Clinical trial NCT02255305
Conditions: Clostridium Difficile Infection
Keywords: CDI C difficile C diff Clostridium difficile
Sponsor: Endeavor Health
Start date: 2015-01-01; Completion date: 2020-01-01
Enrollment: 6 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the study is to determine the safety and efficacy of Fecal Microbiota Transplant (FMT) for the treatment of the recurrence of Clostridium difficile infection (CDI) as compared to standard antibiotic therapy. Patients who have tested positive for CDI within 90 days of an admission for relapse of CDI will be approached to participate in this open-label, randomized controlled trial. Patients will either be randomized to the intervention group (receive FMT via retention enema) or the control group (receive antimicrobials targeting CDI).

Detailed description:
This trial is an open-label, randomized, controlled trial evaluating the safety and efficacy of fecal microbiota transplantation (FMT) for the treatment of the recurrence of Clostridium difficile infection (CDI) as compared to standard antibiotic therapy. Clostridium difficile infection (CDI) has increased in incidence and severity over the last decade and is associated with poor outcomes including increased morbidity, mortality, and healthcare costs (1-8). Relapse occurs in 15-35% of patients after the first episode of CDI and 45-65% of patients who have one relapse will experience a subsequent relapse (9, 10). Dysbiosis - decreased diversity of the fecal microbiome - is thought to contribute to the high rate of relapse (11). FMT quickly and successfully restores normal intestinal microorganisms of the diseased patient via infusion of a liquid stool preparation from a healthy donor. FMT resulted in disease resolution in \~90% of cases reported in a systematic review and meta-analyses without any significant adverse events noted (12, 13).

All hospitalized patients in the NorthShore system \>18 years of age who are diagnosed with active CDI, defined as \>3 diarrheal stools per day and a positive C. difficile polymerase chain reaction (PCR) assay, will be evaluated for inclusion in the study. Hospitalized patients presenting with their first or greater relapse of CDI occurring between 15 and 90 days after an index episode of CDI will be eligible for enrollment. Exclusion criteria will include pregnancy, neutropenia (absolute neutrophil count \<1000/μl), contraindication for retention enema, or food allergy not controlled for in the donor diet. Eligible patients will undergo written informed consent followed by randomization into intervention and control groups.

Patients who are randomized to the intervention group will have antimicrobials targeting C. difficile discontinued at least 6 hours prior to undergoing an FMT via retention enema. A second FMT via retention enema will be administered at 24 hours if diarrhea persists. Patients randomized to the control group will be treated with antimicrobials targeting C. difficile according to the Society for Healthcare Epidemiology of America Clinical Practice Guidelines for CDI (18). FMT will be offered to the control group after 90 days if they experience relapsing CDI.

Two healthy "universal" donors who have previously donated fecal material for FMT have expressed willingness to participate in the study. Donors will complete the American Association of Blood Banks donor questionnaire for exposure to infectious agents as well as undergo serologic and stool testing for communicable diseases or pathogenic bacteria/viruses as previously described (17).

Arms: arm 1: Patients randomized to the FMT group will have antimicrobials targeting C. difficile discontinued at least 6 hours prior to undergoing an FMT via retention enema. A second FMT via retention enema will be administered at 24 hours if diarrhea persists. arm 2: Patients randomized to the antimicrobial group will be treated with antibiotics targeting C. difficile according to the Society for Healthcare Epidemiology of America (SHEA) Clinical Practice Guidelines for CDI. FMT will be offered to this group after 90 days if they experience relapsing CDI.
Interventions: intervention 1: FMT intervention 2: Antimicrobials
Intervention descriptions: intervention 1: Patients in the FMT group will receive \~50 grams of fecal material suspended in bacteriostatic normal saline and glycerol. intervention 2: Patients randomized to the control group will receive antimicrobials targeting C. difficile.

Protocol documents:
Prot_000.pdf: 
 
1
 
 
 
 
 
 
 
SPONSOR:  JENNIFER GRANT, MD 
 
NORTHSHORE UNIVERSITY HEALTHSYSTEM 
 
847-570-1502 (DESK) 
847-657-5764 (FAX) 
 
 
 
 
 
 
 
Fecal Microbiota Transplantation versus Standard Medical Therapy for Initial Treatment of 
Recurrent Clostridium difficile Infection  
 
 
 
 
 
 
 
 
 
 
 
 Product:  
Fecal Microbiota Transplantation (FMT) 
Treatment Protocol  
Proposed Indication:  
Recurrent Clostridium difficile Infection  
Date:  
7/11/2016 (Revision 4) 
 
 
 
 
 
 


 
2
 
Table of Contents 
 
1. PRODUCT NAME AND APPLICATION NUMBER .............................................................................. 3 
2. CHEMICAL NAME AND STRUCTURE .................................................................................................. .3 
3. PROPOSED INDICATION(S) .................................................................................................................... .3 
4. DOSAGE FORM, ROUTE OF ADMINISTRATION AND DOSING REGIMEN .............................. 3 
5. BACKGROUND....................................................................................................................................... …3-5 
6. CHEMISTRY, MANUFACTURING AND CONTROLS INFORMATION ......................................... 5 
7. CLINICAL DATA SUMMARY ..................................................................................................................... 5 
7.1 Proposed Indication ……………………………………………………………………………………………...5 
7.2 Background of the Disease .................................................................................................................... 5 
7.3 Rational for use of an Unapproved Product ................................................................................... 6 
7.4 Summary of Previous Human Experience ....................................................................................... 6 
        7.4.1 Previously Published Case Reports and Case Series ....................................................... 6 
        7.4.2 Investigator‟s Published and Continuing Experience .................................................... 7 
8. TREATMENT PROTOCOL ...................................................................................................................... 12 
8.1. Indications ............................................................................................................................................... 13 
8.2 Donor Eligibility Determination ....................................................................................................... 13 
8.3 Patient eligibility determination ...................................................................................................... 15 
8.4. Preparation of Stool for FMT Infusion .......................................................................................... 16 
8.5. FMT Procedure ...................................................................................................................................... 17 
8.6. Follow up .................................................................................................................................................. 18 
9. ADVERSE EVENT REPORTING ............................................................................................................ 19 
10. RISKS ASSOCIATED WITH FMT........................................................................................................ 26 
10.1. Potential Risks to Patients .............................................................................................................. 26 
10.2. Potential Risks to Donor .................................................................................................................. 27 
11. ADEQUACY OF PROTECTION AGAINST RISKS ........................................................................... 28 
12. SAFETY MONITORING PROTOCOL ................................................................................................. 30 
APPENDIX 1 ..................................................................................................................................................... 31 
APPENDIX 2 ..................................................................................................................................................... 33 
APPENDIX 3 ..................................................................................................................................................... 34 
APPENDIX 4 ..................................................................................................................................................... 35 
APPENDIX 5 ..................................................................................................................................................... 36 
APPENDIX 6 ..................................................................................................................................................... 37 
REFERENCES .................................................................................................................................................. 38 
 
 
 
 
 
 
 
 
 


 
3
1. PRODUCT NAME AND APPLICATION NUMBER  
 
Fecal Microbiota Transplantation (FMT) for Relapsing Clostridium difficile Infection  
Application number: NA  
 
*Note:  This application was modeled after IND 15310 from Dr. Colleen Kelly with 
her permission.  There are no major deviations from her protocol. 
 
*Since July 2013, the FDA approved our Investigational New Drug Application.  All 
research procedures will be completed under IND 15668. 
 
2. CHEMICAL NAME AND STRUCTURE  
 
Not applicable.  
Biologically active human fecal material 
  
3. PROPOSED INDICATION(S)  
 
Recurrent Clostridium difficile infection 
 
4. DOSAGE FORM, ROUTE OF ADMINISTRATION AND DOSING REGIMEN  
 
Dosage form:  
Solution of filtered human donor stool (approximately 50 
grams) homogenized in sterile normal saline (500 mL).  
Route: 
Infused into the colon as a retention enema 
Dosing:  
 
200-300 mL x 1 dose. 
 
5. BACKGROUND  
 
Clostridium difficile  
Clostridium difficile infection (CDI) has increased in incidence and severity over the 
last decade and is associated with poor outcomes including increased morbidity, mortality, 
and healthcare costs (1-8).  Relapse occurs in 15-35% of patients after the first episode of 
CDI and 45-65% of patients who have one relapse will experience a subsequent relapse (9, 
10).  Dysbiosis - decreased diversity of the fecal microbiome – is thought to contribute to 
the high rate of relapse (11).  FMT quickly and successfully restores normal intestinal 
microorganisms of the diseased patient via infusion of a liquid stool preparation from a 
healthy donor.  FMT resulted in disease resolution in ~90% of cases reported in a 
systematic review and meta-analyses without any significant adverse events noted (12, 
13).  A cost-effectiveness analysis examining treatments for recurrent CDI demonstrated 
that administration of FMT via colonoscopy was the most cost effective approach in 
managing the first recurrence of CDI (14).  Colonoscopy was selected as the delivery 
method of choice due to the highest reported success rate with a single donor infusion.  If 
less expensive FMT methods using standardized frozen fecal preparations delivered via 
enema or duodenal infusion could be employed with cure rates of 85%, such approaches 


 
4
could be more cost effective than FMT colonoscopy (14).  Successful treatment of recurrent 
CDI (~90%) using a standardized frozen preparation obtained from a “universal” donor 
has been described (15, 16).  The use of frozen stool preparations obtained from a 
“universal” donor reduced costs associated with donor screening, allowed for the timely 
treatment of patients without delays due to identifying and screening a donor and 
improved the overall aesthetic experience for patients.    We aim to compare the 
effectiveness of FMT using a frozen fecal preparation delivered via enema to standard 
antibiotic therapy on clinical outcomes in patients with their initial CDI recurrence.        
 
 
Fecal Microbiota Transplantation (FMT)  
Most commonly, CDI is associated with use of antimicrobial agents that are thought 
to alter the normal bacterial flora of the gastrointestinal tract to permit colonization and 
subsequent proliferation and toxin elaboration by C. difficile11. Though the precise 
mechanisms by which this occurs are still incompletely understood, depletion of 
physiologic microflora, in particular members of the Bacteroidetes and Firmicutes phyla are 
thought to play an important role13-15. The specific antimicrobials used to treat CDI also 
may predispose patients to further relapses through the maintenance of perturbed 
intestinal flora, and may contribute to the emerging problems of drug resistance. Indeed, 
both metronidazole and vancomycin have broad-spectrum activity against Gram-negative 
and Gram-positive organisms respectively.  
Fecal microbiota transplantation (FMT) (also known as fecal bacteriotherapy, fecal 
flora reconstitution or stool transplant) involves administration of fecal material from a 
healthy individual (donor) into a sick patient (with relapsing CDI) to restore the 
phylogenetic diversity of normal stool and along with this diversity, the “colonization 
resistance” that enables normal intestinal flora resist overgrowth of C. difficile16. Numerous 
case reports and retrospective case series have demonstrated benefit of FMT in patients 
with severe or recurrent CDI with cure rates as high as 100% and a mean cure rate of 89% 
for the approximately 300 cases reported in the world literature13-31. Methods used to 
administer FMT have included fecal suspensions given via nasogastric and nasoduodenal 
tubes, by upper tract endoscopy (EGD), as retention enemas, or through the colonoscope at 
the time of colonoscopy13-30. Colonoscopic administration has the advantage of direct 
infusion of the transplant throughout the colon, while also allowing for direct examination 
of the colonic mucosa, which is often necessary in patients with recurrent CDI to exclude 
any coexistent colonic pathology, such as IBD. 
FMT appears to be safe, with no adverse effects or complications directly attributed 
to the procedure yet reported in the medical literature. Certainly, the possibility of bias 
exists in the current literature, as unsuccessful treatment attempts or adverse events 
related to FMT might be underreported. A well-designed clinical trial would help to 
determine whether or not FMT is effective in the treatment of recurrent C. difficile colitis 
and would establish safety data. I am presently conducting an NIH-approved open-label 
randomized controlled trial of donor stool and recipient stool in the treatment of recurrent 
CDI. Because transmission of infectious agents is a major potential concern, as part of our 
routine clinical use of FMT, we screen all stool donors for common pathogens (bacteria and 
parasites), similar to existing FDA guidelines for donors of human cells, tissues, and cellular 


 
5
and Tissue-Based Products (HCT/Ps). This treatment protocol uses the same process of 
donor eligibility determination and screening as the study IND for our clinical trial. 
 
Proposed Use and Rationale  
Despite overwhelmingly positive anecdotal experience from the growing number of 
physicians who have performed this procedure and reported success in case-studies and 
small series, and a larger number of physicians who have resorted to FMT in cases of 
resistant, recurrent, relapsing CDI, FMT is not yet routinely performed; its acceptance is 
growing, however. It has now become a therapeutic alternative for resistant cases of CDI 
and is recommended as such by the CDI Guidelines Committee of the American College of 
Gastroenterology. As you know, patients suffering from relapsing C. difficile are often 
desperate for a cure and seek guidance from online communities33-35. Many are willing to 
travel great distances to undergo FMT. Some have even resorted to performing home-
enemas of donor stool when they are unable to find a physician who is willing or able to 
perform FMT. Offering this treatment within an FDA approved IND protocol would assure 
that FMT is performed as safely as possible and allows of necessary monitoring for safety 
issues. 
 
6. CHEMISTRY, MANUFACTURING AND CONTROLS INFORMATION  
 
Stool is a heterogeneous substance, composed primarily of bacteria and water, but 
also containing viral and fungal organisms, metabolic products of these organisms, 
undigested foods, bile, bilirubin, cholesterol, inorganic salts, dead cells, and mucus from the 
lining of the intestinal wall. The exact composition of human stool varies from person to 
person and from day to day. The process of donor eligibility determination and screening, 
stool processing and infusion defines the FMT “product” which is analogous to transplant 
in that it restores phylogenetic diversity to the recipient’s (previously deficient) intestinal 
microbiota36. Carefully devised donor screening and testing guidelines and stool processing 
protocol (as detailed in this protocol) ensures that FMT is performed safely and effectively.  
 
7. CLINICAL DATA SUMMARY  
 
7.1 Proposed Indication  
Recurrent Clostridium difficile infection 
 
 
7.2 Background of the Disease  
Clostridium difficile is a common nosocomial pathogen. By far the most common 
cause of infectious diarrhea in hospitalized patients in North America, there has been an 
alarming rise in incidence of C. difficile infection (CDI) since 2000. This rise has been 
accompanied by increasing rates of severe disease resulting in colectomy and/or death. 
Equally as concerning has been the increased incidence of community-associated CDI 
which has been reported in populations previously believed to be low risk. A common 
management problem in CDI is relapse, which occurs in up to 25% of patients after 
treatment of the initial infection. Patients who experience one recurrence have up to a 45% 


 
6
risk of further relapse and those with two or more episodes face up to a 65% risk. While 
the first relapse is generally treated with a second course of metronidazole or vancomycin, 
current guidelines recommend a tapering course of oral vancomycin, which is typically 
given over 4-8 weeks at a cost of $3500, after a second recurrence. Unfortunately, 
treatment options are limited for those patients who develop further recurrences. Patients 
treated with Fidaxomicin currently are faced with an even more expensive cost of therapy. 
A number of patients become “vancomycin dependent,” developing CDI relapse whenever 
this antibiotic is stopped. Antimicrobial agents are thought to alter normal bacterial flora of 
the gastrointestinal tract so as to permit colonization and/or proliferation and toxin 
elaboration by C. difficile. The specific antimicrobials used to treat CDI (metronidazole, 
vancomycin, etc.) also may predispose patients to further relapses through the 
maintenance of perturbed intestinal flora and may contribute to the emerging problems of 
drug resistance. 
 
7.3 Rational for use of an Unapproved Product  
Clostridium difficile is an increasingly common infection. In addition to occurring 
more frequently, there is an epidemic of serious cases which are more refractory to therapy 
and which have high rates of colectomy and death. Most patients with C. difficile respond to 
a course of oral metronidazole or vancomycin, however, up to 25% of patients relapse after 
initial treatment. A number of patients do not respond to these antibiotics or develop 
further recurrences when they are stopped. Unfortunately, treatment options are limited 
for those patients who develop recurrences. Use of antimicrobials to treat C. difficile colitis 
may predispose these patients to further relapses through the maintenance of disturbed 
intestinal flora and may contribute to the emerging problem of drug resistance. FMT has 
been shown to restore the phylogenetic richness and diversity to the intestinal microbiome 
thereby restoring colonization resistance.  
The potential risks associated with this treatment appear to be minimal. Although 
there is a very low risk for complications related to endoscopic administration and 
theoretical risks related to FMT including transmission of infection or risk factors for other 
diseases, the potential benefits of treatment in this group of patients are great, notably 
resolution of C. difficile infection. Thus, the potential benefits of FMT outweigh the potential 
risks of the treatment in these patients who have not responded to standard antimicrobial 
therapy. 
 
7.4 Summary of Previous Human Experience  
 
7.4.1 Previously Published Case Reports and Case Series 
 
Table 1.  Experience with Fecal Microbiota Transplantation 1958-2010 
 
Author 
Indication 
No. Patients 
Method of FMT 
Outcome 
Eiseman et al24 
Pseudomembranous colitis 
4 
Fecal enema 
Symptoms resolve in all 
within 48 hours 
Collins39 
Pseudomembranous colitis 
12 
Fecal enema 
“Favorable reaction in 
10/12” 
Fenton et al40 
Pseudomembranous colitis 
1 
Enema 
Patient Cured 
Bowden et al25 
Pseudomembranous colitis 
16 
Fecal enema (15); enteric 
tube (1) 
Symptoms resolved within 1-
12 days in 13/16 patients 


 
7
Schwan et al17 
Relapsing C. difficile 
1 
Fecal enema 
Prompt & complete 
normalization of bowel 
function 
Tvede and Rask Madsen13 
Relapsing C. difficile 
2 
Rectal infusion 
Symptomatic cure in patient 
1, patient 2 improved after 
infusion of bacterial mixture 
Flotterod and Hopen27 
Refractory C. difficile 
1 
Duodenal tube 
Diarrhea resolved after 
infusion 
Paterson et al41 
Chronic C. difficile 
7 
Rectal tube 
Rapid symptom relief and no 
relapse 
Lund-Tonnesen42 
C. difficile diarrhea 
18 
Colonoscopy (17), 
gastrostomy (1) 
15/18 cured with no relapses 
Persky and Brandt18 
C. difficile diarrhea 
1 
Colonoscopy 
Symptomatic relief within 6 
hours 
Faust et al43 
Recurrent 
pseudomembranous colitis 
6 
Method unstated 
All patients responded and 
4/6 became C. difficile toxin 
negative 
Aas et al19 
Recurrent C. difficile 
18 
Nasogastric tube 
15/18 had no recurrence 
Jorup-Ronstrom et al44 
C. difficile diarrhea 
5 
Fecal lavage (3), enema (1), 
not stated (1) 
4/5 cured 
Wettstein et al45 
C. difficile diarrhea 
16 
Colonoscopy, enema 
15/16 cured 
Borody et al46 
C. difficile in refractory IBD 
6 
Enema 
Negative culture and toxin 
assay at 8 weeks in all 
Louie et al47 
C. difficile diarrhea 
45 
Rectal catheter 
43/45 cured 
Nieuwdorp et al48 
C. difficile diarrhea 
7 
Colonoscopy 
5/7 cured 
You et al20 
Fulminant C. difficile 
diarrhea 
1 
Enema 
Within 36 hours bowel 
function returned and 
abdominal distension 
decreased 
Hellemans et al49 
C. difficile diarrhea 
1 
Colonoscopy 
Patient cured 
MacConnachie et al50 
Recurrent C. difficile 
15 
Nasogastric tube 
12/15 became symptom free 
Khoruts et al15 
C. difficile diarrhea 
1 
Colonoscopy 
Patient cured 
Yoon and Brandt22 
Recurrent/refractory C. 
difficile 
12 
Colonoscopy 
Symptomatic cure in all 12 
Rohlke et al23 
Recurrent C. difficile 
19 
Colonoscopy 
18/19 became asymptomatic 
immediately; 1 patient 
relapsed; 3 had recurrence 
during follow-up period after 
antibiotics 
Silverman et al21 
Chronic C. difficile 
7 
At-home fecal enema 
All responded 
Garborg et al51 
Recurrent C. difficile 
40 
EGD (38), colonoscopy (2) 
83% success rate 
Kelly and deLeon28 
Recurrent C. difficile 
12 
Colonoscopy 
All patients responded 
Russell et al52 
Refractory C. difficile 
1 
Nasogastric tube 
Symptom resolution within 
36 hours in 2 year old girl 
Total 275 Response 246/275=89%  
EGD, esophagogastroduodenoscopy; IBD, Inflammatory Bowel Disease 
 
7.4.2 Investigator’s Published and Continuing Experience 
 
Dr. Smith is board-certified in Infectious Diseases and has a special interest in Clostridium 
difficile infection (CDI).  She has previously published on the epidemiology of community-
acquired and healthcare-associated CDI.  She has experience in treating patients with 
recurrent CDI using fecal microbiota transplantation (FMT).  Dr. Smith, Dr. Eugene Yen, and 
several members of the Division of Infectious Diseases at NorthShore University 
HealthSystem have performed FMT for 18 patients with recurrent CDI.  Table 2 
summarizes our clinical experience to date.  Our primary clinical outcome, prevention of 
CDI relapse and/or significant diarrhea requiring vancomycin within 8 weeks after FMT 
was achieved in 17/18 patients (94.5%) after one infusion of donor stool.  Three patients 


 
8
relapsed (2/3 following receipt of antibiotics).  One of those 3 patients responded to a 
course of oral vancomycin and did not relapse.  The other 2 patients have had multiple 
relapses and are currently awaiting repeat FMT following IND approval.  We have 
successfully and without adverse events treated patients with immunodeficiency including 
CLL, solid organ malignancy, and hypogammaglobulinemia.      


 
9
 
TABLE 2: Patients (18) Treated by Drs. Yen (GI), Smith (ID), Kaplan(ID), Schrantz (ID), Semel (ID), Nega (ID). 
GI=Gastroenterology, ID=Infectious Diseases. ABX = Antibiotics. 
 
Number 
Patient 
(Sex, 
Age) 
Donor 
Relation-
ship 
Inciting Event 
CDI 
Duration 
(Months) 
Other Treatments 
Prior to FMT 
Route of 
Instillation 
Colonoscop
y Findings 
Primary 
Clinical 
Outcome 
FMT Date 
CDI 
Recurrence 
Date 
Adverse 
Events 
1 
F, 81 
Husband 
ABX  
11 
Metronidazole x 1 
Vancomycin taper 
x 2 
Rifaximin ‘chaser’ x 
1 
Fidaxomicin x 1 
Vancomycin 
 
EGD 
N/A 
Cure 
10/10/11 
No 
N/A 
None 
*Died due to 
Metastatic 
pancreatic ca 
1/30/12 
(diagnosed 
during eval for 
recurrent CDI) 
2 
M, 84 
Wife 
ABX  
9 
Metronidazole x 2 
 rash 
Vancomycin taper 
x 2 
Colonoscopy 
Sessile 
polyp 
Diverticuli 
Internal 
Hemorrhoi
ds 
Cure 
11/14/12 
No 
N/A 
None 
*Died on 
Hospice for 
underlying 
severe CHF >1 
month after 
procedure.  
Last office visit 
notes diarrhea 
resolved and 
no GI 
symptoms 
3 
M, 83 
Daughter 
ABX/GI 
surgery 
6 
Vancomycin x 1 
Metronidazole x 4 
Cholestyramine 
Fidaxomicin 
Colonoscopy 
Sigmoid 
circumfere
ntial mass 
(had known 
colon CA) 
and 
diverticuli 
Cure 
2/20/13 
No 
N/A 
None 
4 
F, 78 
Unrelated 
No Antibiotics 
11 
Metronidazole x 1 
Vancomycin x 2 
Vancomycin taper 
Rifaximin taper 
Fidaxomicin 
IVIG 
EGD 
N/A 
Cure 
5/15/12 
No 
N/A 
None 
5 
M, 75 
Daughter 
No Antibiotics 
Caregiver for 
wife who was 
frequently 
hospitalized 
and in Rehab 
4 
Vancomycin x 1 
Vancomycin taper 
x 2 
 
EGD 
N/A 
Cure 
1/27/12 
No 
N/A 
None 


 
10
6 
M, 76 
Daughter 
ABX 
21 
Vancomycin x 1 
Vancomycin taper 
x 4 
Probiotics 
Rifaximin 
EGD 
N/A 
Cure 
9/11/12 
No 
N/A 
None 
7 
F, 62 
Husband 
ABX 
12 
Metronidazole 
Vancomycin x 
multiple courses 
Vancomycin taper 
x multiple courses 
Retention 
enema 
N/A 
Cure 
8/16/12 
Yes 
1/6/13 
None 
*Note prior Hx 
lymphocytic 
colitis and 
hypogammagl
obulinemia on 
IVIG 
8 
F, 77 
Husband 
ABX 
5 
Vancomycin x 1 
Vancomycin taper 
x 2 
Fidaxomicin 
Metronidazole 
intolerance 
EGD 
N/A 
Cure 
11/14/12 
No 
N/A 
None 
9 
F, 61 
Daughter 
ABX 
3 
Metronidazole x 2 
Vancomycin Taper 
x 1 
Retention 
enema 
N/A 
Cure 
2/15/13 
Yes 
4/18/13 
None 
* Note patient 
with ALS who 
would develop 
resp failure 
requiring 
ventilator with 
each episode 
 
10 
F, 34 
Husband 
ABX 
10 
Metronidazole x 1 
Vancomycin x 1 
Vancomycin Taper 
x 2 
EGD 
N/A 
Cure 
3/22/13 
No 
N/A 
None 
 
 
 
 
11 
M, 76 
Son 
ABX 
10 
Metronidazole 
Vancomycin x 1 
Vancomycin Taper 
x 2 
Fidaxomicin 
Colonoscopy 
Diverticuli 
Polyps 
Hemorrhoi
ds 
Cure 
8/22/12 
No 
N/A 
None 
*Note patient 
had advanced 
dementia and 
died 11/28/12 
(not due to 
CDI) 
12 
F, 89 
Unrelated 
ABX 
10 
Metronidazole x 2 
Vancomycin x 1 
Vancomycin Taper 
x 2 
 
 
 
 
Colonoscopy 
Diverticuli 
Hemorrhoi
ds 
Cure 
11/7/12 
No 
N/A 
None 


 
11
13 
M, 86 
Daughter 
ABX 
19 
Metronidazole x 3 
Vancomycin taper 
x 3 
Kefir 
Probiotics 
 
Colonoscopy 
Polyps 
Diverticuli 
Cure 
10/11/12 
No 
N/A 
None 
14 
F, 28 
Husband 
ABX 
36 
Multiple 
vancomycin tapers 
(16 episodes over 
3 years) 
EGD 
Chronic 
Inflammati
on no IBD 
Cure 
5/19/10 
No 
N/A 
None 
 
15 
F, 82 
Husband 
ABX 
14 
Vancomycin  x 
multiple 
Vancomycin Taper 
Maintenance dose 
vanco 
EGD 
N/A 
Cure 
12/14/11 
No 
N/A 
None 
16 
F, 29 
Mother 
ABX 
2 
Vancomycin x 1 
Fidaxomicin x 2 
EGD 
N/A 
Cure 
8/16/12 
No 
N/A 
None 
*Note history 
of Ulcerative 
colitis 
17 
F, 86 
Cousin 
ABX/GI 
Surgery 
10 
Vancomycin x 1 
Vancomycin taper 
x 3 
Colonoscopy 
Diverticuli 
Hemorrhoi
ds 
Cure 
5/10/12 
No 
N/A 
None 
18 
F, 84 
Son 
ABX 
4 
Metronidazole x 1 
Vancomycin x 1 
Vancomycin taper 
x 1 
Fidaxomicin 
Tigecycline 
Colonoscopy 
Colitis (bx 
negative 
for other 
etiology) 
Cure 
3/14/13 
Yes 
3/25/13 
None 
* Patient had 
UTI and was 
treated with 
Cefpodoxime 
by PCP then 
relapsed 
within days 


 
12
Safety 
All patients tolerated the procedure well without any procedure (colonoscopy, EGD, or 
retention enema) – related complications.  Three of the patients died, as noted, within 1 
year following the procedure, none of which were directly related to the procedure or C. 
difficile infection (CDI)  but rather related to underlying severe comorbid conditions.  
Documentation in the medical record conforms resolution of diarrhea and no infectious 
symptoms to suggest active CDI at the time of death.   There were no other significant 
complications or adverse outcomes.  
 
8. TREATMENT PROTOCOL  
 
Study Design 
A one-year, open-label randomized controlled trial from 1/1/15-12/31/15 at all 
NorthShore hospitals.   
 
Patient Selection 
All hospitalized patients in the NorthShore system >18 years of age who are diagnosed 
with active CDI, defined as >3 diarrheal stools per day and a positive C. difficile PCR assay, 
will be evaluated for inclusion in the study.  Hospitalized patients presenting with a relapse 
of CDI occurring at least 15 days after an index episode of CDI will be eligible for 
enrollment.  Exclusion criteria will include pregnancy, neutropenia (absolute neutrophil 
count <1000/μl), contraindication for retention enema, toxic megacolon or health-
threatening food allergy not controlled for in the donor diet.  Eligible patients will undergo 
written informed consent followed by randomization into intervention and control groups. 
  
Outcomes 
The primary outcome will be clinical resolution of diarrhea without recurrence of CDI 
within 90 days.  Secondary outcome measurements will include the time to clinical 
resolution of symptoms (number of daily bowel movements, daily white blood cell count, 
daily creatinine, and temperature), hospital length of stay (LOS), ICU admission and LOS, 
total charges, 90-day mortality, 90-day readmission, colectomy, antibiotic use, co-
colonization of the gastrointestinal (GI) tract with other multidrug-resistant organisms 
(MDROs), and the presence of adverse events. 
 
Study Procedures 
Patients will be eligible for enrollment within 48 hours of the positive C. difficile PCR or EIA 
test.  Subjects will be randomized with a 1:1 ratio to either the FMT or the standard 
antibiotic treatment arms by computer-generated randomization numbers. There will be a 
separate randomization for the subjects on their first relapse vs. their second or greater 
relapse since these two patient populations may respond differently to FMT and/or 
antibiotics.   
 
Patients who are randomized to the intervention group will have antimicrobials targeting 
C. difficile discontinued at least 6 hours prior to undergoing an FMT via retention enema.  A 
second FMT via retention enema will be administered at 24-48 hours if diarrhea and 
clinical symptoms persist.  Patients randomized to the control group will be treated with 


 
13
antimicrobials targeting C. difficile according to the Society for Healthcare Epidemiology of 
America Clinical Practice Guidelines for CDI (18).  FMT will be offered to the control group 
after 90 days if they experience relapsing CDI. If a patient in the control arm progresses to 
refractory CDI, FMT will be offered (which will be accounted for with the ITT statistical 
analysis).  Donor and recipient stool will be collected before and after the FMT procedure 
to be cultured later for future research studies.  Collected stool will stored in the 
Department of Pathology and will be under the supervision of the Infectious Disease 
physicians overseeing the research study.  All samples will be coded with subject-ID 
numbers that are created by the research staff.  In addition, the date/time of collection will 
be included on the stool sample label.  Lastly, the severity of each patients CDI episode will 
be recorded based on Society for Healthcare Epidemiology of America Clinical Practice 
Guidelines for CDI (18).  Please note that severity of C. difficile will not determine 
randomization status.    
 
8.1. Indications  
This is a protocol for use of fecal microbiota transplantation (FMT) in adult (≥18 year old) 
hospitalized patients suffering from recurrent C. difficile infection (CDI). FMT will be used 
to treat CDI in the following circumstances:  
 
1. Recurrent or relapsing CDI (first relapse)  
a. At least 3 diarrheal stools per day and a positive C. difficile PCR assay 
b. Hospitalized patients presenting with their first relapse of CDI occurring  
at least 15 days after an index episode of CDI  
 
2. Recurrent or relapsing CDI (second or greater relapse)  
a. At least 3 diarrheal stools per day and a positive C. difficile PCR assay 
b. Hospitalized patients presenting with their second or greater relapse of 
CDI occurring at least 15 days after an index episode of CDI  
 
Definitions  
 Clostridium difficile infection: as per SHEA-IDSA guidelines, at least three unformed 
stools over 24 hours for two consecutive days and either positive stool testing 
(ELISA or PCR) for C. difficile toxins or pseudomembranes on colonoscopy.  
 
8.2 Donor Eligibility Determination  
I. Donor selection and screening: Two healthy “universal” donors who have previously 
donated fecal material for FMT have expressed willingness to participate in the study.   
Donors will complete the American Association of Blood Banks donor questionnaire for 
exposure to infectious agents as well as undergo serologic and stool testing for 
communicable diseases or pathogenic bacteria/viruses as previously described (17). 
 
A. Donor Interview: Potential donors will have a brief interview to determine the 
presence of systemic medical conditions, which will preclude donation.  
1. Known communicable disease  
2. Systemic autoimmunity or atopic diseases  
3. Chronic pain syndromes (for example: fibromyalgia, chronic fatigue)  


 
14
4. Neurologic, neurodevelopmental or neurodegenerative disorders  
5. Malignancy  
6. Diarrheal disorder (IBS, IBD, celiac disease)  
7. Use of antibiotics for any indication within the past 3 months 
 
B. Donor Screening Questionnaire. Potential donors will undergo informed consent 
for screening tests and if they wish to participate will be interviewed using a 
questionnaire based on the Donor History Questionnaire (DHQ) materials prepared 
by the AABB Donor History Task Force for use in screening blood donors. The DHQ 
is especially important to identify risks for diseases and conditions for which there 
are no laboratory tests, for which tests are not sensitive enough to detect infectious 
disease agents, and for which tests are unable to identify early stage or window 
period infections. Additional questions which are felt relevant to FMT, including 
recent use of antimicrobials, and history of relevant medical conditions have been 
added to this questionnaire (appendix 1).  
 
Our modified DHQ will be used to exclude donors with these and other risk factors:  
1. High risk sexual behaviors (examples: sexual contact with anyone with 
HIV/AIDS or hepatitis, men who have sex with men, sex for drugs or money)  
2. Known exposure to HIV or viral hepatitis within the previous 12 months.  
3. Being held in a correctional facility for more than 72 hours in the last 12 
months  
4. Use of intravenous drugs or intranasal cocaine  
5. Recent tattoo or body piercing  
6. Recent transfusion, transplant or skin graft  
7. Risk factors for variant Creutzfeldt-Jakob disease  
 
DHQ will be completed within 30 days of FMT. Use of antibiotics will preclude 
donation for a period of 3 months. 
 
C. Donor Laboratory Testing. HIV 1 & 2 testing will be performed within 2 weeks of 
donation for FMT. The other serologic and stool screening will be performed within 
one month of donation for FMT. (appendix 2).  
1. Stool:  
 Clostridium difficile toxin by PCR  
 Routine bacterial culture for enteric pathogens (E coli, Salmonella, 
Shigella, Yersinia, Campylobacter)  
  Culture for Listeria monocytogenes and Vibrio (parahaemolyticus and 
cholerae)  
  Fecal Giardia antigen  
  Fecal Cryptosporidium antigen  
  Acid-fast stain for Cyclospora and Isospora  
  Ova and parasites  
  Stool for Rotavirus via EIA  
  Helicobacter pylori stool antigen 


 
15
 Norovirus by PCR 
 
2. Blood:  
  HIV, type 1 and 2  
  HAV IgM  
  HBsAg, anti-HBc (both IgG and IgM), and anti-HBs.  
  HCV Ab 
  RPR  
 
D. Day of donation: On the day of the stool donation, donor will be questioned 
regarding the following:  
1. Fever, vomiting, diarrhea or other symptoms of infection within the last 30 
days.  
 
8.3 Patient eligibility determination  
 
A. Potential FMT patients will undergo a medical interview to determine eligibility 
for the treatment and a physical exam will be performed.  
 
B. Only patients ≥18 years old will be treated under this FMT protocol.  
 
C. Serologic Testing will be done on all patients to document baseline status prior 
to FMT including: HIV 1 & 2, Hepatitis A total, Hepatitis B surface Ag, surface Ab 
and core Ab, Hepatitis C Ab, and RPR.  
 
D. Pre-treatment Medications  
1. Relapsing CDI patients will have completed at least a 10 day course of 
vancomycin (or other antibiotics with activity against CDI including 
metronidazole, fidaxomicin and rifaximin) for their initial episode of CDI (the 
one prior to hospital stay) prior to undergoing FMT.  
 
2. To control disease while awaiting FMT, vancomycin will be continued by 
relapsing subjects until at least 6 hours prior to scheduled procedure and by 
refractory subjects until the evening prior to the procedure. Other antibiotics 
with activity against CDI are also permissible while awaiting FMT including 
metronidazole, fidaxomicin and rifaximin.  
 
E. Female patients  
1. Females of childbearing potential will have a urine pregnancy test on the 
day of the FMT procedure (to ensure eligibility). Patients who are pregnant 
will not be permitted to receive FMT.  
 
2. Female subjects should not become pregnant nor breast-feed an infant 
within 4 weeks of treatment by FMT. In order to reduce the risk of 
pregnancy, patient or her partner should use an acceptable method of birth 


 
16
control listed below, regularly and consistently. Acceptable methods of birth 
control (continuing pre-FMT and for one month after treatment) include:  
  An approved oral contraceptive (birth control pill)  
  Intra-uterine device (IUD)  
  Hormone implants  
  Contraceptive injection (Depo-Provera)  
  Barrier methods (diaphragm with spermicidal gel or condoms)  
  Transdermal contraceptives (birth control patch)  
  Vaginal contraception ring (birth control ring)  
  Sterilization (tubal ligation, hysterectomy or vasectomy)  
  Abstinence  
3. If patients become pregnant or suspect that they are pregnant, or if they 
make someone pregnant, within 4 weeks of treatment with FMT, they will be 
instructed to immediately inform the treating physician. If patients suspect 
that they are pregnant within 4 weeks of FMT, a pregnancy test will be done. 
If conception occurs within the 30-day post-FMT period, the study physician 
will assist the patient in getting obstetrical care and will follow the progress 
of the pregnancy. The study physician will request access to patients and/or 
infants medical records for up to at least eight weeks after delivery. 
 
8.4. Preparation of Stool for FMT Infusion  
 
A. Collection and handling  
1. Donors will be supplied a toilet hat and clean, sealable plastic containers for 
collection and transport of stool specimens. Containers will be labeled with the 
name, date of birth and date/time of stool collection.  
 
2. Collected stool will be immediately processed and stored at -80C for future use. 
 
B. Location & preparation of processing  
 Stool will be processed in a designated area at each site. This is typically within the 
endoscopy unit or area where the FMT will be performed.  
 Universal precautions will be used during processing (gown, gloves, eye 
protection).  
 Clean counter surface will be covered with a Chux® pad.  
 After the FMT, all surfaces will be wiped with hospital-approved disinfectant 
solution.  
 
C. Preparation materials  
 1 liter bottle of sterile, nonbacteriostatic normal saline  
 60 cc disposable slip (catheter)-tip syringes  
 Clean gauze  
 Clean plastic spoon  
 
D. Preparation method  


 
17
Fecal microbiota preparations will be handled as described by Hamilton et al (15).   
 500 cc of saline will be poured out of the 1-liter bottle and discarded.  
 RA will suspend at least 50 grams (or available quantity) of stool in 250 mL of 
sterile, non-bacteriostatic normal saline within 2 hours of collection.   
 The slurry will be filtered, centrifuged, and re-suspended in sterile, non-
bacteriostatic normal saline and sterile pharmaceutical grade glycerol to a final 
concentration of 10% 
 The final product will be stored at -80ºC for up to 8 weeks 
 When needed for use, the material will be thawed in an ice bath over 2-4 hours 
and then diluted to 250 mL sterile, non-bacteriostatic normal saline before 
infusion into the recipient. 
 The fecal suspension will be drawn into five 60 cc slip (catheter) tip syringes for 
infusion.  
 
8.5. FMT Procedure.  
 
A. Patient preparation  
1. Patients will have completed at least a 10-day course of vancomycin (or other 
anti-CDI therapy such as fidaxomicin or metronidazole) for the most recently 
diagnosed acute CDI prior to undergoing FMT (e.g. their first episode) 
 
2. To prevent disease relapse while awaiting FMT, anti-CDI therapy will be 
continued by patients until at least 6 hours prior to scheduled procedure.  
 
3. Subject will be ordered to take no food or liquids (NPO) at least 4 hours prior to 
the procedure.  
 
4. 1-2 hours before retention enema, the patient may take 2 loperamide tablets to 
aid in retention of administered donor stool.  
 
B. Methods of FMT infusion.  
1. Procedure will be performed in the patient’s hospital room (NorthShore 
University HealthSystem).  
 
2. The method used to deliver the FMT will be a retention enema: 
 A rectal tube will be placed by the staff nurse.   
 The donor specimen will be infused into the rectum via the rectal tube in 
place.  Once the sample has been instilled, the tube will be clamped for 1 
hour.   
 Vitals signs will be collected every 15 minutes by clinical staff (nursing staff) 
and recorded in patient’s EMR. 
 
 After one hour the rectal tube will be unclamped and removed. The rectal 
tube will be kept in place only if medically necessary.  


 
18
 
 
 If patient has not improved based on clinical parameters, a 2nd FMT will be 
completed within 24- 48 hours. 
3. The physician will administer ~250-300 mL of the fecal suspension in aliquots of 
60 mL via retention enema.  
 
4. The patient is encouraged to retain stool for as long as possible (optimally 1 
hour). 
 
 
8.6. Follow up  
 
A. Plan for clinical follow up:  
 Patients will be encouraged to contact the research team immediately if they 
experience recurrence of diarrhea so that stool can be tested for C. difficile toxins A 
& B and treatment with anti-CDI therapy can be initiated if necessary.  
 Patients will be contacted daily by telephone or in-person while hospitalized after 
the FMT procedure.  In addition, research staff will complete chart review to collect 
vital signs, lab results, and medication information.  If patient is unavailable or 
unable to respond to questions, research staff will speak with nurse assigned to 
patient.   
 Patients will be asked to submit a stool sample 7 days post-FMT for C. difficile toxin 
testing as well as co-colonization of the GI tract with multi-drug resistant organisms 
(MDROs). 
 In addition, patients will be contacted via telephone by a member of the research 
staff 7 days post FMT (+ 3 days). 
 Regardless of symptoms, all subjects will be scheduled in the office for follow up 
visit at 30 days post-FMT (+30 days).  During this time, patients will submit stool 
specimens for C. difficile toxin testing as well as co-colonization of the GI tract with 
multi-drug resistant organisms (MDROs) 
 Patients will also provide a third stool sample at their 4 week follow up visit. 
 Patients will be contacted via telephone by a member of the research staff 3 months, 
6 months, and annually post-FMT (all contacts with a window of ±14 days). The 
annual follow-up calls will occur indefinitely.  
 Patients will be instructed to inform the treating physician of any infectious 
symptoms or new medical conditions which develop after FMT. Adverse events will 
be elicited at follow up telephone contacts and follow up visits and all patients will 
be contacted via telephone by research staff member 3 months, 6 months, and 
annuallyafter the last treatment to record any SAEs, new medical 
conditions/diagnoses or changes in medical conditions/medications since last 
clinical contact.  
 
 


 
19
B. Patients who relapse  
1. In the event of treatment failure (defined as CDI recurrence requiring additional 
anti-infective therapy), the treating physician will have the following options.  
 Patient may undergo a second FMT using the same or an alternate donor. 
This second FMT will be completed within 24-48 hours of the first FMT if 
diarrhea persists.   
 Patient may choose not to receive further FMT, but may continue to be 
treated in accordance with the current standard of care. The patient will 
continue to be followed for closely for AEs with telephone calls and clinic 
visits as per this protocol.  
 Alternatively, patients who chose not to receive further FMT may decide to 
be treated at another facility of their choosing. They will still be followed as 
per protocol through the 30 day post FMT period and asked to receive a 3 
month and 6 month follow-up telephone call to assess for late SAEs or 
changes in medical conditions/diagnoses or medications.  
 
Patients who chose to undergo a second FMT will have the identical procedure, including 
donor eligibility determination, follow up, and safety monitoring. 
 
C. Withdrawal of patients  
Patients who withdrawal from treatment protocol will be characterized as follows:  
1. Patients who receive FMT and are then lost to follow up: Every reasonable effort 
will be made to contact these patients to ensure they are receiving appropriate 
follow up care with documentation of any SAEs/AEs or changes in medical 
conditions/diagnoses or medications.  
2. Patients withdrawn because of SAE/AE or at the discretion of the physician will 
continue to receive treatment (outside this protocol) in accordance with current 
standard of care. Patients having AEs will be monitored with relevant clinical 
assessments and laboratory tests, as determined by the treating physician. 
 
D. Adverse Events  
We will specifically document and report to FDA:  
 Complications related to the colonoscopy or sigmoidoscopy (sedation related, 
perforation, bleeding)  
 Complications related to FMT (infection, inflammatory or allergic reaction)  
 Solicited and unsolicited AEs, including fever, will be assessed at follow up 
telephone contacts and clinic visits.  
 Development of new symptoms/diagnoses (irritable bowel syndrome, inflammatory 
bowel disease, autoimmune disorder, neurologic disorder) which may be related or 
unrelated to FMT will be elicited at the 6 month follow up telephone call, 
documented and reported to the FDA.  
 Subjects who have an SAE that is possibly, probably or definitely related to FMT will 
not receive a second FMT, if, after review of the SAE, it is determined that they are at 
risk for another SAE if a second FMT is performed. For example, if the subject 
develops an allergic reaction post FMT and it is determined that the donor 


 
20
inadvertently ingested the known allergen prior to donation, the subject may qualify 
for a second FMT after subsequent donor screening minimizes exposure to the 
allergen.  
 The sponsor will notify FDA of any unexpected fatal or life-threatening suspected 
adverse reaction as soon as possible but in no case later than 7 calendar days after 
the sponsor's initial receipt of the information.  
 We will notify the FDA within 7 days if an infectious disease is possibly, probably or 
definitely transmitted to a patient via FMT.  
 All SAEs will be reported within 15 days to the FDA  
 All other AEs will be reported in an annual report to the FDA.  
 
1. Patient reporting of AEs:  
Patient will be instructed to contact the treating physician/research staff at any time point 
post-FMT to report symptoms experienced.  The following AEs will be solicited at 
telephone contacts (daily case report forms, 1-week follow up, 3-month follow up, and 6-
month follow).   and at 4-week clinic visit along with the intensity of each.  
PARAMETER 
GRADE 1 MILD 
GRADE 2 
MODERATE 
GRADE 3 SEVERE 
GRADE 4 POTENTIALLY 
LIFE-THREATENING 
ESTIMATING SEVERITY GRADE 
 
Symptoms 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Symptoms causing inability 
to perform basic self-care 
functions OR Medical or 
operative intervention 
indicated to prevent 
permanent impairment, 
persistent disability, or 
death 
SYMPTOM SPECIFIC SEVERITY GRADE 
Fever (oral) 
(99.9-100.5°F) 
(100.6-102.5°F) 
(102.6-104°F) 
> 104°F 
Diarrhea 
Transient or 
intermittent 
episodes of 
unformed stools 
OR Increase of ≤ 
3 stools over 
baseline per 24-
hour period 
Persistent episodes 
of unformed to watery 
stools OR Increase of 
4 – 6 stools over 
baseline per 24-hour 
period 
Bloody diarrhea OR 
Increase of ≥ 7 stools 
per 24-hour period 
OR IV fluid 
replacement 
indicated 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
Nausea 
Transient (< 24 
hours) or 
intermittent 
nausea with no 
or minimal 
interference with 
oral intake 
Persistent nausea 
resulting in 
decreased oral intake 
for 24 – 48 hours 
Persistent nausea 
resulting in minimal 
oral intake for > 48 
hours OR Aggressive 
rehydration indicated 
(e.g., IV fluids) 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
Fatigue 
Malaise 
 
Symptoms 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Incapacitating fatigue/ 
malaise symptoms causing 
inability to perform basic 
self-care functions 


 
21
Vomiting 
Transient or 
intermittent 
vomiting with no 
or minimal 
interference with 
oral intake 
Frequent episodes of 
vomiting with no or 
mild dehydration 
Persistent vomiting 
resulting in orthostatic 
hypotension OR 
Aggressive 
rehydration indicated 
(e.g., IV fluids) 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
Headache 
Symptoms 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Symptoms causing inability 
to perform basic self-care 
functions OR Headache 
with significant impairment 
of alertness or other 
neurologic function 
Distension/bloating, abdominal 
discomfort 
Asymptomatic 
Symptomatic, but not 
interfering with GI 
function 
Symptomatic, 
interfering with GI 
function 
--- 
Abdominal Pain 
Symptoms 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Disabling pain causing 
inability to perform basic 
self-care functions OR Life 
threatening consequences 
(i.e. acute peritonitis) 
Dehydration 
Increased oral 
fluids indicated; 
dry mucous 
membranes; 
diminished skin 
turgor 
IV fluids indicated 
<24 hours 
IV fluids indicated 
>24 hours 
Life-threatening 
consequences (e.g. 
hemodynamic collapse) 
Dizziness 
With head 
movements or 
nystagmus only; 
not interfering 
with function 
Interfering with 
function, but not 
interfering with ADL 
Interfering with ADL 
Disabling 
Colitis Symptoms 
Asymptomatic, 
pathologic or 
radiographic 
findings only 
Abdominal pain; 
mucus or blood in 
stool 
Abdominal pain, 
fever, change in 
bowel habits with 
ileus; peritoneal 
Life-threatening 
consequences (e.g. 
perforation, bleeding, 
ischemia, necrosis, toxic 
megacolon) 
Weight Loss 
5 to <10% from 
baseline; 
intervention not 
indicated 
10-<20% from 
baseline; nutritional 
support indicated 
≥20% of baseline 
--- 
Rash 
Macular or 
popular eruption 
or erythema 
without 
associated 
symptoms 
Macular or popular 
eruption or erythema 
with pruritus or other 
associated 
symptoms; localized 
desquamation or 
other lesions covering 
<50% of body surface 
area (BSA) 
Severe, generalized 
erythroderma or 
macular, popular, or 
vesicular eruption; 
desquamation 
covering ≥50% BSA 
Generalized exfoliative, 
ulcerative, or bullous 
dermatitis 
Dysphagia 
Symptomatic; 
able to eat 
regular diet 
Symptomatic and 
altered 
eating/swallowing 
Symptomatic and 
severely altered 
eating/swallowing 
Life-threatening 
consequences (e.g. 
obstruction, perforation) 


 
22
(e.g., altered dietary 
habits, oral 
supplements); IV 
fluids indicated 
<24hrs 
(e.g. inadequate oral 
caloric or fluid intake); 
IV fluids, tube 
feedings, or TPN 
indicated ≥24hrs 
 
9. Adverse Event Reporting  
A. Definitions  
1. Adverse Event (AE)  
An AE is any untoward medical occurrence in a patient or clinical trial subject administered  
FMT that does not necessarily have to 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 FMT, whether or not 
related to the FMT.  
• AEs may be new events or may be pre-existing conditions that have become aggravated 
or have worsened in severity or frequency.  
• AEs may be clinically significant changes from baseline in physical examination, 
laboratory tests, or other diagnostic investigation (e.g., laboratory results, x-ray findings).  
 
Pregnancy is not an AE; however, if a female subject becomes pregnant during 4-week 
period post-FMT, the treating physician will notify the FDA. 
 
2. Serious Adverse Event (SAE)  
A serious adverse event is any adverse experience occurring during or after FMT that 
results in any of the following outcomes:  
• Death;  
• Life-threatening experience;  
Note: An adverse event or suspected adverse reaction is considered “life-threatening” if, in 
the view of either the investigator or sponsor, its occurrence places the patient or subject at 
immediate risk of death. It does not include an adverse event or suspected adverse reaction 
that, had it occurred in a more severe form, might have caused death.  
• Requires inpatient hospitalization or prolongation of existing hospitalization.  
Note: Adverse events requiring hospital admissions that are less than 24 hours in duration 
do not meet this criterion. A scheduled hospitalization for a pre-existing condition that has 
not worsened during participation in the study does not meet this criterion. Pre-planned 
hospitalizations for an elective medical/surgical procedure or routine check-ups do not 
meet this criterion;  
• Results in persistent or significant disability or incapacity;  
• Is a congenital anomaly or birth defect;  
• Is considered to be an important medical event.  
Note: Important medical events are those that may not be immediately life threatening or 
result in death or hospitalization but may jeopardize the patient or may require 
intervention to prevent one of the outcomes listed in the definition above. 
 
3. Planned Hospitalization  


 
23
A hospitalization planned prior to FMT is to be considered a therapeutic intervention and 
not the result of a new SAE. If the planned hospitalization or procedure is executed as 
planned, it will be recorded in the subject’s medical history or procedures. However, if the 
event/condition worsens during the trial, it must be reported as an AE.  
 
4. Adverse reaction 
An adverse reaction means any adverse event caused by FMT. Adverse reactions are a 
subset of all suspected adverse reactions for which there is reason to conclude that FMT 
caused the event.  
 
5. Suspected Adverse Reaction  
Suspected adverse reaction means any adverse event for which there is a reasonable 
possibility that FMT caused the adverse event. For the purposes of IND safety reporting, 
reasonable possibility‟ means there is evidence to suggest a causal relationship between 
FMT and the adverse event. A suspected adverse reaction implies a lesser degree of 
certainty about causality than adverse reaction, which means any adverse event caused by 
a drug.  
 
6. Unexpected  
An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed 
in the investigator brochure or is not listed at the specificity or severity that has been 
observed; or is not consistent with the risk information described in the general 
investigational plan or elsewhere in the current application. 
 
B. Monitoring  
1. Monitoring of Adverse Events  
Each patient will be monitored for the occurrence of AEs, including SAEs, beginning 
immediately after FMT. Patients will be questioned at each follow up time-point regarding 
stool form/frequency, presence of abdominal pain, fevers and subjective well-being and/or 
examined (at 4-week follow up visits) by the treating physician for evidence of AEs. The 
questioning of subjects with regard to the possible occurrence of adverse events will be 
generalized such as, "How have you been feeling since your last visit?”  
 Patients having AEs will be monitored with relevant clinical assessments and 
laboratory tests, as determined by the treating physician.  
 AEs, actions taken as a result of AEs, and follow-up results must be recorded in the 
patient’s medical record.  
 Patients will receive a follow up phone call 6 months post-transplant to record any 
SAEs, new medical conditions/diagnoses or changes in conditions or diagnoses 
since last study contact.  
 
For all SAEs and AEs, relevant clinical assessments and laboratory tests will be repeated as 
clinically appropriate, until final resolution or stabilization of the event(s). 
 
C. Assessment of Adverse Events  
1. Assessment of Severity  


 
24
The severity of AEs will be assessed according to the following definitions:  
•Mild: the AE is noticeable to the patient and/or the Investigator, but does not interfere 
with routine activity.  
•Moderate: the AE interferes with routine activity, but responds to symptomatic therapy 
or rest.  
•Severe: the AE significantly limits the patient’s ability to perform routine activities 
despite symptomatic therapy.  
 
2. Assessment of Causality  
The physician must assess the relationship of any AE (including SAEs) to FMT, as related or 
not related, based on clinical judgment and using all available information, and may include 
consideration of the following factors:  
• Possible alternative causes of the AE, including the disease under treatment, pre-existing 
conditions, concomitant use of other drugs, and presence of environmental or genetic 
factors.  
• The temporal association between FMT exposure and onset of the AE.  
• Whether the manifestations of the AE are consistent with known actions or theoretical 
toxicity of FMT. 
 
The causal relationship between FMT and the AE will be assessed using one of the 
following categories:  
Not Related: An AE is not associated with FMT if:  
• Temporal relationship is lacking (e.g., the event did not occur within a reasonable time 
frame following administration of FMT); or  
• Other causative factors more likely explain the event (e.g. pre-existing condition, other 
concomitant treatments);  
Related: An AE is attributed to FMT if:  
• There is a positive temporal relationship (e.g., the event occurred within a reasonable 
time frame following FMT); and  
• The AE is more likely explained by FMT than by another cause 
 
D. Reporting Safety Observations by the Investigator to the Sponsor  
1. Reporting of Nonserious AEs  
All AEs, regardless of seriousness, severity, or causal relationship to FMT, will be 
recorded in the patient’s medical record.  
 
2. Reporting of FMT Exposure during Pregnancy  
If a female patient or the female partner of a male patient becomes pregnant during 
4-week period post-FMT, the physician is required to follow up on the pregnancy 
until it has completed. The outcome of the pregnancy and the status of the newborn 
(if applicable) will be reported within 24 hours of becoming aware. If the female 
partner of a male subject becomes pregnant, the physician must obtain consent to 
collect pregnancy information (including the status of the newborn, if applicable).  
 
3. Reporting of Safety Observations by the Physician  


 
25
Any occurrence of the following events or outcomes a patient treated under this IND 
must be reported expeditiously by the treating physician to the FDA.  
1. SAE  
2. Death of a subject  
 
The investigator is to report any safety observations from the list above to the FDA within 7 
days of becoming aware of the event. Any observation that is also an AE will be recorded in 
the medical record along with any actions taken. If not all information is available at the 
time of initial report, follow up SAE reports will be completed and submitted.  
The investigator is required to follow SAEs until resolution. Resolution is defined as:  
 Resolved with or without residual effects  
 Return to baseline for a pre-existing condition  
 Fatal outcome; if autopsy is performed, the autopsy report must be provided to the 
sponsor.  
 
4. Protocol-Specific Exceptions to (Serious) Adverse Event Reporting  
A suspected clinical endpoint event, regardless of when the event occurs, is not to be 
reported as an AE or SAE or reported in an expedited manner as an SAE.  
The suspected clinical endpoint event includes:  
Recurrent CDAD: The patient meets all of the following:  
• Initial response to therapy with cure of CDI at end of treatment (vancomycin) pre-
FMT; and  
• A minimum of three unformed bowel movements over a 24-hour period  
and  
• A positive result for C. difficile toxin by EIA or PCR. 
 
E. Monitoring and submitting safety reports.  
The sponsor will notify FDA of any unexpected fatal or life-threatening suspected adverse 
reaction as soon as possible but in no case later than 7 calendar days after the sponsor's 
initial receipt of the information. The sponsor will notify the FDA in an IND safety report of 
potentially serious risks as soon as possible, but no later than 15 calendar days after the 
sponsor receives the safety information and determines that the information qualifies for 
reporting. Participating providers include all persons treating patients under the sponsor’s 
IND. In addition, the sponsor will identify in each IND safety report, all IND safety reports 
previously submitted to FDA concerning a similar suspected adverse reaction and will 
analyze the significance of the suspected adverse reaction in light of previous, similar 
reports or any other relevant. The sponsor will evaluate a suspected adverse reaction in the 
context of other related reports or adverse events. Sponsor will maintain records (binder: 
database) documenting AEs. Physician will periodically review and analyze the entire 
safety database for IND safety reporting purposes. An IND safety report will be submitted 
when any of the following criteria are met:  
A. Serious and unexpected suspected adverse reaction  
B. Findings from other sources  


 
26
The sponsor will also report expeditiously any findings from clinical, 
epidemiological, or pooled analysis of multiple studies or any findings that suggest a 
significant risk in humans exposed to FMT.  
C. Increased occurrence of serious suspected adverse reactions  
The sponsor will report any clinically important increase in the rate of a serious 
suspected adverse reaction over that listed in the protocol or investigator brochure 
 
F. Annual Safety Reports.  
Although this is an expanded access IND, the sponsor will provide the following for the 
annual report under 21 CFR 312.33(b);  
 percentage of patients with at least one AE (within pre-specified time periods)  
 percentage of patients with at least one SAE (within pre-specified time periods)  
 percentage of patients who did/did not experience relapse in the 8 weeks post first 
FMT  
 percentage of patients who received a second FMT within 8 weeks  
 other pertinent statistics which would help to evaluate the safety and effectiveness 
of FMT  
 
10. Risks Associated with FMT  
Based on the existing literature (>800 case reports to date over a 60 year period) and the 
sponsors previous experience, the risks from FMT are felt to be low. This protocol details 
and minimizes risks to patients through the following methods.  
1. Expanded access IND from FDA obtained for using FMT in patients with relapsing 
or refractory CDI.  
2. Patients will be given informed consent using the standard consent process for 
retention enema. Additional risks related to FMT, such as transmission of infectious 
agents, allergens, and other diseases and conditions will also be discussed. Patients 
will sign a separate informed consent form (appendix 6.) for the FMT procedure.  
3. Donor will be tested for most common infectious agents. Individuals with 
communicable disorders or a history of high-risk behaviors will not be permitted to 
donate. Patient privacy rules will be applied to donor screening and testing.  
4. Protections against risk are provided in detail below. 
 
10.1. Potential Risks to Patients  
There are 3 areas of risk to patients associated with treatment. These include:  
1) Physical risks related to the retention enema. 
2) Theoretical risks (infectious and otherwise) related to FMT and  
3) Psychological or other risks related to confidentiality and loss of privacy.  
Standard retention enema risks include possible damage to the colonic membrane 
that lines the rectum and overload.  Overload occurs when too much fluid is 
absorbed into the bloodstream resulting in cardiopulmonary complications. Many 
adverse effects of retention enema resolve shortly after the procedure has been 
completed, but in some cases abdominal discomfort and gaseous pain side can 
persist for several hours. There have been no infectious complications directly 
attributable to FMT reported in the literature to date. However, since the process 


 
27
involves infusion of one person’s “body fluids” into another person, transmission of 
an infectious agent or other disease or condition remains a theoretical possibility. 
From infusion of donor microflora, they could potentially acquire antibiotic 
resistance or risk factors for chronic diseases such as diabetes, inflammatory bowel 
disease, or colon cancer. Risks will be minimized by a rigorous donor-selection 
process and evaluative studies on stool and blood of the donor to exclude 
transmission of infectious agents prior to FMT. Donors will not have history of 
systemic autoimmunity, chronic pain syndromes, neurologic or neurodegenerative 
disorders, malignancy, diarrheal disorder or use of antibiotics within 3 months. 
Patients will be informed that the treatment or procedure may involve these 
theoretical risks and additional risks that are currently unforeseeable. Infusion of 
fecal material containing a potential agent to which the subject is allergic is also a 
concern and so patients with a history of severe (anaphylactic) food allergy will be 
excluded from this study and donors will be queried regarding ingestion of potential 
allergens during the 5-day period preceding donation. 
 
Physical Risks to Patient:  
Very Likely  
• Mild to moderate abdominal pain or gaseous discomfort during/after retention enema  
• Fatigue the day of the retention enema from sedatives  
• Blood drawing: pain, bruising, feeling faint, slight risk of infection  
Less Likely  
• Nausea with possible vomiting from ingestion of colon prep solution  
Less Likely But Serious  
• Contracting infection from donor specimen  
• Allergic reaction to unknown antigen present in donor stool  
• Risks and side effects related to the retention enema including overload and adverse 
cardiopulmonary events related to sedation  
• Acquisition of antibiotic resistance or risk factors for chronic diseases such as diabetes, 
inflammatory bowel disease, obesity, or colon cancer  
 
10.2. Potential Risks to Donor  
This protocol also involves individuals (donors) recruited to donate stool for FMT. There 
are 3 areas of risk to the potential stool donor. These include:  
1) Physical risks related to laboratory testing and the stool collection protocol and  
2) Psychological risks related to revealing sensitive information during donor 
screening process  
3) Risks related to confidentiality and loss of privacy.  
 
Healthy related and volunteer donors will be recruited at each site. In order to exclude 
donors at high risk of passing on infection, a donor-screening questionnaire (appendix 1) 
will be administered. This questionnaire does contain sensitive and potentially 
embarrassing questions about incarceration, drug use, and high-risk sexual behaviors. 
Additionally, they will be asked questions about their baseline health status and co- 
morbidities. Laboratory tests drawn as part of the screening process will include testing for 
HIV, viral hepatitis and syphilis. These serologic results, if found to be abnormal, could 


 
28
cause psychological distress to the donor. However, the benefit of being made aware of a 
previously undiagnosed infectious condition outweighs this risk. Potential donors may 
experience psychological distress if they are excluded from donating stool based on these 
screenings. To facilitate proper stool consistency, donors will take a single dose of an 
osmotic laxative on the night prior to donation.  
 
Physical Risks to Donor:  
Very Likely  
• Blood drawing: pain, bruising, feeling faint, slight risk of infection  
Less Likely  
• Mild nausea or abdominal discomfort from ingestion of an osmotic laxative (if 
needed)  
 
Nonphysical Risks to Donor:  
Less Likely  
• Embarrassment or psychological distress from answering questions regarding 
drug use and sexual habits asked during the donor screening process.  
• Psychological distress (guilt and embarrassment) if screening questionnaire or 
laboratory test results exclude the person from donation.  
Unlikely  
• There is also risk of compromising donor privacy through breach of data 
confidentiality of sensitive protected health information such as results of HIV or 
viral hepatitis testing. 
 
11. Adequacy of Protection against Risks  
A. Recruitment of Donors  
Two healthy “universal” donors who have previously donated fecal material for FMT have 
expressed willingness to participate in the study.  Recruits will be informed of the commitment 
including a detailed description of the donor screening process and a stool donation 
protocol. The research staff will explain that a thorough medical history interview, focused 
physical exam and screening questionnaire will be completed. They will be informed that 
the questionnaire asks potentially sensitive questions regarding incarceration, drug use, 
and sexual habits. They will be informed of the requirements to have laboratory blood 
work (including HIV testing) and stool studies and to submit stool specimen on the day of 
the fecal transplant procedure.  
 
B. Protection against risk  
Additionally, the risks described above will be minimized by the following procedures:  
 
1. We will minimize potential risks due to loss of confidentiality by having all information 
collected and handled by research staff trained to deal appropriately with sensitive clinical 
issues. Potential donors will also be informed about the risk of being ineligible to donate 
stool due to positive results on screening questionnaires or laboratory testing. Results of 
donor medical interview, screening and laboratory testing will be kept separate from 
patient data and will not be available to the patient at any time. All information will be 
treated as confidential material and will be available only to clinical staff. Computer data 


 
29
files will be available only to authorized personnel and no names or obvious identifying 
information will be stored in data files. No participant will be identified in any report to the 
FDA. Further, when contacting participants for follow-up, no identifying information other 
than the first name of the caller will be used when leaving messages or speaking to anyone 
other than the patient him/herself. Written consent will be obtained to contact other 
persons for the purpose of locating the participant for follow-up and participants can 
refuse or revoke such consents. No information about participants will be released without 
their permission or where required by law.  
 
2. We will minimize the theoretical risks of infectious disease or other condition possibly 
transmitted through FMT by using donor-screening protocols modeled after blood banks 
and organ transplant programs. Potential volunteer donors will undergo thorough 
screening to determine eligibility for donation. The primary purpose of the donor 
examination and interview is to ensure that the donor is in good health, and to identify risk 
factors for diseases transmissible by stool. The donor interview will be used to identify 
risks for diseases and conditions for which there are no laboratory tests, for which tests are 
not sensitive enough to detect infectious disease agents, and for which tests are unable to 
identify early stage or window period infections. Potential donors will be interviewed using 
a donor screening questionnaire (appendix item 1) based on the Donor History 
Questionnaire materials prepared by the AABB Donor History Task Force for use in 
screening blood donors. Additional questions which are felt relevant to fecal microbiota 
transplantation including recent use of antimicrobials, and history of malignancy, 
gastrointestinal, neurologic or autoimmune disorders have been added to this 
questionnaire. Donor screening and serologic testing for relevant communicable diseases 
will be performed based on relevant portions of FDA guidelines for donors of human cells, 
tissues, and cellular and tissue-based products (HCT/Ps). This includes testing donors for 
HIV types 1 and 2, Hepatitis A, Hepatitis B, Hepatitis C, and Treponema pallidum. Donor 
stool will be tested for bacterial culture, Culture for Listeria monocytogenes and Vibrio 
(parahaemolyticus and cholerae), Rotavirus via EIA, Clostridium difficile toxins A&B, Fecal 
Giardia & Cryptosporidium antigens, Cyclospora, Isospora and Ova and Parasites. Subjects 
will be tested for HIV 1 & 2, Hepatitis A, B and C and Syphilis to confirm baseline status and 
prevent future questions about disease transmission. Potential donors will undergo a 
thorough medical history and examination to exclude any diseases which could 
(theoretically) be transmitted through the microflora including gastrointestinal diseases 
(IBD, IBS, chronic diarrhea or constipation), autoimmune or atopic conditions, malignancy 
or neurologic/neurodegenerative disease. Donors will be questioned on the day of 
donation for FMT and those who report fever, vomiting, diarrhea or other symptoms of 
infection within the last 30 days or ingestion of potential allergen where the recipient has a 
known allergy to the agent will not be permitted to donate.  
 
3. We will minimize the risk of severe C. difficile relapse by maintaining close clinical 
contact with all patients. Patients will be encouraged to contact the research staff if they 
experience recurrence of diarrhea, fever or abdominal pain so that stool can be tested for C. 
difficile toxins A & B and antibiotics can be resumed if necessary. Patients will be contacted 
via telephone by a research staff member daily while hospitalized 7 days, 3 months, and 6 
months after the treatment. They will have follow-up visits in the clinic 4 weeks post-FMT. 


 
30
 
12. Safety monitoring protocol  
Safety monitoring plan  
Solicited and unsolicited AEs will be elicited and reviewed daily while patients are 
hospitalized, at 1-week phone calls, 30-day clinic visits, and 3 month and 6 month 
telephone calls.  Patients will be contacted via telephone by a member of the research staff 
approximately 6 months after the FMT to record any SAEs, new medical 
conditions/diagnoses or changes in medical conditions/medications since last study 
contact.  
The safety of patients will be monitored during each contact with patients. Both 
anticipated and unanticipated adverse events and problems will be formally monitored and 
recorded. Unanticipated serious adverse events or problems will be reported to the 
hospital and university IRBs (as per local reporting requirements), the FDA (within 15 
days; or 7 days for unexpected fatal or life threatening events or transmission of infectious 
agent). Anticipated and less serious adverse events will be submitted annually in reports to 
the FDA. The Sponsor will be responsible for monitoring the safety and efficacy of this 
treatment and complying with the reporting requirements.  
The sponsor will convene a safety monitoring board independent of this protocol 
(composed of ID and/or GI specialists) who will review the outcomes of patients treated 
under this protocol every 6 months. This board will have the power to halt the treatment of 
patients under this protocol if it is determined that safety concerns exist. The FDA will be 
notified within 48 hours if the expanded access IND is halted for review. 
 


 
31
Appendix 1.  
FMT Donor History Questionnaire 
Are you:  
1. Feeling healthy and well today?   
 
 
 
 
 
Yes  
No  
2. Currently taking any medication for infection?   
 
 
 
Yes  
No  
 
Have you:  
3.Taken any antibiotics within the past 6 months?  
 
 
 
Yes  
No  
4. Had any fevers, vomiting, diarrhea or other symptoms of infection within the past 4 
weeks?  
 
 
 
 
 
 
 
 
 
Yes  
No  
 
In the past 8 weeks have you: 
5. Had any vaccinations or other shots? 
 
 
 
 
  
Yes  
No  
6.Had contact with someone who has had the Smallpox vaccine?  
 
 Yes  
No 
  
In the past 12 months have you:  
 
7. Had a blood transfusion?   
 
 
 
 
  
 
Yes  
No  
8. Had a transplant (organ, tissue, bone marrow, dura mater- brain covering)?  
Yes 
 
No  
9. Had a skin or bone graft?   
 
 
 
 
 
 
Yes  
No  
10. Come into contact with someone else’s blood?  
 
 
 
Yes  
No  
11. Had an accidental needle stick?  
 
 
 
 
 
Yes  
No  
12. Had sexual contact with anyone who has HIV/AIDS?   
 
 
Yes  
No  
13. Had sexual contact with a prostitute or anyone else who takes money or drugs as 
payment for sex?  
 
 
 
 
 
 
 
 
 Yes  
No  
14. Had sexual contact with anyone who has ever used needles to take drugs or steroids, or 
anything NOT prescribed by their doctor?  
 
 
 
  
Yes  
No  
15. Had sexual contact with anyone who has hemophilia or has used clotting factor 
concentrates?  
 
 
 
 
 
 
 
 
Yes  
No 
16. Female donors: Had sexual contact with a male who has ever had sexual contact with 
another male (male donors circle “I am male)?  
 
 
Yes  
No  
I am male  
17. Had sexual contact with a person who has hepatitis?  
 
 
Yes  
No  
18. Lived with a person who has hepatitis?  
 
 
 
 
Yes  
No  
19. Had a tattoo?  
 
 
 
 
 
 
 
 
Yes  
No  
20. Had an ear or body piercing?   
 
 
 
 
 
Yes  
No  
21. Been treated for syphilis or gonorrhea?  
 
 
 
 
Yes  
No  
22. Been in lockup, jail or prison for >72 hours?   
 
 
 
Yes  
No 
  
In the past three years have you:  
23. Been outside the United States or Canada?  
 
 
 
 
Yes  
No  
List location/time spent:________________________________________________  
 
 
From 1980 through 1996: 
24. Did you spend time that adds up to three (3) months or more in the United Kingdom?  
Yes  
No  


 
32
25. Were you a member of the U.S. military, a civilian military employee or a dependent 
member of the U.S. military?  
 
 
 
 
 
 
Yes  
No 
 
From 1980 to the present: 
26. Did you spend time that adds up to five (5) or more years in Europe?  
Yes 
No 
27. Receive a blood transfusion in the United Kingdom or France?  
 
Yes  
No  
 
From 1977 to the present, have you:  
28. Received money, drugs, or other payment for sex?   
 
 
Yes  
No  
29. Male donors: had sexual contact with another male, even once (female donors circle “I 
am female”)?   
 
 
 
 
 
Yes  
 
No  
I am female  
 
Have you EVER:  
30. tested positive for HIV/AIDS virus?  
 
 
 
 
 
Yes  
No  
31. used needles to take drugs or steroids or anything NOT prescribed by your doctor?  
Yes  
No  
32. used clotting factor concentrates?  
 
 
 
 
 
Yes  
No  
33. had viral hepatitis?  
 
 
 
 
 
 
 
Yes  
No  
34. had any type of cancer (including leukemia)?   
 
 
 
Yes  
No  
35. had sexual contact with anyone who was born or lived in Africa?   
Yes  
No  
36. been in Africa?   
 
 
 
 
 
 
 
Yes  
No  
37. had sex for drugs or money?  
 
 
 
 
 
 
Yes  
No  
38. had any of the following gastrointestinal diseases or problems?  
 Irritable bowel syndrome?  
 
 
 
 
 
Yes  
No  
 Crohn’s disease?   
 
 
 
 
 
 
Yes  
No  
 Ulcerative Colitis?  
 
 
 
 
 
 
Yes  
No  
 Chronic diarrhea?  
 
 
 
 
 
 
Yes  
No  
 Gastrointestinal cancers?  
 
 
 
 
 
Yes  
No  
 Celiac disease?   
 
 
 
 
 
 
Yes  
No  
39. received growth hormone made from human pituitary glands?  
 
Yes  
No 
40. Have any of your relatives had Creutzfeldt-Jakob disease?   
 
Yes  
No  
 
General Medical History  
41. Do you have any autoimmune diseases (for example: Rheumatoid arthritis, Multiple 
Sclerosis, Lupus)  
 
 
 
 
 
 
 
 
Yes  
No  
If yes, please list:_______________________________________________________  
42. Do you have any neurologic diseases (example: Parkinson’s, Autism, ALS)?  
Yes 
No  
If yes, please list: ______________________________________________________ 
 
 


 
33
Appendix 2.  
 
Donor Testing  
Serologic:  
1. HIV, type 1 (FDA-licensed screening test either for anti-HIV-1 or combination test 
for anti-HIV-1 and anti-HIV-2)  
 
2. HIV, type 2 (FDA-licensed screening test either for anti-HIV-2 or combination test 
for anti-HIV-1 and anti-HIV-2)  
3. HAV IgM (FDA-licensed screening test for anti-HAV IgM)  
4. HBV (FDA-licensed screening test for Hepatitis B surface antigen (HBsAg) and for 
total antibody to Hepatitis B core antigen (anti-HBc) (IgG and IgM)  
5. HCV (FDA-licensed screening test for anti-HCV;and FDA-licensed screening NAT test 
for HCV, or combination NAT)  
6. Treponema pallidum (FDA-cleared screening test for syphilis or FDA-cleared 
diagnostic serologic test for syphilis). As an exception for syphilis test results under 
§ 1271.80(d)(1), one may determine to be eligible a donor whose specimen tests 
positive or reactive on a non-treponemal (VDRL, RPR) screening test for syphilis 
and negative or nonreactive on a specific treponemal confirmatory test (e.g., 
fluorescent treponemal antibody with absorption test (FTA-ABS), so long as all 
other required testing and screening are negative or nonreactive. A donor whose 
specimen tests positive or reactive on either a specific treponemal confirmatory test 
for syphilis or on a treponemal screening test is not eligible. 
 
Confirmatory tests: Confirmatory tests will be performed when a positive or reactive 
screening test result is received for such purposes as donor counseling or investigating 
discordant test results. However, negative or nonreactive results on a confirmatory test 
would not override a positive or reactive screening test (except for syphilis tests as 
previously described in this section).  
 
Hepatitis B surface antibody (anti-HBs) test: If you obtain a positive or reactive anti-HBs test 
and other markers for Hepatitis B infection are negative or non-reactive, the donor may be 
eligible. The presence of anti-HBs alone would not disqualify the donor, because it usually 
is an indication of vaccination against Hepatitis B. However, in this situation, if the anti-HBc 
were also positive or reactive, the donor is ineligible. Data suggests that such results can be 
associated with infectivity.  
Stool:  
1. Stool culture for enteric pathogens (routine pathogens tested include: E coli 
0157:H7, Salmonella, Shigella, Yersinia, Campylobacter)  
2. Culture for Listeria monocytogenes  
3. Culture for Vibrio (parahaemolyticus and cholerae)  
4. Clostridium difficile toxins A&B (PCR)  
5. Fecal Giardia and Cryptosporidium antigens  
6. Microscopic examination for Ova and Parasites including Cyclospora and Isospora.  
7. Testing for Rotavirus via EIA 
8. Helicobacter pylori stool antigen 


 
34
Appendix 3.  
Collection and Preparation of Stool for FMT Infusion  
1. Donors will be supplied a toilet hat and clean, sealable plastic containers for 
collection and transport of stool specimens. Containers will be labeled with the 
name, date of birth and date/time of stool collection.  
2. Collected stool will be delivered to the outpatient lab where it will be processed 
within 2 hours of delivery. 
 
B. Location & preparation of processing  
 Stool will be processed in the Evanston Microbiology lab.  
 Universal precautions will be used during processing (gown, gloves, eye 
protection).  
 Clean counter surface will be covered with a Chux® pad.  
 After the FMT, all surfaces will be wiped with hospital-approved disinfectant 
solution.  
 
C. Preparation materials  
 1 liter bottle of sterile, nonbacteriostatic normal saline  
 blender 
 Stainless steel filters 
 Glycerol 
 Storage tubes 
 
D. Preparation method  
Fecal microbiota preparations will be handled as described by Hamilton et al (15).   
 
50g of fecal material homogenized with 250 mL of sterile, non-bacteriostatic normal 
saline within 2 hours of collection.   
 The slurry will be filtered, centrifuged, and re-suspended in sterile, non-
bacteriostatic normal saline and sterile pharmaceutical grade glycerol to a final 
concentration of 10% 
 The final product will be stored at -80ºC for up to 8 weeks in the Pathology 
Department at NorthShore University HealthSystem with subject ID number 
 When needed for use, the material will be thawed in an ice bath over 2-4 hours 
and then diluted to 250 mL sterile, non-bacteriostatic normal saline before 
infusion into the recipient. 
 The fecal suspension will be drawn into five 60 cc slip (catheter) tip syringes for 
infusion.  
 
 
 
 
 
 
 


 
35
Appendix 4. 
Table of Visits and Interventions (Donor) 
 
Initial Visit 
informed consent 
x 
medical interview 
x 
clinic visit 
x 
HIV 1 & 2 testing 
x 
serologic testing2 
x 
stool testing3 
x 
DHQ 
administered 
x 
Day of donation 
checklist4 
At time of donation 
2HAV IgM, HBsAg, anti-HBs, HCV Ab, RPR 
3 C. diff toxin by PCR, routine bacterial culture for enteric pathogens, culture for 
listeria monocytogenes and vibrio (parahaemolyticus and cholerae), fecal giardia 
antigen, fecal cryptosporidium antigen, acid-fast stain for cyclospora and isospora, 
ova and parasites, rotavirus EIA, Helicobacter pylori antigen (stool) 
4Symptoms of infection, ingestion of allergens, recent use of antibiotics, verification of 
DHQ and screening 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
36
 
Appendix 5. 
Table of Visits and Interventions (Patient) 
 
  
Initial 
Visit 
≥ 6 
hours 
prior to 
FMT 
Day 
of 
FMT 
Daily while 
hospitalized 
post FMT 
7 
days 
post 
FMT 
30 
days 
post 
FMT 
3 
months 
post 
FMT 
6 
months 
post 
FMT 
Medical Interview 
x 
 
x 
 
 
 
 
x 
Physical exam 
x 
 
x 
 
 
 
 
 
Symptoms elicited1 
x 
 
x 
x 
x 
x 
x 
x 
Retention Enema 
 
 
x 
 
 
 
 
 
Telephone Contact 
 
 
 
x 
x 
 
x 
x 
Clinic visit 
 
 
 
 
 
x 
 
 
Serologic testing2 
x 
 
 
 
 
 
 
 
Stool testing4 
 
 
 
 
x 
x 
 
 
Urine pregnancy 
test (females) 
x 
 
x 
 
 
 
 
 
Stop antibiotic 
medication 
 
x 
x 
 
 
 
 
 
Adverse events 
 
 
 
x 
x 
x 
x 
x 
Changes in medical 
conditions, 
diagnoses or 
medications 
elicited 
 
 
 
x 
x 
x 
x 
x 
1Stool form/frequency, presence of abdominal pain, fevers, subjective well being 
2HIV 1 & 2, Hepatitis A total, Hepatitis B surface Ag, Hepatitis B surface Ab, Hepatitis core Ab, Hepatitis C Ab, RPR 
3Stool may also be collected for C. difficile PCR at any time if dictated by patient symptoms 
 
 
 
 
 
 
 
 
 
 
 


 
37
 
 
 Appendix 6: Criteria to define severity of CDI episode and antimicrobials targeting 
C. difficile according to the Society for Healthcare Epidemiology of America Clinical 
Practice Guidelines for CDI  
 
Clinical Definition 
Supportive Clinical Data 
Recommended Treatment 
Mild or Moderate 
WBC  < 15,000  AND 
Creatinine < 1.5x pre-morbid level 
Vancomycin 125 mg po q 6 
hours x 14 days 
Severe 
WBC  > 15,000 OR 
Creatinine > 1.5x pre-morbid level 
Vancomycin 125 mg po q 6 
hours x 14 days 
Severe, Complicated* 
WBC  > 15,000 OR 
Creatinine > 1.5x pre-morbid level OR 
Hypotension /Shock 
*patients are excluded from the study if 
they have toxic megacolon 
 
Vancomycin 125 mg po 
q 6 hours x 14 days 
 
Metronidazole 500 mg 
IV q8 hours 
 
If ileus, may add rectal 
vancomycin  if okay 
with GI/surgical service 
 


 
38
References 
 
1. Kelly C. A 76 Year Old Man with Recurrent Clostridium difficile Associated Diarrhea: 
Review of C difficile Infection. JAMA 2009;301(9):954-62.  
 
2. McDonald LC, Owings M, Jernigan DB. Clostridium difficile Infection in Patients 
Discharged from US Short Stay Hospitals, 1996-2003. Emerging Infectious Diseases 
2006;12(3):409-15.  
 
 
3. Zilberberg M, Shorr AF, Kollef MH. Increase in Adult Clostridium difficile–related 
Hospitalizations and Case-Fatality Rate, United States, 2000–2005. Emerging 
Infectious Diseases 2008;14(6):929-31  
 
4. McFarland LV, Mulligan ME, Kwok RY, et al. Nosocomial acquisition of Clostridium 
difficile infection. N Engl J Med 1989;320:204-10.  
 
 
5. O‟Brien JA, Lahue BJ, Caro JJ, et al. The emerging infectious challenge of clostridium 
difficile-associated disease in Massachusetts hospitals: clinical and economic 
consequences. Infect Control Hosp Epidemiol 2007; 28:1219-1227.  
 
6. Cohen SH, Gerding D, Johnson S, et al. Clinical Practice Guidelines for Clostridium 
difficile Infection in Adults: 2010 Update by the Society for Healthcare Epidemiology 
of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infection 
Control and Hospital Epidemiology 2010;31(5):431-55.  
 
 
7. McFarland LV, Surawicz CM, Rubin M, et al. Recurrent Clostridium difficile disease: 
Epidemiology and clinical characteristics. Infect Control Hosp Epidemiol 1999;20:43-
50.  
 
8. McFarland LV. Alternative treatments for Clostridium difficile disease: what really 
works? Journal of Medical Microbiology 2005;54:101-11.  
 
 
9. McFarland LV, Elmer GW, Surawicz CM. Breaking the Cycle: Treatment Strategies for 
163 Cases of Recurrent Clostridium difficile Disease. Am J Gastro 2002;97(7):1769-
75.  
 
10. Johnson S, Schriever C, Galang M, et al. Interruption of recurrent Clostridium difficile 
associated diarrhea episodes by serial therapy with vancomycin and rifaximin. Clin 
Infect Dis. 2007;44(6):846-48.  
 
 


 
39
11. Wilcox MH. Descriptive Study of intravenous immunoglobulin for the treatment of 
recurrent Clostridium difficile diarrhea. J Antimicrob Chemother. 2004;53(5):882-84. 
  
12. Louie TJ, Miller MA, Mullane KM, et al for the OPT-80-003 Clinical Study Group. 
Fidaxomicin versus Vancomycin for Clostridium difficile Infection. N Engl J Med 
2011; 364:422-43112. 
 
 
13. Tvede M, Rask-Madsen JR. Bacteriotherapy for Chronic Relapsing Clostridium 
difficile Diarrhoea in Six Patients. Lancet 1989;i:1156-60.  
 
14. Rolfe RD, Finegold SM. Inhibitory interactions between normal fecal flora and 
Clostridium difficile. American Journal of Clinical Nutrition. 1980;33:2539.  
 
 
15. Khoruts A, Dicksved J, Jansson J, et al. Changes in the Composition of the Human 
Fecal Microbiome After Bacteriotherapy for Recurrent Clostridium difficile-
associated Diarrhea. J Clin Gastroenterol 2010;44(5):354-360.  
 
16. Borody TJ, Warren EF, Leis SM, et al. Bacteriotherapy using fecal flora: toying with 
human motions. J Clin Gastroenterol. 2004;38(6):475-83.  
 
17. Schwan A, Sjolin S, Trottestam U, et al. Relapsing Clostridium difficile enterocolitis 
cured by rectal infusion of normal feces. Scand J Infect Dis. 1984;16(2):211-15.  
 
18. Persky S, Brandt L. Treatment of Recurrent Clostridium difficile Associated Diarrhea 
by Administration of Donated Stool Directly Through a Colonoscope. Am J Gastro. 
2000; 95(11):3283-5.  
 
 
19. Aas J, Gessert C, Bakken J. Recurrent Clostridium difficile Colitis: Case Series 
involving 18 Patients Treated with Donor Stool Administered via a Nasogastric 
Tube. Clin Infect Dis. 2003;36:580-5.  
 
20. You D, Franzos M, Holman R. Successful Treatment of Fulminant Clostridium difficile 
Infection with Fecal Bacteriotherapy. Annals of Internal Medicine. 2008;148(8):632-
3.  
 
21. Silverman MS, Davis I, Pillai DR. Success of Self-Administered Home Fecal 
Transplantation for Chronic Clostridium difficile Infection. Clinical Gastroenterology 
and Hepatology. 2010;8:471-473.  
 
22. Yoon SS, Brandt LJ. Treatment of Refractory/Recurrent C difficile-associated Disease 
by Donated Stool Transplanted Via Colonoscopy. J Clin Gastroenterol. 
2010;44(8):562-66.  
 


 
40
 
23. Rohlke F. Surawicz CM. Stollman N. Fecal Flora Reconstitution for Recurrent 
Clostridium difficile Infection: Results and Methodology. J Clin Gastroenterol. 
2010;44(8):567-70.  
 
24. Eiseman B, Silen W, Bascom, GS, et al. Fecal enema as an adjunct in the treatement of 
pseudomembranous enterocolitis. Surgery. 1958;44:854. 
 
 
25. Bowden TA, Mansberger AR, Lykins LE. Pseudomembranous enterocolitis: 
mechanism for restoring floral homeostasis. Am Surg. 1981;47(4):178-83.  
 
26. Gustafsson A, Berstad A, Lund-Tonnesen S, et al. The Effect of Faecal Enema on Five 
Microflora-Associated Characteristics in Patients with Antibiotic-Associated 
Diarrhea. Scand J Gastroenterol. 1999;34:580-86.  
 
 
27. Flotterod O, Hopen G. Refractory Clostridium difficile infection. Untraditional 
treatment of antibiotic-induced colitis. Tidsskr Nor Laegeforen. 1991;111(11):1364-
5.  
 
28. Kelly CR, de Leon L. Successful Treatment of Recurrent Clostridium difficile with 
Donor Stool Administered at Time of Colonoscopy: A Case Series. Am J Gastro 
2010;S135.  
 
 
29. Mellow M, Kanatzar. Colonoscopic Fecal Bacteriotherapy in the Treatment of 
Recurrent Clostridium difficile Infection-Results and Follow-up. Am J Gastro 
2010;S135.  
 
30. Kelly CR, deLeon L, Jasutkar N. Fecal Microbiota Transplantation for Relapsing 
Clostridium difficile Infection in 26 Patients:Methodology and Results. J Clin 
Gastroenterol 2011 (in press) 
 
 
31. Brandt LJ, Reddy SS.Fecal Microbiota Transplantation for Recurrent Clostridium 
difficile Infection. J Clin Gastroenterol 2011 (in press)  
 
32. Kelly CR, et al. Barriers to Greater Utilization of Fecal Bacteriotherapy for Chronic 
Clostridium difficile Infection. Am J Gastro 2010:S135.  
 
 
33. http://cdiffsupport.com/  
 
34. http://cdiffdiscuss.org/phpBB3/  
35. www.cdiff-support.co.uk 


 
41
36. Ley RE, Peterson DA, Gordon JI. Ecological and evolutionaryforces shaping microbial 
diversity in the human intestine. Cell.2006;124:837–848. 
37. Guidance for Industry: Eligibility Determination for Donors of Human Cells, Tissues, 
and Cellular and Tissue-Based Products (HCT/Ps) [U.S. Food and Drug 
Administration Website]. November 18, 2010. Available at: 
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInfor
mation/Guidances/CellularandGeneTherapy/ucm072929.htm.  
 
 
38. Backhed F, Ley RE, Sonnenburg JL, Peterson DA, Gordon JI. Host-bacterial mutualism 
in the human intestine. Science 2005;307:1915-20.  
 
39. Collins DC. Pseudomembranous enterocolitis. Further observations on the value of 
donor fecal enemata as an adjunct in the treatment of pseudomembranous 
enterocolitis. Am J Proctol. 1960;2:389–391.  
 
 
40. Fenton S, Stephenson D, Weder C. Pseudomembranous colitis associated with 
antibiotic therapy-an emerging entity. Can Med Assoc J. 1974;111:1110–1111.  
 
41. Paterson DL, Irdell J, Whitby M. Putting back the bugs: bacterial treatment relieves 
chronic diarrhea. Med J Aust. 1994; 160:232–233.  
 
42. Lund-Tonnesen S, Berstad A, Schreiner A, et al. Clostridium difficile-associated 
diarrhea treated with homologous feces. Tidsskr Nor Laegeforen. 1998;118:1027–
1030.  
 
43. Faust G, Langelier D, Haddad H, et al. Treatment of recurrent pseudomembranous 
colitis with stool transplantation: report of six cases. Can J Gastroenterol. 
2002;16:A43.  
 
 
44. Jorup-Ronstrom C, Hakanson A, Perrson AK, et al. Feces culture successful therapy 
in Clostridium difficile diarrhea. Lakartidningen. 2006;103:3603–3605.  
 
45. Wettstein A, Borody TJ, Leis S, et al. Fecal bacteriotherapy-an effective treatment for 
relapsing symptomatic Clostridium difficile infection (Abstract no. G-57). In: 15th 
United European Gastroenterology Week 2007 (France). Austria, Vienna: United 
European Gastroenterology Federation; 2007.  
 
 
46. Borody J, Wettstein AR, Leis S, et al. Clostridium difficile complicating inflammatory 
bowel disease: pre- and posttreatment findings. Gastroenterol. 2008;134(4 suppl 
1):A-361. 
  


 
42
47. Louie TJ, Louie MR, Krulicki W, et al. Home-based fecal flora infusion to arrest 
multiply-recurrent Clostridium difficile infection (CDI). In: Abstracts of the 
Interscience Conference on Antimicrobial Agents & Chemotherapy (Washington 
DC). Arlington, Virginia: Infectious Disease Society of America; 2008.  
 
 
48. Nieuwdorp M, van Nood E, Speelman P, et al. Treatment of recurrent Clostridium 
difficile-associated diarrhea with a suspension of donor feces. Ned Tijdschr 
Geneeskd. 2008;152:1927–1932.  
 
49. Hellemans R, Naegels S, Holvoet J. Fecal transplantation for recurrent Clostridium 
difficile colitis, an underused treatment modality. Acta Gastroenterol Belg. 
2009;72:269–270. 
 
 
50. MacConnachie AA, Fox R, Kennedy DR, et al. Fecal transplant for recurrent 
Clostridium difficile-associated diarrhea: a UK case series. QJM. 2009;102:781–784.  
 
51. Garborg K, Waagsbo B, Stallemo A, et al. Results of fecal donor instillation therapy 
for recurrent Clostridium difficileassociated diarrhea. Scand J Infect Dis. 
2010;42:857–861.  
 
 
52. Russell G, Kaplan J, Ferraro MJ, et al. Fecal bacteriotherapy for relapsing Clostridium 
difficile infection in a child: a proposed treatment protocol. Pediatrics. 
2010;126:e239–e242.  
 
53. Brandt LJ, Aroniadis OC, Mellow M, Kanatzar A, Kelly C, Park T, Stollman N, Rohlke F, 
Surawicz C. Long-term Follow-up of Colonoscopic Fecal Microbiota Transplant for 
Recurrent Clostridium difficile Infection. Am J Gastro 2012; 107:1079-87. 
 
54. Konijeti GG, Sauk J, Shrime MG, Gupta M, Ananthakrishnan AN. Cost-effectiveness of 
competing strategies for management of recurrent Clostridium difficile infection: a 
decision analysis. Clin Infect Dis. 2014 Jun;58(11):1507-14.  
 
55. Youngster I, Sauk J, Pindar C, Wilson RG, Kaplan JL, Smith MB, Alm EJ, Gevers D, 
Russell GH, Hohmann EL. Fecal microbiota transplant for relapsing Clostridium 
difficile infection using a frozen inoculum from unrelated donors: a randomized, 
open-label, controlled pilot study. Clin Infect Dis. 2014 Jun;58(11):1515-22. 
 
56. Hamilton,MI, Weingarden AR, Sadowsky MJ, Khoruts A. Standardized frozen 
preparation for transplantation of fecal Microbiota for recurrent Clostridium difficile 
infection. Am J Gastroenterol. 2012 May; 107 (5) 761-7.