. Clin. Infect. Dis. 
62, 1479–1486 (2016). 
29. 
Lombardo, M. 757. Vancomycin-resistant enterococcal (VRE) titers 
diminish among patients with recurrent Clostridium difficile infection after 
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30. 
Zipursky, J. S., Sidorsky, T. I., Freedman, C. A., Sidorsky, M. N. & Kirkland, K. B. 
Patient attitudes toward the use of fecal microbiota transplantation in the 
treatment of recurrent Clostridium difficile infection. Clin. Infect. Dis. Off. Publ. 
Infect. Dis. Soc. Am. 55, 1652–1658 (2012). 
31. 
Kelly, C. R. et al. Fecal microbiota transplant for treatment of Clostridium 
difficile infection in immunocompromised patients. Am. J. Gastroenterol. 109, 
1065–1071 (2014). 
32. 
Baxter, M. & Colville, A. Adverse events in faecal microbiota transplant: 
a review of the literature. J. Hosp. Infect. 92, 117–127 (2016). 
33. 
Fischer, M. et al. A Multi-Center, Cluster Randomized Dose-Finding Study of 
Fecal Microbiota Transplantation Capsules for Recurrent Clostridium Difficile 
Infection. United Eur. Gastroenterol. J. 3, 565–566 (2015). 
34. 
Allegretti, J. R. et al. Su1738 Fecal Microbiota Transplantation Delivered via 
Oral Capsules Achieves Microbial Engraftment Similar to Traditional Delivery 
Modalities: Safety, Efficacy and Engraftment Results From a Multi-Center Cluster 
Randomized Dose-Finding Study. Gastroenterology 150, S540 (2016). 
35. 
Fischer, M. et al. Faecal microbiota transplantation plus selected use of 
vancomycin for severe-complicated Clostridium difficile infection: description of 
a protocol with high success rate. Aliment. Pharmacol. Ther. 42, 470–476 (2015). 
36. van Nood, E. et al. Duodenal Infusion of Donor Feces for Recurrent 
Clostridium difficile. NEJM. 368, 407-415 (2013).  
37. Brandt, LJ. et al. Long-term follow-up of colonoscopic fecal microbiota 
transplant for recurrent Clostridium difficile infection. Am J Gastroenterol. 
107(7), 1079-87 (2012).  
38. Wang, S. et al. Systematic Review: Adverse Events of Fecal Microbiota 
Transplantation. PLOS One, 11(8):e0161174 (2016).  
39. Vrieze, A. et al. Transfer of Intestinal Microbiota From Lean Donors Increases 
Insulin Sensitivity in Individuals With Metabolic Syndrome. Gastroenterology, 
143(4), 913-6 (2012). 
40. Hamilton MJ, Weingarden AR, Sadowsky MJ, Khoruts A. Standardized frozen 
preparation for transplantation of fecal microbiota for recurrent Clostridium 
difficile infection. Am J Gastroenterol. 107(5),761-767 (2012). 
41. Youngster I, Mahabamunuge J, Systrom HK, et al. Oral, frozen fecal 
microbiota transplant (FMT) capsules for recurrent Clostridium difficile 
infection. BMC Med. 14(1), 134 (2016).  
42. Warren DK, Kollef MH, Seiler SM, Fridkin SK, Fraser VJ. The epidemiology of 
vancomycin-resistant Enterococcus colonization in a medical intensive care 
unit. Infect Control Hosp Epidemiol. 24(4), 257-63 (2003). 
 
 

 
 
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C.16. PROTOCOL ABSTRACTS 
 
C.16.1 
Eysenbach et al. ID Week 2016 
 
Abstract #59960 
Title: Clearance of Vancomycin-Resistant Enterococcus Colonization with Fecal 
Microbiota Transplantation among Patients with Recurrent Clostridium difficile 
Infection 
 
Authors: Lindsay Eysenbach, AB1, Jessica R. Allegretti, MD, MPH2,3, Olga 
Aroniadis, MD4, Lawrence Brandt, MD4, Danyel Donovan, BS5, Monika Fischer, 
MD, MSCR6, Ari Grinspan, MD7, Zain Kassam, MD MPH1, Colleen R. Kelly, MD8, 
Christina Kim, BS1, Casey Morrow, PhD9, Majdi Osman, MD MPH1, Julia Quan, BS5, 
Martin Rodriguez, MD, FIDSA9, Terry Walker, PhD5 and Mark Smith, PhD1,  
 
Affiliations: (1)OpenBiome, Medford, MA, (2)Harvard Medical School, Boston, 
MA, (3)Brigham and Women's Hospital, Boston, MA, (4)Montefiore Medical 
Center, Bronx, NY, (5)OpGen, Gaithersburg, MD, (6)Indiana University, 
Indianapolis, IN, (7)Icahn School of Medicine at Mount Sinai, New York, NY, 
(8)The Warren Alpert Medical School of Brown University, Providence, RI, 
(9)University of Alabama at Birmingham, Birmingham, AL 
 
Background:  Vancomycin-resistant enterococcus (VRE) is a public health threat 
to hospitalized patients and gastrointestinal colonization with VRE is a major risk 
factor for active infection, including bacteremia. Fecal microbiota 
transplantation (FMT) is a well-tolerated and effective treatment for recurrent C. 
difficile (rCDI). Data from animal models and clinical case reports suggest that 
FMT may reverse dysbiosis and eliminate colonization with antibiotic-resistant 
organisms, including VRE; however, there is a paucity of clinical data. This study 
aims to determine whether FMT may decolonize VRE in rCDI patients treated 
with FMT. 
 
Methods:  A multicenter retrospective analysis was performed using stool 
samples from rCDI patients treated with FMT (n=31) or autologous FMT as a 
control (n=18). Material was accessed from 6 academic hospitals under existing 
research protocols. VRE was assessed using a PCR-based assay targeting VanA 
(Acuitas® MDRO Gene Test). Colonization was defined as positive result at any 
dilution. VRE decolonization was defined as absence of VRE colonization post-
FMT among a patient colonized with VRE pre-FMT. 
 
Results:  Among the cohort, 9/31 (29%) of patients in the FMT group and 7/18 
(39%) of patients in the control group were colonized with VRE at baseline. At 
the first time point measured post-FMT, 9/9 (100%) of colonized patients in the 
FMT group tested VRE-negative compared to 3/7 (43%) in the control group 

 
 
60
(p=0.02, Fisher's Exact Test). On subgroup analysis, samples collected at ≤6 
weeks, 5/5 (100%) patients in the FMT group and 3/7 (43%) controls were 
decolonized; for samples collected at >6 weeks, 4/4 (100%) in the FMT group 
and 6/7 (86%) in the control group were decolonized. These results from 
subgroup analyses were not statistically significant given the high rate of 
spontaneous VRE decolonization. 
 
Conclusion:  FMT may be able to eliminate gastrointestinal colonization with VRE. 
However, a well-powered RCT with short follow-up time points is necessary to 
prospectively examine colonization dynamics and clinical outcomes. These 
results from a heterogeneous retrospective cohort study suggest that FMT or 
related microbial therapies may be effective to prevent infection and 
transmission of VRE in high-risk settings. 
 
 
C.16.2 
Osman et al. ID Week 2016 
 
Osman et al. ID Week 2016, “Safety and efficacy of fecal microbiota 
transplantation for recurrent Clostridium difficile infection”  
 
Abstract #59497 
Title: Safety and efficacy of fecal microbiota transplantation for 
recurrent Clostridium difficile infection from an international public stool bank: 
Results from a 2,050 patient multi-center cohort 
Original Submission Date: May 17, 2016 
Last Edited Date: May 18, 2016 
Authors: Majdi Osman, MD MPH1, Kelsey O'Brien, MPH2, Zachery Stoltzner, BS2, 
Kelly Ling, BS1, Emily Koelsch, RN BSN1, Nancy Dubois, MSN MBA3, Adila Khoiri, 
MD4, Kanchana Amaratunga, MD, MPH5, Mark Smith, PhD1 and Zain Kassam, 
MD MPH1, (1)OpenBiome, Medford, MA, (2)Clinical Safety, OpenBiome, 
Medford, MA, (3)William F. Connell School of Nursing, Boston College, Chestnut 
Hill, MA, (4)Sydney Children's Hospital, Sydney, Australia, (5)Infectious Disease, 
The Ottawa Hospital, Ottawa, ON, Canada 
 
Background 
Clostridium difficile infection (CDI) is a public health threat and fecal microbiota 
transplantation (FMT) appears to be an effective therapy. Recently, universal 
stool banks have emerged to enable safe and seamless access to FMT. 
However, there is a paucity of real-world safety and efficacy data from stool 
banks.  
 
Methods 
Quality assurance data on CDI classification, FMT delivery modality and clinical 
efficacy was consecutively collected from 482 healthcare facilities across 50 U.S 

 
 
62
Severe 
90 
83.3 
0.85 
65 
81.5 
<0.01 
25 
88 
0.205 
 
 
C.16.3 
Dubois et al. ID Week 2015 
 
Title: Prospective Assessment of Donor Eligibility for Fecal Microbiota 
Transplantation at a Public Stool Bank: Results From the Evaluation of 1,387 
Candidate Donors  
 
Authors: Nancy E. Dubois MN, MBA1, Kelly Ling1, Majdi Osman MD, MPH1, Laura 
Burns1, Gina Mendolia1, Dan Blackler, James Burgess1, Carolyn Edelstein MPA1, 
Andrew Noh1, Elaine Vo PhD, Eric Alm PhD1,2,3, Mark Smith PhD1,2 Zain Kassam 
MD, MPH1,2  
 
1. OpenBiome 
2. Massachusetts Institute of Technology 
3. Broad Institute 
 
Character count: 1,948/1,950 
 
Background: Recurrent Clostridium difficile infection is a major public health 
threat and fecal microbiota transplantation is a promising therapy. Public stool 
banks have emerged to meet increasing demand, supplied with fecal material 
from rigorously screened, universal donors. However, limited data exists 
regarding best practices for donor assessment. Accordingly, we aim to outline a 
donor screening framework, capture etiology of exclusion, and quantify the 
number of qualified stool donors.  
 
Methods: Enrollment was conducted prospectively over a 1-year period. 
Candidates were directed to an online registry to complete a pre-screening 
survey to rule out common exclusion criteria. Eligible participants were invited for 
a 109-point, in-person clinical assessment by a nurse or physician and overseen 
by an internal medicine specialist to exclude risk factors for transmissible 
diseases and potential microbiome-mediated conditions. Candidate donors 
completed stool and serologic screening by a CLIA-approved laboratory (Figure 
1).  
 
Results: Overall, 1,387 participants enrolled in the donor program. At Stage 1, 
candidates completed a pre-screen survey with 910 (66%) individuals excluded, 
commonly for abnormal body mass index, logistic constraints and recent 
antimicrobial use. At Stage 2, remaining participants underwent a clinical 
assessment with 403 (84%) participants excluded, most commonly for loss to 
follow-up with 235 (58%) candidates failing to attend an invited assessment. 

 
 
63
During the clinical interview, psychiatric illness, medications and infectious 
disease risk factors were identified as the most common reasons for exclusion. At 
Stage 3, remaining candidates underwent laboratory investigation with 35 (47%) 
candidates excluded, commonly for rotavirus and C. difficile. Overall, 39 
participants qualified as stool donors resulting in a 2.8% acceptance rate (Figure 
2). 
 
Conclusions: Healthy, rigorously screened stool for use in FMT is rare with only 
2.8% donors qualifying. An unanticipated, large number of asymptomatic 
potential donors were not eligible and logistics as well as loss to follow-up 
appear to be important factors for stool banks. Consensus-based guidelines are 
urgently needed to ensure safe standards for stool donors. 
 
 
 

 
 
64
 
 
 

 
 
65
C.17. STUDY DESIGN 
 
C.17.1 
Study Schematic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
67
C.17.3 
NIH Common Terminology Criteria for Adverse Events (CTCAE) 
 
 
 

 
 
68
C.17.4 
Adverse Event Assessment Flow Chart