Safety and Efficacy of Fecal Microbiome Transplantation (FMT) in the Treatment of Antibiotic Dependent Pouchitis (ADP)
Phase: PHASE1
Conditions: Pouchitis
Sponsor: University of North Carolina, Chapel Hill

 
Safety and efficacy of fecal microbiome transplantation (FMT) in the 
treatment of antibiotic dependent pouchitis (ADP) 
A placebo-controlled proof of concept study with open label 
extension 
 
NCT number  NCT02782325 
 
 
Document Date: Protocol Version 1.4.1, October 30, 2017 
 
 

Safety and efficacy of fecal microbiome transplantation (FMT) in the 
treatment of antibiotic dependent pouchitis (ADP) 
A placebo-controlled proof of concept study with open label extension 
 
Protocol Version 1.4.1, October 30, 2017 
 
Sponsor/Principal 
Investigator:  
 
 
Hans H. Herfarth, MD, PhD 
Division of Gastroenterology and Hepatology 
University of North Carolina 
Phone:919-966-6806 
Fax: 919-966-7592 
email: hherf@med.unc.edu 
 
Clinical Co-Investigators 
Millie Long, MD, MPH 
Division of Gastroenterology and Hepatology 
University of North Carolina 
 
 
Kim Isaacs, MD, PhD 
Division of Gastroenterology and Hepatology 
University of North Carolina 
 
 
Data Management Center 
 
Center of Gastrointestinal Biology and Disease 
Biostatistics Core 
University of North Carolina  
 
Collaborators/Stool Bank 
Zain Kassam, MD, MPH 
Mark Smith, PhD 
Open Biome 
196 Boston Ave 
Medford Ma, 02155 
 
 
 

 
2 
1. 
PROTOCOL SUMMARY 
5 
CLINICAL REMISSION (MPDAI SCORE ≤4 POINTS AND A DECREASE IN THE BASELINE MPDAI> 2 POINTS) 
AND NO NEED FOR ANTIBIOTIC THERAPY AT WEEK 4. 
7 
EXPLORATORY ANALYSES (OL=OPEN LABEL): 
8 
2. 
BACKGROUND: 
10 
PATHOGENESIS OF POUCHITIS 
10 
GENETIC SUSCEPTIBILITY AND POUCHITIS 
10 
BACTERIAL FLORA AND POUCHITIS 
10 
CURRENT THERAPEUTIC APPROACHES FOR POUCHITIS 
11 
3. 
RATIONALE FOR THIS STUDY 
11 
4. 
JUSTIFICATION AND OBJECTIVE OF THE CLINICAL TRIAL 
12 
SAFETY PROFILE OF FECAL TRANSPLANT 
13 
CHOICE OF STUDY DRUG DOSAGE 
13 
5. 
TRIAL ENDPOINTS 
13 
PRIMARY ENDPOINT: 
13 
SECONDARY ENDPOINTS CLINICAL REMISSION (MPDAI SCORE ≤4 POINTS AND A DECREASE IN THE 
BASELINE MPDAI> 2 POINTS) AND NO NEED FOR ANTIBIOTIC THERAPY AT WEEK 4. 
14 
EXPLORATORY ANALYSES (OL=OPEN LABEL): 
14 
ALTERATIONS IN STOOL MICROBIOME BEFORE AND AFTER FMT IN STUDY PATIENTS WITH ANTIBIOTIC 
DEPENDENT POUCHITIS 
14 
EVALUATION OF CALPROTECTIN AS A MARKER OF POUCH INFLAMMATION BEFORE AND AFTER FMT 
15 
6. 
STUDY DESIGN 
15 
STUDY POPULATION 
15 
TREATMENT PERIOD. 
15 
INCLUSION CRITERIA 
15 
EXCLUSION CRITERIA 
16 
CONCOMITANT MEDICATIONS 
16 
7. 
OVERVIEW OF TRIAL SEQUENCE 
17 
8. 
SCREENING VISIT AND STUDY VISITS 1-4 
20 
SITE SCREENING VISIT 
20 
VISIT 1: SITE VISIT WEEK 0 
21 
VISIT 2: PHONE VISIT WEEK 1 (7 DAYS AFTER ENDOSCOPIC FMT /PLACEBO AND ON ORAL FMT/PLACEBO)
 
22 
VISIT 3: PHONE VISIT WEEK 2 (14 DAYS AFTER ENDOSCOPIC FMT /PLACEBO AND ON ORAL 
FMT/PLACEBO) 
22 
VISIT 4: PHONE VISIT WEEK 4 (2-3 DAYS BEFORE PLANNED WEEK 4 SITE VISIT) 
22 
VISIT 5: SITE VISIT WEEK 4 OR EARLY TERMINATION VISIT DUE TO FLARE DAY 15-28 
23 
9. 
FOLLOW-UP VISITS OF PATIENTS IN REMISSION AT WEEK 4 OR NOT PARTICPATING IN THE 
OPEN LABEL EXTENSION 
24 
VISIT 6: PHONE VISIT WEEK 6 
24 

 
3 
VISIT 7: VISIT WEEK 8 
24 
VISIT 8: PHONE VISIT WEEK 16 
25 
VISIT 9: PHONE VISIT WEEK 24 
25 
10. 
FOLLOW UP VISITS OF PATIENTS PARTICIPATING IN OPEN LABEL EXTENSION AFTER 
WEEK 4 
26 
VISIT 6OL:SITE VISIT WEEK 6 (WEEK 0 OL) 
26 
VISIT 7OL: PHONE VISIT WEEK 7 OL (WEEK 1 OL) 
27 
VISIT 8OL: PHONE VISIT WEEK 8 (WEEK 2 OL) 
27 
VISIT 9OL: SITE VISIT WEEK 10 (WEEK 4 OL) 
27 
VISIT 10OL: PHONE VISIT WEEK 12 (WEEK 6 OL) 
28 
VISIT 11:OL: SITE VISIT WEEK 14 (WEEK 8 OL) 
28 
VISIT 12OL: PHONE VISIT WEEK 22 (WEEK 16 OL) 
29 
VISIT 13OL: PHONE VISITS WEEK 30 (WEEK 24OL) 
29 
11. 
POUCHOSCOPY AND LABORATORY PARAMETERS 
29 
POUCHOSCOPY (SCREENING, VISIT 5 OR VISIT 6OL) 
29 
LABORATORY PARAMETERS 
29 
12. 
RECORDING OF COMPLIANCE 
30 
13. 
ADVERSE EVENTS 
30 
DEFINITIONS 
30 
ADVERSE EVENTS (AES) 
30 
SERIOUS ADVERSE EVENTS (SAE) 
30 
UNEXPECTED ADVERSE DRUG REACTIONS 
31 
EXPECTED ADVERSE DRUG REACTIONS 
31 
14. 
DOCUMENTATION AND REPORTING OF ADVERSE EVENTS 
31 
DOCUMENTATION AND REPORTING OF SERIOUS ADVERSE EVENTS 
33 
15. 
ABNORMAL LABORATORY RESULTS 
33 
16. 
WITHDRAWAL CRITERIA 
34 
CRITERIA IN INDIVIDUAL CASES 
34 
CRITERIA FOR THE TERMINATION OF THE WHOLE STUDY 
34 
17. 
DATA SAFETY MONITORING BOARD (DSMB) AND SAFETY OFFICER 
35 
18. 
RANDOMIZATION, DATA MANAGEMENT AND DATA MONITORING 
35 
19. 
MODIFIED POUCHITIS DISEASE ACTIVITY INDEX (PDAI) 
36 
SUBJECT DATA COLLECTED VIA DIARY CARD 
36 
CALCULATING THE MPDAI 
37 
POUCHOSCOPY 
37 
20. 
STATISTICAL ANALYSIS 
38 
PRIMARY ENDPOINT: 
38 

 
4 
SECONDARY ENDPOINTS CLINICAL REMISSION (MPDAI SCORE ≤4 POINTS AND A DECREASE IN THE 
BASELINE MPDAI> 2 POINTS) AND NO NEED FOR ANTIBIOTIC THERAPY AT WEEK 4. 
38 
EXPLORATORY ANALYSES (OL=OPEN LABEL): 
38 
CLINICAL ANALYSES 
39 
SAMPLE SIZE CALCULATION 
39 
MICROBIOME ANALYSES 
40 
21. 
STUDY VISITS CHART 
41 
1.1 
STUDY VISITS CHART PLACEBO CONTROLLED TRIAL SCREENING – WEEK 4 (SITE VISIT) 41 
1.2 
STUDY VISITS CHART FOR PATIENTS CONTINUING IN OBSERVATION PHASE 
41 
1.3 
STUDY VISITS CHART OPEN LABEL EXTENSION FOR PATIENTS WITH RESPONSE ONLY OR 
NO RESPONSE OR EARLY TERMINATION DUE TO FLARE IN PLACEBO-CONTROLLED TRIAL 
SECTION 
43 
22. 
APPENDIX B: STUDY FLOW CHART 
45 
23. 
APPENDIX C: MODIFIED POUCHITIS DISEASE ACTIVITY INDEX (MPDAI) 
48 
24. 
STUDY PATIENT STOOL DIARY 
49 
25. 
ADVERSE EVENT DIARY 
50 
26. 
REFERENCES 
53 
 
 
 

 
5 
1. PROTOCOL SUMMARY 
Title: 
Safety and efficacy of fecal microbiome transplant (FMT) in the treatment 
of antibiotic dependent pouchitis (ADP) in patients with IPAA after 
colectomy for therapy refractory ulcerative colitis 
Research 
Hypothesis: 
Fecal transplant is a safe and effective treatment for patients with antibiotic 
dependent pouchitis.  
Study design: 
Randomized, double blind study with open label extension 
Study population: 
Patients with ADP and IPAA after colectomy for ulcerative colitis  
Sample size: 
20 study patients 
Treatment: 
Fecal microbiome transplantation  
Treatment 
duration: 
Endoscopic FMT followed by oral FMT or placebo endoscopic and placebo 
oral FMT for 14 days in the placebo-controlled arm. In case of no clinical 
remission open label endoscopic FMT followed by oral FMT for 14 days. 
Main criteria for 
inclusion: 
• 
Signed informed consent. 
• 
Man or woman between 18 and 70 years of age. 
• 
IPAA after colectomy for ulcerative colitis 
• 
Active pouchitis, defined as a mPDAI ≥ 5 and a history of ≥ 4 
antibiotic therapies for pouchitis in the last 12 months  
or  
• 
Need for ongoing antibiotic therapy (> 4 weeks) to maintain clinical 
remission and a history of at least 2 attempts in the last 24 months to 
stop antibiotic therapy resulting in pouchitis episodes.  
• 
Concomitant oral 5 ASA or local therapies containing 5-ASA 
(enemas, suppositories) or steroid enemas are permitted but not 
required but have to be stable for 4 (oral) or 2 weeks (topical) before 
inclusion in the study. 
 
Main criteria for 
exclusion: 
• 
Treatment with biologics (e.g. infliximab, adalimumab, golimumab, 
vedolizumab) 
• 
Treatment 
with 
immunomodulators 
(azathioprine, 
6-MP, 
methotrexate), steroids or any investigational drugs 
• 
Use of cholestyramine 
• 
Crohn’s disease of the pouch 
• 
Known cytomegalovirus infection of the pouch 

 
6 
• 
Clostridium difficile infection 
• 
Isolated moderate/severe cuffitis  
• 
Clinical significant strictures of the pouch inlet or outlet 
• 
Concurrent intestinal obstruction 
• 
History of familial adenomatous polyposis 
• 
History of uncontrolled lactose intolerance 
• 
History of confirmed (serological test and/or histology) celiac disease 
• 
Pregnancy, breast feeding, or planning to become pregnant during the 
trial 
• 
Non - steroidal inflammatory medications (NSAIDs) as long-term 
treatment, defined as use for at least 4 days a week each month.  
Daily use of aspirin up to 81 mg a day for cardiovascular prophylaxis 
is acceptable.   
• 
Dysphagia (oropharyngeal, esophageal, functional, neuromuscular) 
• 
History of recurrent aspiration episodes 
• 
Proven gastroparesis 
• 
Allergy to the following generally regarded as safe ingredients 
(GRAS): glycerol, acid resistant HPMC, gellan gum, cocoa butter, 
titanium dioxide 
• 
Adverse event attributable to previous FMT 
• 
Allergy/intolerance to pump inhibitor therapy  
• 
Any condition for which the investigator thinks the FMT treatment 
may pose a health risk (e.g. severely immunocompromised) 
• 
Participation in another clinical trial within the last 30 days, 
simultaneous participation in another clinical trial, or previous 
participation in this trial 
• 
During the trial period until one week after the trial end: Non-use of 
appropriate contraceptives in females of childbearing potential (e.g. 
condoms, intrauterine device {IUD}, hormonal contraception, or 
other means considered adequate by the responsible investigator) or 
in males with a child-fathering potential (condoms, or other means 
considered adequate by the responsible investigator during 
treatment 
• 
Well-founded doubt about the patient’s cooperation 
Concomitant 
medication: 
• 
All antibiotic therapies for pouchitis have to be stopped 1 day before 
FMT.  
Following drug groups are permitted as concomitant medication:  
• 
Orally administered mesalazine containing drugs should be stable for 
the last 4 weeks 
• 
Local therapies containing 5-ASA (enemas, suppositories) or steroid 
enemas should be at a stable dose 2 weeks before inclusion in the 
study. 
Following drug groups are not permitted as concomitant medication: 

 
7 
• 
Antibiotic therapy for treatment of pouchitis 
• 
Cytostatics/immunosuppressants, cyclosporine, tacrolimus, 
mycophenolate mofetil. 
• 
Anti-TNF therapies or anti-adhesion therapy. 
• 
Non - steroidal anti-inflammatories (NSAIDs) as long-term 
treatment, defined as use for at least 4 days a week each month.  
Daily use of aspirin up to 81 mg a day for cardiovascular prophylaxis 
is acceptable 
Criteria for 
Evaluation:  
Safety and Tolerability of FMT will be evaluated determining the number 
of study patients, who discontinued therapy, determining the adverse events 
grouped by body system and evaluation of changes in laboratory values. 
 
The outcome will be determined by the modified pouchitis disease activity 
index (mPDAI) and the need for antibiotic therapy to control symptoms. 
The mPDAI is a composite index consisting of 2 disease variables (clinical 
criteria of pouchitis: number of bowel movements, blood in stool, urgency 
and fever with a maximum score of 6 and endoscopy criteria of pouch 
inflammation with a maximum score of 6. The maximum combined score 
is 12).  
• Complete remission is defined as a mPDAI score = 0 and no need for 
antibiotics. 
• Clinical remission is defined as a clinical mPDAI score ≤ 4 and no need 
for antibiotics.  
• Symptomatic improvement is defined as a decrease from baseline in the 
mPDAI clinical subscore of 2 points and no need for antibiotics.  
• Symptomatic worsening of the disease is defined by an increase in the 
mPDAI clinical subscore of 2 points or the need for antibiotics.  
The severity of the pouch inflammation will be evaluated by two 
pouchoscopies (week 0 and week 4). Endoscopic improvement is defined 
as a decrease from baseline in the mPDAI endoscopic subscore of 2 points. 
Primary variables 
Safety and tolerability of endoscopically and orally applied FMT  
Secondary 
variables: 
• Clinical remission (mPDAI score ≤4 points ) and no need 
for antibiotic therapy at week 4. 
• Clinical remission (clinical mPDAI score ≤ 4) and no need for 
antibiotics at week 8*. 
• Clinical remission (clinical mPDAI score ≤ 4) and no need for 
antibiotics at week 16*. 
• Endoscopic improvement of active pouchitis (decrease from baseline 
in mPDAI endoscopic subscore > 2 points) at week 4. 

 
8 
• Response: Symptomatic improvement of active pouchitis (decrease 
from baseline in mPDAI clinical subscore > 2 points) and no need for 
antibiotic therapy at week 4. 
• Response: Symptomatic improvement of active pouchitis (decrease 
from baseline in mPDAI clinical subscore > 2 points) and no need for 
antibiotic therapy at week 8*. 
• Response: Symptomatic improvement of active pouchitis (decrease 
from baseline in mPDAI clinical subscore > 2 points) and no need for 
antibiotic therapy at week 16*. 
 
*Only patients who do not continue in open label extension 
• Exploratory analyses (OL=Open label): 
• Endoscopic improvement of active pouchitis (decrease from baseline 
in mPDAI endoscopic subscore > 2 points) at in open label extension 
week 8. 
• Clinical remission (mPDAI score ≤4 points and a decrease in the 
baseline mPDAI> 2 points) and no need for antibiotic therapy at week 
10 OL. 
• Clinical remission (clinical mPDAI score ≤ 4) and no need for 
antibiotics at week 14 OL. 
• Clinical remission (clinical mPDAI score ≤ 4) and no need for 
antibiotics at week 22 OL. 
• Response: Symptomatic improvement of active pouchitis (decrease 
from baseline in mPDAI clinical subscore > 2 points) and no need for 
antibiotic therapy at week 10 OL. 
• Response: Symptomatic improvement of active pouchitis (decrease 
from baseline in mPDAI clinical subscore > 2 points) and no need for 
antibiotic therapy at week 14 OL. 
• Response: Symptomatic improvement of active pouchitis (decrease 
from baseline in mPDAI clinical subscore > 2 points) and no need for 
antibiotic therapy at week 22 OL. 
• Symptomatic worsening of active pouchitis (decrease from baseline in 
mPDAI clinical subscore > 2 points) from FMT week 0 – week 16 
• Quantitative changes in mPDAI from baseline values 
• Quantitative changes of calprotectin from baseline 
• Alterations in stool microbiome after FMT 
• Engraftment of donor FMT 
Statistical analysis: 
Remission and response as defined by mPDAI scores will be analysed by 
intention-to-treat design. Wilcoxon rank sum tests will be carried out to 
assess differences in the pre- and post-treatment mPDAI total scores and 
subscores. P values < 0.05 will be considered to be statistically significant. 
Duration of study 
2 weeks of FMT/ placebo therapy followed by evaluation of clinical and 
endoscopic outcome at week 4, and clinical evaluation at week 8 and 16. 
In case the study patients does not achieve clinical remission at week 4 or 

 
9 
experiences a flare of disease on day 15-28 after start of the study he/she 
will be offered the possibility to participate in open label extension with an 
additional endoscopic FMT followed by 2 weeks of oral FMT and clinical 
follow up at week 10, 14 and 22. 
 
The anticipated time of the overall study is 18 months  
Number of centres: 
Single center study 

 
10 
2.  BACKGROUND: 
Ulcerative colitis (UC) is a chronic inflammatory gastrointestinal disorder, which is limited to the colon 
and characterized by the involvement of the mucosa only (in contrast to the transmural inflammation 
seen in CD). UC affects approx. 500.000 Americans, most of them being primarily young adults (20 - 
40 years) but the disease may present also at a very early age (5-10 years) or in later in life (>60 years) 
1-3. The inflammatory process in UC is primarily localized to the rectum (proctitis) or can extend 
proximally in a contiguous manner involving the mucosa up to the splenic flexure (left sided colitis) or 
involving the entire colon (extensive colitis). The key clinical feature is bloody diarrhea. Approximately 
20-35% of patients with UC eventually have to undergo colectomy, which is most often performed in 
conjunction with ileal pouch-anal anastomosis (IPAA) due to a refractory course of UC or histological 
proven dysplasia 4-6. The ileal pouch serves as a reservoir for the stool and improves functional outcomes 
following IPAA. Pouchitis is the most common long-term complication after IPAA affecting up to 50% 
of patients following operation for UC 7-10. The clinical symptoms include diarrhea, crampy abdominal 
pain, fever, bloody bowel movements, dehydration as well as extraintestinal manifestations such as joint 
pain.  
• Pathogenesis of Pouchitis 
The pathogenesis of pouchitis remains is only incompletely elucidated. The currently most favored 
underlying pathomechanisms of pouchitis are dysbiosis of the bacterial flora of the pouch and 
dysregulation of the mucosal inflammatory responses in genetically susceptible patients. Also bile acid 
toxicity, ischemia and infections may contribute in some patients to the clinical and endoscopic picture 
of pouchitis. 
• Genetic susceptibility and pouchitis 
The role of an aberrant regulation of the mucosal immune system is highlighted by the fact that pouchitis 
rarely occurs in patients with familial adenomatosis coli (FAP), who underwent a colectomy with IPAA 
11. There are also other known genetic or genetically influenced risk factors for the development of 
pouchitis, such as the presence of antineutrophil cytoplasmatic antibody with perinuclear staining pattern 
(pANCA), a history of primary sclerosing cholangitis (PSC) as well as an association of known IBD risk 
genes such as CARD15 with pouchitis pouchitis 12. 
• Bacterial Flora and pouchitis 
The role of the bacterial flora in the pathogenesis of pouchitis has been strongly suggested by clinical 
trials demonstrating a high clinical efficacy of antibiotics (e.g. ciprofloxacin, metronidazole) to treat and 
prevent pouchitis. There seem to be a bacterial dysbiosis present in patients with pouchitis 13-16. Studies 
comparing the bacterial flora of pouches of patients with FAP and UC found sulfate reducing bacteria 
in the majority of UC patients but none in FAP patients 17. Also strict anaerobes (Clostridium perfringens, 
Bifidobacteria and Bacteroides) predominate over facultative anaerobes (Enterococci, Coliforms and 
Lactobacilli) in stool and mucosal biopsies of UC patients 18. Using a 16S ribosomal RNA technique to 
determine qualititativ changes in the mucosa of the pouch, Komaduri et al. report the persistence of 
Fusobacter and Enteric species and the absence of specific bacteria such as Streptococcus species in 
association with pouchitis 16. More recently an increase in Ruminococcus gnavus, Bacteriodes vulgatus 
and Clostridium perfringens with a concomitant reduction of Lachnospiraceae Blauatia and Roseburia 
before colectomy was found to be a risk factor for developing pouchitis in the first year after IPAA.19 
 

 
11 
• Current therapeutic approaches for pouchitis 
Different antibiotic therapies including ciprofloxacin, metronidazole, rifaximin have been shown to 
successfully treat pouchitis in subgroups of patients 20-24. The probiotic VSL#3, which is a highly 
concentrated bacterial cocktail of 8 different bacterial species, prevents acute and chronic pouchitis, but 
is only effective in a subgroup of patients 25-29. Agents known to be efficacious in left-sided ulcerative 
colitis including budesonide enemas 30, mesalamine enemas 31 and suppositories 32, butyrate and glutamine 
suppositories 33 have all been used with some success. Allopurinol, inulin and bismuth carboner foam 
enemas were also investigated without significant clinical efficacy 34-36. More recently a single center study 
described a therapeutic efficacy of AST-120, a spherical carbon adsorbent in acute pouchitis 37. A 
placebo-controlled trial has to confirm these findings in the future.  
 
3. RATIONALE FOR THIS STUDY 
Active pouchitis can be treated successfully with antibiotics (metronidazole, ciprofloxacin), but relapse 
of pouchitis is common. The probiotic VSL#3 is effective to treat recurrent pouchitis, but is effective 
only in a subgroup of patients and is associated with high costs for the patients since considerable 
amounts of VSL#3 are necessary to achieve clinical effectiveness. Frequent antibiotic therapies, often in 
rotating therapeutic schedules are usually required to treat patient with pouchitis.  The overuse of 
antibiotics predisposes to the development of bacterial resistance and is often associated with numerous 
side effects (nausea, vomiting, neurotoxicity, kidney toxicity, tendon rupture). There may also be the 
risk of secondary gastrointestinal infections, such as Clostridium difficile especially with 
fluoroquinolones 38, 39. Patients may develop a refractory course of pouchitis after long-term antibiotic 
use, which may be due to bacterial selection 40. Additionally patients with IPAA have an increased risk 
for the development of intra-abdominal infections and complications such as an ileus, which often 
require antibiotic therapy. Therefore the development of bacterial resistance from overuse of antibiotics 
for pouchitis might jeopardize the treatment of these complications.  
 
Fecal Microbial transplant (FMT) 
FMT has been shown to be an effective therapy for patients with dysbiosis in the setting of C. diff 
colitis.41, 42 In patients with active UC 3 placebo controlled FMT studies have been reported.43-45 One 
showed a beneficial effect mainly based on the efficacy of a single donor, whereas the other study 
revealed no effect of FMT. The most robust evidence for FMT comes from the so far largest placebo 
controlled study, which was conducted at 3 Australian centers and included 81 patients.45 This study 
revealed a significant therapeutic efficacy of repeated intense FMT (5 multidonor FMT enemas/ week 
for 8 weeks) vs placebo (steroid free remission at week 8 27% FMT group vs 8% placebo group). 
 
So far only two small case series and 2 case reports in patients with pouchitis (one with concomitant C. 
difficile infection) are published.46-49 Two case reports describe success after a single endoscopic 
application of FMT, but the treatment success appeared weeks after the stool transplant, one patient also 
needed again antibiotic therapy.47, 48 Landi et al published a case series of 8 patients with chronic 
refractory pouchitis treated with a single application of FMT via nasogastric tube. 50 FMT was not 
effective in achieving clinical remission, but significant changes in the pouch bacterial flora towards a 
supposedly healthier composition was observed in some FMT recipients and the quinolone sensitivity 
of 2 patients was re-established, who then were successfully maintained again on ciprofloxacin therapy. 
The engraftment success varied, which suggest that a single FMT in patients with refractory pouchitis 
might be not sufficient. Similar to the results of repeated FMT applications in patients with UC by 

 
12 
Paramsothy et al, a recently published case series by Stallmach et al. supports the need for repeated FMT 
in 5 patients with antibiotic dependent or refractory pouchitis.45, 49 A single endoscopically performed 
FMT was only effective in 1/5 patients, but lasting remission (3/5) or improvement (1/5) was achieved 
with repeated FMT in the remaining patients. The efficacy of FMT in inflammatory bowel diseases 
(IBD) most likely depends on the frequency of donor microbiome applications. Several studies in IBD 
patients employed a single FMT, others performed daily or weekly repeated FMT. A recent meta-
analysis of FMT in IBD revealed a trend to better success rates with a higher number of FMT, mostly in 
the form of enemas.51 Thus a single FMT in patients with C. difficile colitis may be sufficient, but a 
prolonged therapy with daily FMT may be more beneficial in patients with chronic intestinal 
inflammation. Another important aspect of FMT is the microbial composition, the diversity and the 
microbiome metabolic profile of the donor feces. The beneficial effect of FMT derived from a unique 
donor (Donor B) in the Canadian UC FMT trial point towards donor specific microbiota quality such as 
diversity or specific bacterial products such as butyrate, which all may be key drivers of FMT therapeutic 
success.43, 44, 52 
 
Oral FMT 
Just recently oral FMT in an encapsulated form has become available in the US (FMT capsule G3).53, 54 
This capsule was developed by OpenBiome, a non-profit stool bank. The company formulated a 
microbial emulsion matrix encapsulating rigorously screened and processed microbiota preparations 
(www.openbiome.org). Initial trials indicate a high but slightly inferior efficacy in treating patients with 
C. difficile colitis with a single oral encapsulated FMT.53-56 Data about the efficacy and safety of daily 
repeated oral FMT over longer time periods are currently not known, but weekly applications of 6 
capsules in patients with Crohn’s disease appear to be safe and well tolerated (OpenBiome, unpublished 
data). At this stage the encapsulated FMT offers an exciting possibility to explore the efficacy and safety 
of daily oral applications of fecal microbiota. In contrast to daily FMT enemas, as it has been performed 
in some studies, the oral FMT approach is also the patient preferred therapeutic modality, which 
increases compliance and the overall chance of therapeutic success.57  
 
4. JUSTIFICATION AND OBJECTIVE OF THE CLINICAL TRIAL 
FMT for ADP is a promising approach, given the documented role of bacteria in the pathogenesis of this 
condition. However, whereas a single FMT in patients with C. difficile colitis seems to be sufficient to 
achieve a high therapeutic success rate, an intensified therapy with daily or repeated FMT to firmly 
establish the donor microbiome in the recipient appears to be the therapy of choice in patients with 
chronic intestinal inflammation (as outlined above). However, repeated endoscopic FMT is costly and 
not feasible. An alternative therapeutic modality is the repeated application of FMT via enemas. But this 
approach is suboptimal due a) patient preferences (oral> rectal), b) the occurrence of severe rectal pain 
during the application in patients with concomitant cuffitis and c) problems with retention of the enema 
content.58-60 Thus the optimal approach is a combination of endoscopic FMT and consecutive therapy 
with oral FMT to help establish the donor microbiome in the host. With the recent availability of 
capsulated FMT this approach became feasible. The objective of this proof of concept trial is to evaluate 
the safety of endoscopic followed by oral FMT in patients with ADP and to estimate the effect size to 
be achieved from FMT therapy in patients with ADP for subsequent evaluation in a large definitive trial. 
A secondary objective is to study the microbial engraftment of donor FMT in the recipients.  
 

 
13 
Specific hypothesis  
We hypothesize that FMT is a novel therapeutic option for patients ADP. This form of pouchitis is 
predestined to benefit from FMT, since bacterial dysbiosis, which can only be controlled with antibiotics, 
appears to be the major driver of the clinical symptoms. We choose two distinct outcomes, a clinical and 
translational aim, to investigate the effect of FMT in patients with ADP.  
 
Aim 1: Evaluation of safety, tolerability and clinical effectiveness (measured as clinical response or 
remission and discontinuation of antibiotic therapy) of FMT in patients with ADP.  
 
Aim 2: Evaluation of the impact of FMT on the fecal bacterial microbiome in patients with ADP, which 
will provide functional data about possible mechanisms of this therapy. 
 
• Safety profile of fecal transplant 
 
Fecal transplant has an excellent safety profile in patients with C. difficile colitis. Also FMT for C. 
difficile colitis seems to be safe in immunocompromised patients.  
In patients with IBD often mild flu symptoms after transplant have been observed.51 However, these are 
only transitory and no organ failure or organ toxicity has been reported.  
 
• Choice of Study Drug Dosage 
The endoscopic FMT is an established method in patients with C. difficile colitis. The advantage of 
endoscopic rather than enema applied FMT is the possibility to install the FMT proximal to the pouch, 
which facilitates mucosal contact of the FMT not only in the pouch but also in the distal terminal ileum. 
However a single application most likely leads to an incomplete engraftment of the donor microbiome 
and repeated FMT is likely to have superior results as shown in several uncontrolled observations as 
well as in a large placebo controlled trial in patients with ulcerative colitis and a case series of 5 ADP 
patients.45, 49, 51, 61 Repeated endoscopic FMT is not a feasible option. Oral FMT has been recently 
established and seems to have slightly inferior efficacy in patients with C. difficile colitis compared to 
endoscopic FMT.53, 55, 56 Daily FMT using enema is another alternative, but in our opinion is suboptimal 
due to patient preferences, often pain during application of the enemas due to concurrent cuffitis and 
problems with retention in the setting of enema therapy.58-60 Oral FMT offers the possibility to a superior 
engraftment and maintenance of the donor microbiome over longer time periods.58 However, no data 
about such an approach are yet available. The only available data for patients with pouchitis and FMT 
are based on single FMT or repeated endoscopic FMT as outlined above.  
 
5. TRIAL ENDPOINTS 
• Primary Endpoint:  
Safety and Tolerability of FMT 
• Number of study patients, who discontinued therapy 

 
14 
• Adverse events grouped by body system  
• Changes in laboratory values 
•  Secondary Endpoints 
 
• Clinical remission (mPDAI score ≤4 points) and no need for antibiotic therapy at week 
4. 
• Clinical remission (clinical mPDAI score ≤ 4) and no need for antibiotics at week 8*. 
• Clinical remission (clinical mPDAI score ≤ 4) and no need for antibiotics at week 16*. 
• Endoscopic improvement of active pouchitis (decrease from baseline in mPDAI 
endoscopic subscore > 2 points) at week 4. 
• Response: Symptomatic improvement of active pouchitis (decrease from baseline in 
mPDAI clinical subscore > 2 points) and no need for antibiotic therapy at week 4. 
• Response: Symptomatic improvement of active pouchitis (decrease from baseline in 
mPDAI clinical subscore > 2 points) and no need for antibiotic therapy at week 8*. 
• Response: Symptomatic improvement of active pouchitis (decrease from baseline in 
mPDAI clinical subscore > 2 points) and no need for antibiotic therapy at week 16*. 
 
*Only patients who do not continue in open label extension 
• Exploratory analyses (OL=Open label): 
• Endoscopic improvement of active pouchitis (decrease from baseline in mPDAI 
endoscopic subscore > 2 points) at in open label extension week 8. 
• Clinical remission (mPDAI score ≤4 points and a decrease in the baseline mPDAI> 2 
points) and no need for antibiotic therapy at week 10 OL. 
• Clinical remission (clinical mPDAI score ≤ 4) and no need for antibiotics at week 14 
OL. 
• Clinical remission (clinical mPDAI score ≤ 4) and no need for antibiotics at week 22 
OL. 
• Response: Symptomatic improvement of active pouchitis (decrease from baseline in 
mPDAI clinical subscore > 2 points) and no need for antibiotic therapy at week 10 OL. 
• Response: Symptomatic improvement of active pouchitis (decrease from baseline in 
mPDAI clinical subscore > 2 points) and no need for antibiotic therapy at week 14 OL. 
• Response: Symptomatic improvement of active pouchitis (decrease from baseline in 
mPDAI clinical subscore > 2 points) and no need for antibiotic therapy at week 22 OL. 
• Symptomatic worsening of active pouchitis (decrease from baseline in mPDAI clinical 
subscore > 2 points) from FMT week 0 – week 16 
• Quantitative changes in mPDAI from baseline values 
• Quantitative changes of calprotectin from baseline 
• Alterations in stool microbiome after FMT 
• Engraftment of donor FMT 
• Alterations in stool microbiome before and after FMT in study patients with antibiotic 
dependent pouchitis 
Since the bacterial dysbiosis in the pouch plays an important role in the pathogenesis of pouchitis a 
secondary endpoint is the evaluation of the fecal microfloral pattern by 16S rDNA collected before and 
2,4,8 and 16 weeks after FMT.  

 
15 
 
• Evaluation of calprotectin as a marker of pouch inflammation before and after FMT 
Repeated pouchoscopies to evaluate the degree of pouch inflammation are not feasible. Also due to 
safety concerns, biopsies of the pouch will not be taken before FMT. Calprotectin, a member of the S100 
family of calcium-binding proteins is abundant in the stool and its level correlates with the endoscopic 
degree of intestinal inflammation in patients with ulcerative colitis and pouchitis. 62, 63 Calprotectin can 
be readily quantified in feces using enzyme-linked immunosorbent assay (ELISA) or an immunoassay. 
We will collect stool samples for the measurement of calprotectin at the screening visit and on weeks 2, 
4, 8 and 12 after FMT. 
 
6. STUDY DESIGN  
• Study Population 
The study will include 20 patients who have undergone total proctocolectomy and ileal pouch-anal 
anastomosis (IPAA) for ulcerative colitis (UC). The study patient qualifies for the study if  
he/she has episode of active pouchitis, defined as a mPDAI ≥ 5 and a history of > 3 antibiotic therapies 
for pouchitis in the last 12 months or if he/she is in need for chronic antibiotic therapy to maintain 
clinical remission and has history of at least 2 attempts in the last 24 months to stop continuous 
antibiotic therapy resulting in pouchitis episodes. 
• Treatment period. 
2 weeks of FMT/ placebo therapy followed by evaluation of clinical and endoscopic outcome at week 
4, and clinical evaluation at week 8 and 16. In case the study patient does not achieve clinical 
remission at week 4 or experiences a flare of disease on day 15-28 after start of the study he/she will be 
offered the possibility to participate in open label extension with an additional endoscopic FMT 
followed by 2 weeks of oral FMT and clinical follow up at week 4, 8 and 16. 
 
• Inclusion Criteria 
• Signed informed consent. 
• Man or woman between 18 and 70 years of age. 
• IPAA after colectomy for ulcerative colitis 
• The subject has been diagnosed with one of the following 2 pouchitis subtypes:  
o Active pouchitis, defined as a mPDAI ≥ 5 and a history of ≥ 4 antibiotic therapies for 
pouchitis in the last 12 months  
or  
o Need for ongoing antibiotic therapy (> 4 weeks) to maintain clinical remission and a 
history of at least 2 attempts in the last 24 months to stop antibiotic therapy resulting in 
pouchitis episodes. Concomitant oral 5 ASA or local therapies containing 5-ASA 
(enemas, suppositories) or steroid enemas are permitted but not required but have to be 
stable for 4 (oral) or 2 weeks (topical) before inclusion in the study. 
 
 

 
16 
• Exclusion criteria 
• Treatment with biologics (e.g. infliximab, adalimumab, golimumab, vedolizumab) 
• Treatment with immunomodulators (azathioprine, 6-MP, methotrexate), steroids or any 
investigational drugs 
• Use of cholestyramine 
• Crohn’s disease of the pouch 
• Known cytomegalovirus infection of the pouch 
• Clostridium difficile infection 
• Isolated moderate or severe cuffitis  
• Clinical significant strictures of the pouch inlet or outlet 
• Concurrent intestinal obstruction 
• History of familial adenomatous polyposis 
• History of uncontrolled lactose intolerance 
• History of confirmed (serological test and/or histology) celiac disease 
• Pregnancy, breast feeding, or planning to become pregnant during the trial 
• Non - steroidal inflammatory medications (NSAIDs) as long-term treatment, defined as use for at 
least 4 days a week each month 
• Dysphagia (oropharyngeal, esophageal, functional, neuromuscular) 
• History of recurrent aspiration episodes 
• Proven gastroparesis 
• Allergy to the following generally regarded as safe ingredients (GRAS): glycerol, acid resistant 
HPMC, gellan gum, cocoa butter, titanium dioxide 
• Adverse event attributable to previous FMT 
• Allergy/intolerance to pump inhibitor therapy  
• Any condition for which the investigator thinks the FMT treatment may pose a health risk (e.g. 
severely immunocompromised) 
• Participation in another clinical trial within the last 30 days, simultaneous participation in another 
clinical trial, or previous participation in this trial 
• During the trial period until one week after the trial end: Non-use of appropriate contraceptives in 
females of childbearing potential (e.g. condoms, intrauterine device {IUD}, hormonal 
contraception, or other means considered adequate by the responsible investigator) or in males 
with a child-fathering potential (condoms, or other means considered adequate by the responsible 
investigator during treatment 
• Well-founded doubt about the patient’s cooperation 
• Concomitant Medications 
 
All antibiotic therapies have to be stopped 1 day before FMT.  
 
Following drug groups are permitted as concomitant medication:  
• 
Orally administered mesalazine containing drugs should be stable for the last 4 weeks 
• 
Local therapies containing 5-ASA (enemas, suppositories) or steroid enemas should be 
at a stable dose 2 weeks before inclusion in the study. 
Following drug groups are not permitted as concomitant medication: 

 
17 
• 
Antibiotic therapy for treatment of pouchitis 
• 
Cytostatics/immunosuppressants, cyclosporine, tacrolimus, mycophenolate mofetil. 
• 
Anti-TNF therapies or anti-adhesion therapy. 
• 
Non - steroidal anti-inflammatories (NSAIDs) as long-term treatment, defined as use for 
at least 4 days a week each month 
7. OVERVIEW OF TRIAL SEQUENCE 
See also study flow chart in appendix as well as study visit charts in appendix. 
The trial will begin with the screening visit (days -14 to 0). The investigator will ask patients who are 
interested in participating in the study after a careful explanation, to sign an informed consent form prior 
to study specific examinations. The study patient will receive a copy of the consent form, which outlines 
the sequence of events in brief and summarizes the advantages and disadvantages of participation in the 
study. 
After the patient has given his/her written consent, the screening examination will be performed to 
evaluate whether the patient is probably eligible for the study. 
At the screening visit, a complete history will be taken including concomitant medication and 
demographic data will be collected. A physical examination will be performed and vital signs will be 
documented. Blood samples (max. 20 ml) will be taken from the study patient (all study patients:   
hematology, serum chemistry, creatinine, female study patients: urine samples for pregnancy test). Also 
the study patient will be provided with a stool collection kit to provide a stool sample, which should be 
collected at this visit or before the week 0 visit. This stool kit will also contain a sample kit for C. difficile 
toxin. The study patient will also be provided with a diary, which he/she will be asked to complete the 
diary every day in the evening during the trial. It will be also evaluated if the patient is able to swallow 
the oral FMT test capsule. 
 
At least 10 days before the planned endoscopic FMT at week 0 all patients will be started on antibiotic 
therapy as standard of care for treatment of pouchitis. Patients on continuous antibiotic therapy will 
continue their regimen. Since all patients must fulfil the criteria for antibiotic pouchitis, the antibiotic 
with the best efficacy to treat the pouchitis episodes in the past will be used. In patients on chronic 
antibiotic therapy to prevent pouchitis recurrence the antibiotic regimen will be continued. 24 hours 
before the planned FMT the antibiotic will be discontinued.  
 
Placebo-controlled trial period 
At week 0 visit the study patient will have a physical exam and a urine pregnancy test.  The patient’s AE 
and symptom diary should be reviewed and the clinically modified PDAI calculated. The patient’s 
concomitant medications will be reviewed.  If the study patient fulfils all inclusion criteria and does not 
have an exclusion criterion the study patient will be randomized to either the placebo or the FMT group 
and a unique study ID number will be assigned, which will appear on all medication packs.  
The study patient then undergoes a pouchoscopy for evaluation of the pouch inflammation and to rule 
out complications in the pouch structure (e.g. strictures, isolated cuffitis, which would lead to exclusion 
of the trial). If all inclusion criteria are met during an endoscopically guided placebo or real FMT will 
be performed. Additionally, the study patient will be started on omeprazole 20 mg (1 tablet/daily) as 

 
18 
long as he/she undergoes oral FMT or placebo therapy. The study patient will receive 2 diaries, which 
need to be filled out on a daily basis, the stool diary and the adverse event diary. The stool diary should 
be daily completed either until Visit 8 or if the patient participates in the open label extension until visit 
12OL. The adverse event diary has to be daily completed until visit 6 or visit 10OL. 
At visits 2 and 4 (phone visits) the coordinator will ask the study patient if adverse events occurred and 
will review the adverse event diary with the study patient. The coordinator will also evaluate the clinical 
components of the mPDAI of the last 3 days before the phone call (stool frequency, rectal bleeding, fecal 
urgency/ abdominal cramping, fever) as well as the concomitant medications.  
Visit 3 (site visit) the coordinator will review the adverse event diary with the study patient, and will 
assess the mPDAI and concomitant medication. The patient will also bring a stool sample for the stool 
bank, which was collected earliest on day 1 after the end of the oral or placebo FMT period.  
At phone visit 4 the coordinator will ask the study patient if adverse events occurred and review the 
adverse event diary. The coordinator will evaluate the clinical components of the mPDAI of the last 3 
days before the phone call (stool frequency, rectal bleeding, fecal urgency/ abdominal cramping, fever) 
as well as the concomitant medications. If the patient is in remission according to the diary (mPDAI≤4) 
and is on no concomitant medications, a pouchoscopy will be planned for site visit 5. If the study patient 
is not in remission (mPDAI>4) or had an early relapse after FMT the open label extension will be offered 
and the patient can be started on oral antibiotics again. For safety analyses a site visit 5 should be planned 
in the following 3-4 days. If the study patient chooses not to participate, he should be followed according 
the same schedule as patients who are in remission. 
 
Early termination visit due to flare on day 1-28 after FMT or due to adverse event or patient 
unwillingness to continue in study necessitating early termination 
If at any time between day 1-28 after endoscopic FMT the patient experiences recurrence of his pouchitis 
symptoms, he/she will contact the coordinator. The coordinator will ask the study patient if adverse 
events occurred and review the adverse event diary. The coordinator will evaluate the clinical 
components of the mPDAI of the last 3 days before the phone call (stool frequency, rectal bleeding, fecal 
urgency/ abdominal cramping, fever) as well as the concomitant medications.  
If the study patient has active disease (mPDAI>4), an early termination study visit will be scheduled.  A 
physical exam will be completed and, if possible, stool will be collected before the start of antibiotic 
therapy as standard of care. Blood labs will also be collected.  The patient will be started on the same 
antibiotic, which he was on before entering the study. At the study visit the coordinator will review 
possible adverse events, evaluate the clinical components of the mPDAI of the last 3 days before the 
visit (stool frequency, rectal bleeding, fecal urgency/ abdominal cramping, fever) as well as the 
concomitant medications. If the patient wants to proceed into the open label study, he has to undergo at 
least 10 days of standard of care antibiotic therapy, before he can undergo the open label therapy with 
FMT (endoscopic and oral FMT).  
If the patient is not willing to continue in the open label part of the study, he/she will be followed in the 
regular arm with visits 6-9.  
 
Study visits for patients at remission at phone visit 4 and site visit 5 
Phone visit 6 will evaluate for adverse events and review the adverse event diary. At this point (4 weeks 
after stopping the oral FMT) the patient can stop filling out the daily adverse event diary.  However, the 
patient will be reminded to bring the completed adverse event diary to site visit 7. Additionally, the 
mPDAI will be calculated and the concomitant medications will be assessed.  

 
19 
Site visit 7 will collect all pages of the adverse event diary, and review the adverse events, which 
occurred since visit 6. A physical exam and blood tests will be performed and the mPDAI will be 
calculated.  The concomitant medications will be assessed.  A stool sample will be collected from the 
patient. 
Site visit 8 will review new adverse events, concomitant medications and the mPDAI score. A stool 
sample will be collected from the patient. 
On the last phone visit 9 the coordinator will review serious adverse events only, which may have 
occurred since visit 8.  
 
Open label extension period 
After at least 10 days of antibiotic therapy a pouchoscopy and FMT will be performed at site visit 6OL. 
A physical exam will be completed, adverse events and concomitant medications reviewed.  Female 
patients will provide a urine sample for a pregnancy test before FMT. Similar to the previous FMT the 
study patient will be started on omeprazole 20 mg (1 tablet/daily) as long as he/she undergoes oral FMT 
therapy.  
In phone visit 7OL the coordinator will ask the study patient if adverse events occurred, review the 
adverse event diary, and will evaluate the clinical components of the mPDAI of the last 3 days before 
the phone call (stool frequency, rectal bleeding, fecal urgency/ abdominal cramping, fever) as well as 
the concomitant medications.  
At site visit 8OL the study coordinator will ask the study patient if adverse events occurred, review the 
adverse event diary, and will evaluate the clinical components of the mPDAI of the last 3 days before 
the visit (stool frequency, rectal bleeding, fecal urgency/ abdominal cramping, fever) as well as review 
the concomitant medications.   The coordinator will collect the stool sample from the patient, which 
should be collected 1-3 days after the end of the oral FMT therapy .  
The 9OL site visit will review adverse events and the adverse event diary, collect safety blood labs, 
perform a physical exam and calculate the mPDAI. A stool sample for the stool bank will be collected 
from the patient. A pouchoscopy will also be performed. 
Phone visit 10OL will evaluate for adverse events and review the adverse event diary. At this point 4 
weeks after stopping the oral FMT the patient can stop filling out the daily adverse event diary The 
patient will be reminded to bring the filled out adverse event diary to site visit 11OL. Additionally, 
mPDAI will be calculated and the concomitant medications will be assessed.  
Site visit 11OLwill collect all pages of the adverse event diary, and review the adverse events, which 
occurred since visit 10OL. A physical exam and blood tests will be performed and the mPDAI will be 
calculated. The concomitant medications will be reviewed.  A stool sample for the stool bank will be 
collected from the patient.  
Site visit 12OL will review new adverse events, concomitant medications and the mPDAI score.   A 
stool sample for the stool bank will be collected from the patient. 
On the last phone visit 13OL the coordinator will review serious adverse events only, which may have 
occurred since visit 12OL.  
 
 
 

 
20 
Study patients experiencing a recurrence of symptoms in the open label extension period 
If the study patient is experiencing worsening of disease after the second FMT, antibiotic therapy will 
be re-initiated as a standard of care approach. The patient will nevertheless be followed up according to 
the same schedule as patients not experiencing a relapse.  
 
8. SCREENING VISIT AND STUDY VISITS 1-4 
• Site screening visit 
Data to be recorded: 
General parameters: 
Initials 
Date of birth 
Sex 
Smoker (yes/no/ex-smoker) 
Race (NIH categories) 
Ethnicity (NIH categories) 
Case history 
Date of confirmation of the diagnosis 
Classification of UC before IPAA (proctitis, left sided colitis, pancolitis) 
Type of extraintestinal symptoms 
Specific therapies for pouchitis within the last year 
Type of medication 
Specific therapies for pouchitis within the last 4 weeks 
Type of medication 
Examinations 
Vital signs: blood pressure (mm Hg), heart rate (min-1), weight (kg), calculation of BMI, 
temperature 
Height (cm) 
Physical examination:  
- Head (including ENT and eyes) 
- Gastrointestinal tract, liver, spleen 
- Lymphatic system 
- Urogenital system 
- Endocrine system 
- Nervous system 
- Lungs and respiratory tract 
- Muscular and skeletal system 
- Peripheral vascular system 
- Skin and connective tissue 
- Cardiovascular system 
- Other 

 
21 
 
each: actual status: Present finding / normal condition / not examined 
Blood sampling and measurement of laboratory parameters 
- 
Hematology  
- 
Serum chemistry  
- 
Urine pregnancy test 
- 
Stool sample for C. difficile toxin 
 
 
Formal aspects: 
Informed consent procedure 
Verification of inclusion / exclusion criteria (eligibility check), as far as possible 
Dispense stool collection kit for stool sample (stool sample should be brought back at visit week 
0)  
Explain and distribute stool diary to study patient 
Perform test if patient is able to swallow an empty FMT test capsule 
 
 
• Visit 1: Site visit week 0 
Examinations 
Vital signs: blood pressure (mm Hg), heart rate (min-1), weight (kg), temperature 
Physical examination:  
- Head (including ENT and eyes) 
- Gastrointestinal tract, liver, spleen 
- Lymphatic system 
- Urogenital system 
- Endocrine system 
- Nervous system 
- Lungs and respiratory tract 
- Muscular and skeletal system 
- Peripheral vascular system 
- Skin and connective tissue 
- Cardiovascular system 
- Other 
 
each: actual status: Present finding / normal condition / not examined 
Blood sampling and measurement of laboratory parameters (must be performed in the 24 hours before 
FMT) 
- 
Urine pregnancy test 
Dispense stool collection kit for stool sample (stool sample should be brought back at visit week 2) 
 
Formal Aspects: 
Calculation of the mPDAI  
Verification of inclusion / exclusion criteria (eligibility check) 
Randomization 

 
22 
Dispense oral FMT or placebo 
Dispense omeprazole 20 mg (1 tablet) daily for 14 days during oral FMT 
Dispense PDAI diary 
Dispense adverse events diary 
 
Pouchoscopy: Evaluation of endoscopic PDAI and perform “blinded” (real or placebo) FMT.  
 
• Visit 2: Phone visit week 1 (7 (+1 day) days after endoscopic FMT /placebo and on 
oral FMT/placebo) 
Formal aspects: 
Adverse events (review adverse events diary) 
Concomitant medication 
Calculation of clinical mPDAI (stool frequency, rectal bleeding, fecal urgency/abdominal 
cramping, fever) 
 
 
• Visit 3: Site visit week 2 (15 +3 days after endoscopic FMT /placebo and on oral 
FMT/placebo) 
Formal aspects: 
Adverse events (review adverse events diary) 
Concomitant medication 
Calculation of clinical mPDAI (stool frequency, rectal bleeding, fecal urgency/abdominal 
cramping, fever) 
Reminder stool collection on day 15, 16 or 17 (day 1-3 after end of oral FMT) and bring in stool. 
 
• Visit 4: Phone visit week 4 (2-3 days before planned week 4 site visit) 
Formal aspects: 
Adverse events (review adverse events diary) 
Concomitant medication 
Reminder to bring stool day 25, 26 or 27.  
Calculation of clinical mPDAI (stool frequency, rectal bleeding, fecal urgency/abdominal 
cramping, fever) 
 
If patient is in clinical remission (mPDAI ≤4) and no need for antibiotics plan for pouchoscopy  week 4 
 

 
23 
If patient is not in clinical remission (mPDAI > 4) or need for antibiotics or comes in due to exacerbation 
of symptoms with possibility to continue with open label extension. Need to restart 10 day course of 
antibiotics as standard of care similar to initial antibiotic treatment before the first FMT  
 
• Visit 5: Site visit Week 4 (day 28 +/- 3 days after first transplant) or early termination 
visit due to flare (day 1-28 after first transplant) 
Examinations 
Vital signs: blood pressure (mm Hg), heart rate (min-1), weight (kg), temperature 
Physical examination:  
- Head (including ENT and eyes) 
- Gastrointestinal tract, liver, spleen 
- Lymphatic system 
- Urogenital system 
- Endocrine system 
- Nervous system 
- Lungs and respiratory tract 
- Muscular and skeletal system 
- Peripheral vascular system 
- Skin and connective tissue 
- Cardiovascular system 
- Other 
 
each: actual status: Present finding / normal condition / not examined 
 
Measurement of laboratory parameters  
Hematology  
Serum chemistry 
 
Stool collection: Bring to visit.  
 
Formal aspects: 
Return of study medication (empty containers) 
Compliance assessment (count of empty containers returned) 
Concomitant medication 
Adverse events (review adverse events diary) 
Calculation of mPDAI score (before pouchoscopy) 
Pouchoscopy (in patients in clinical remission and no need for antibiotics only): Evaluation of 
endoscopic PDAI.  
 
If patient is in clinical remission (mPDAI ≤4) and no need for antibiotics proceed to pouchoscopy  
If patient is not in clinical remission (mPDAI > 4) or need for antibiotics or comes in due to exacerbation 
of symptoms with possibility to continue with open label extension. Need to restart 10 day course of 
antibiotics as standard of care similar to initial antibiotic treatment before the first FMT  
 

 
24 
In case of premature withdrawal from the study (yes, no)  
If yes, reason:  
• Intolerance of medication 
• Lack of efficacy (need for steroids e.g. increase of steroids or re-introduction of steroids 
after previously successful taper) 
• Severe adverse event 
• Lack of patient’s cooperation 
• Inclusion criterion not fulfilled or exclusion criterion fulfilled coming to knowledge after 
recruitment  
• Other reason 
 
9. FOLLOW-UP VISITS OF PATIENTS IN REMISSION AT WEEK 4 OR NOT 
PARTICPATING IN THE OPEN LABEL EXTENSION 
• Visit 6: Phone visit week 6 (42 +/- 3 days after first transplant) 
Formal aspects: 
Adverse events (review adverse events diary, last day of filling out the diary is 28 days after end 
of oral FMT, which is around week 6; patient needs to be advised to bring filled out diaries to visit 
7) 
Concomitant medication 
Calculation of clinical mPDAI (stool frequency, rectal bleeding, fecal urgency/abdominal 
cramping, fever) 
 
• Visit 7: Site visit week 8 (56 +/- 5 days after first transplant) 
 
Examinations 
Vital signs: blood pressure (mm Hg), heart rate (min-1), weight (kg), temperature 
Physical examination:  
- Head (including ENT and eyes) 
- Gastrointestinal tract, liver, spleen 
- Lymphatic system 
- Urogenital system 
- Endocrine system 
- Nervous system 
- Lungs and respiratory tract 
- Muscular and skeletal system 
- Peripheral vascular system 
- Skin and connective tissue 
- Cardiovascular system 
- Other 
 
each: actual status: Present finding / normal condition / not examined 

 
25 
 
Measurement of laboratory parameters  
Hematology  
Serum chemistry 
 
Stool collection: Bring to clinic.  
Formal aspects: 
Concomitant medication 
Adverse events (adverse events diary filled out until visit 6) 
Calculation of mPDAI score  
Reminder stool collection and bring in stool week 16. 
Collect adverse event diary (filled out until week 6) 
• Visit 8: Site visit week 16 (112 +/- 7 days after first transplant) 
Formal aspects: 
Adverse events  
Concomitant medication 
Calculation of clinical mPDAI (stool frequency, rectal bleeding, fecal urgency/abdominal 
cramping, fever) 
Stool collection: Stool collection  
 
• Visit 9: Phone visit week 24 (168 +/- 10 days after first transplant) 
Formal aspects: 
Review if serious adverse events occurred in previous 8 weeks  
 
 

 
26 
 
10. FOLLOW UP VISITS OF PATIENTS PARTICIPATING IN OPEN LABEL EXTENSION 
AFTER WEEK 4 
• Visit 6OL: Site visit week 6 (week 0 OL) 
This visit should be performed after the patient completed at least 10 days of antibiotics  
 
Examinations 
Vital signs: blood pressure (mm Hg), heart rate (min-1), weight (kg) 
Physical examination:  
- Head (including ENT and eyes) 
- Gastrointestinal tract, liver, spleen 
- Lymphatic system 
- Urogenital system 
- Endocrine system 
- Nervous system 
- Lungs and respiratory tract 
- Muscular and skeletal system 
- Peripheral vascular system 
- Skin and connective tissue 
- Cardiovascular system 
- Other 
 
each: actual status: Present finding / normal condition / not examined 
 
Formal aspects: 
Concomitant medication 
Calculation of mPDAI score (before pouchoscopy) 
Dispense oral FMT capsules 
Dispense omeprazole 20 mg (1 tablet) daily for 14 days during oral FMT 
Dispense PDAI diary 
Dispense adverse events diary for OL follow-up phase 
 
 
Blood sampling and measurement of laboratory parameters (be performed in the 24 hours before FMT) 
- 
Urine pregnancy test 
 
 
Pouchoscopy: Evaluation of endoscopic PDAI and perform FMT.  
 

 
27 
• Visit 7OL: Phone visit week 7  (week 1 OL; 7 days (+1 day) after second transplant) 
Formal aspects: 
Adverse events (review adverse events diary) 
Concomitant medication 
Calculation of clinical mPDAI (stool frequency, rectal bleeding, fecal urgency/abdominal 
cramping, fever) 
 
 
• Visit 8OL: Site visit week 8 (week 2 OL, 15 + 3 days after second transplant) 
Formal aspects: 
Adverse events (review adverse events diary) 
Concomitant medication 
Calculation of clinical mPDAI (stool frequency, rectal bleeding, fecal urgency/abdominal 
cramping, fever) 
Reminder stool collection on day 15, 16 or 17 (day 1-3 after end of oral FMT) and bring in stool. 
Plan for pouchoscopy visit 9OL 
 
• Visit 9OL: Site visit week 10 (week 4 OL, 28 +/- 3 days after second transplant) 
Examinations 
Vital signs: blood pressure (mm Hg), heart rate (min-1), weight (kg) 
Physical examination:  
- Head (including ENT and eyes) 
- Gastrointestinal tract, liver, spleen 
- Lymphatic system 
- Urogenital system 
- Endocrine system 
- Nervous system 
- Lungs and respiratory tract 
- Muscular and skeletal system 
- Peripheral vascular system 
- Skin and connective tissue 
- Cardiovascular system 
- Other 
 
each: actual status: Present finding / normal condition / not examined 
 
Measurement of laboratory parameters  
Hematology  
Serum chemistry 
 
Stool collection: Bring in.  
Formal aspects: 
Concomitant medication 

 
28 
Adverse events (review adverse events diary) 
Calculation of mPDAI score  
Pouchoscopy: Evaluation of endoscopic PDAI.  
 
 
• Visit 10OL: Phone visit week 12 (week 6 OL; 42 +/- 3 days after second transplant)  
 
Formal aspects: 
Adverse events (review adverse events diary, which needs to be filled out 28 days after the last 
FMT, which is week 6 OL) 
Concomitant medication  
Calculation of clinical mPDAI (stool frequency, rectal bleeding, fecal urgency/abdominal 
cramping, fever) 
 
 
• Visit 11OL: Site visit week 14 (week 8 OL; 56 +/- 5 days after second transplant) 
Examinations 
Vital signs: blood pressure (mm Hg), heart rate (min-1), weight (kg) 
Physical examination:  
- Head (including ENT and eyes) 
- Gastrointestinal tract, liver, spleen 
- Lymphatic system 
- Urogenital system 
- Endocrine system 
- Nervous system 
- Lungs and respiratory tract 
- Muscular and skeletal system 
- Peripheral vascular system 
- Skin and connective tissue 
- Cardiovascular system 
- Other 
 
each: actual status: Present finding / normal condition / not examined 
 
Measurement of laboratory parameters  
Hematology  
Serum chemistry 
 
Stool collection: Bring in.  
Formal aspects: 
Concomitant medication 
Adverse events 

 
29 
Calculation of mPDAI score  
Reminder for stool collection week 16 
 
Collect adverse event diary (filled out until week 6OL) 
 
 
• Visit 12OL: Site visit week 22 (week 16 OL; 112 +/- 5 days after second transplant)  
Formal aspects: 
Adverse events  
Concomitant medication 
Calculation of clinical mPDAI (stool frequency, rectal bleeding, fecal urgency/abdominal 
cramping, fever) 
 
Stool collection: Stool collection  
 
• Visit 13OL: Phone visits week 30 (week 24OL 168 +/- 10 days after second transplant)  
Formal aspects: 
Review if serious adverse events occurred in previous 8 weeks  
 
11. POUCHOSCOPY AND LABORATORY PARAMETERS 
• Pouchoscopy (Screening, visit 5 or visit 6OL) 
Pouchoscopy will be performed to evaluate the pouch, prepouch ileal segment and the cuff. The pouch 
and prepouch inflammation will be graded according mPDAI (see attachment). 
 
• Laboratory parameters 
All laboratory analyses will be carried out in at the local laboratory of the investigational site. 
Acute phase reactants (nonspecific inflammatory markers) 
C-reactive protein (CRP) 
Hematology: 
Blood count (erythrocytes, hemoglobin, hematocrit, leukocytes, platelets) 
Serum chemistry: 
Kidney function: creatinine 
Liver function (alanine aminotransferase {ALT}, aspartate aminotransferase {AST}, alkaline 
phosphatase, bilirubin) 

 
30 
Urine pregnancy test screening visit and in the 24 hours before FMT  
 
12. RECORDING OF COMPLIANCE 
Compliance will be assessed by checking the study medication (containers) returned at the follow-up 
visits and the final visit by the investigator.  
All returned containers will be counted by the study coordinator and the number will be documented in 
the CRF.  
13. ADVERSE EVENTS 
• Definitions 
Adverse events (AEs) 
Adverse events (AEs) will be recorded at each regular scheduled study visit or study phone contact in 
the study patient record (source document) as well as on a specific AE form on the CRF. 
An AE is any untoward medical occurrence in a study patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, 
whether or not related to the medicinal product, e.g.: 
• any new diagnosis 
• any symptom that requires medical clarification or leads to in-patient admission (surgery or 
accident) 
• any suspected adverse drug reaction (ADR) 
• any symptom that appears on the study patient’s medical records 
• any event related in time with the application of the study medication and affecting the health of 
the study patient (including laboratory value changes) 
 
Serious Adverse Events (SAE) 
A serious adverse event (experience) is any untoward medical occurrence that at any dose: 
• results in death 
• is life-threatening 
• requires inpatient hospitalization or prolongation of existing hospitalization  
• results in persistent or significant disability/incapacity 
Non-serious adverse events are all AEs that do not fall into any of the above categories. 
 

 
31 
Unexpected Adverse Drug Reactions  
An unexpected adverse drug reaction (ADR) is an adverse reaction, the nature or severity of which is 
not consistent with the applicable product information. 
 
Expected Adverse Drug Reactions 
Fecal transplant has an excellent safety profile in patients with C. difficile colitis. Also FMT for C. 
difficile colitis seems to be safe in immunocompromised patients.64, 65  
In patients with IBD mild flu symptoms, abdominal pain and diarrhea after transplant have been 
observed.51 However, these are only transitory and no organ failure or organ toxicity has been reported.  
 
14. DOCUMENTATION AND REPORTING OF ADVERSE EVENTS 
The study patients will be instructed to contact the investigator, if any serious or unexpected AE occurs, 
so that appropriate action can be taken. 
Moreover, the investigator must ask at each follow-up visit a generally worded question without 
searching for any special symptoms, e.g. ”Has your state of health worsened since we last met?” If the 
answer to this question is “no”, no further questions will be asked. If the answer to the question is “yes”, 
the investigator will document the nature, time, severity, seriousness and duration as well as the causality 
of the AE. For each AE a specific AE documentation form will be provided, which should be completed 
by the PI as an initial report. The report must contain a detailed description of the symptoms observed 
and the concomitant treatment administered. Furthermore, the investigator must comment on a possible 
causative relationship between the AE and the trial medication. Each AE must be followed until it is 
resolved or can be explained satisfactory. 
The following has to be documented for each AE: 
• Nature of the event 
• Time of onset: date, time 
• Concomitant treatment: product (generic name), indication, dosage, dosage interval, presentation, 
mode of administration, administration regimen 
• Duration of the AE 
• Severity 
• Seriousness 
• Causality 
• Outcome 
 
Severity 
The severity is evaluated as follows: 
1. Mild: 
- event/symptom does not interfere with normal daily activities 
2. Moderate: 
- event/symptom interferes with normal daily activities 

 
32 
3. Severe: 
- event/symptom prevents normal daily activities 
 
Causality 
The relationship between an AE and the study medication is classified according to the WHO 
classification: 
Certain 
A clinical event, including laboratory test abnormality, is occurring in a plausible time relationship to 
drug administration, and which concurrent disease or other drugs or chemicals cannot explain. The 
response of the study patient to withdrawal of the drug should be clinically plausible. The event must be 
definite pharmacologically or phenomenologically, using a satisfactory rechallenge procedure if 
necessary. 
Probable/Likely 
A clinical event, including laboratory test abnormality, with a reasonable time sequence to the 
administration of the drug, unlikely to be attributed to concurrent disease or other drugs or chemicals, 
and which follows a clinically reasonable response on withdrawal (de challenge). Rechallenge 
information is not required to fulfil this definition. 
Possible  
A clinical event, including laboratory test abnormality, with a reasonable time sequence to administration 
of the drug, but which could also be explained by concurrent disease or other drugs or chemicals. 
Information on drug withdrawal may be lacking or unclear. 
Unlikely  
A clinical event, including laboratory test abnormality, with a temporal relationship to drug 
administration which makes a causal relationship improbable, and in which other drugs, chemicals or 
underlying disease provide plausible explanations. 
Conditional/Unclassified 
A clinical event, including laboratory test abnormality, reported as an adverse reaction, about which 
more data are essential for a proper assessment or the additional data are under examination. 
Not assessable / Unclassifiable 
A report suggesting an adverse reaction, which cannot be judged because information is insufficient or 
contradictory, and which cannot be supplemented or verified. 
As an alternative to the above-mentioned WHO assessments, the following assessment can be made: 
Not related 
There is sufficient information available to show that the etiology is unrelated to the study medication. 
Measures at the onset of adverse events  
Measures at the onset of adverse events are classified and described as follows: 
1) 
None, i.e. the study medication was not changed 
2) 
The dose of the study medication was reduced 
3) 
The study medication was withdrawn and/or 
4) 
Other measures (clear text) 

 
33 
The course and outcome of the adverse event will be commented on as follows: 
• Recovered without sequelae 
• Not yet recovered 
• Recovered with sequelae 
• Fatal 
 
• Documentation and Reporting of Serious Adverse Events 
On enrolment in the study, the study patients will be instructed to contact the investigator if a serious or 
unexpected AE occurs, so that appropriate measures can be taken. 
Any SAE (including death, irrespective of the cause) occurring during or for up to 14 days after 
the end of the study will be immediately reviewed by the PI, i.e. within 24 hours.  
 
A specific SAE documentation form will be provided. In case of an SAE, this form will be completed 
and reviewed by the PI as an initial report, and if the SAE is judged to be possible related or related to 
study drug will be sent  (via fax) to the IRB of the University of North Carolina. The report must contain 
a detailed description of the symptoms observed and the concomitant treatment administered. 
Furthermore, the investigator must comment on a possible causative relationship between the AE and 
the trial medication. Each SAE must be followed until it is resolved or can be explained satisfactorily. 
The general procedure for the observation, collection and analysis of drug risks (regulatory affairs) in 
conformity with the appropriate national Drug Law shall apply without qualification. 
In accordance with drug safety and national requirements, the study PI will inform the IRB of the study 
at the University of North Carolina and will make sure that the involved persons will obtain adequate 
information.  
The following instructions must be heeded: 
In the case of an intolerable SAE, the study patient must, at the decision of the investigator, be withdrawn 
from the clinical trial, and symptomatic treatment must be administered. The measures taken must be 
recorded on the CRF. 
In accordance with local legislation, the investigators will submit copies of the final SAE-report to the 
Regulatory Authorities concerned, if necessary. 
15. ABNORMAL LABORATORY RESULTS  
All laboratory values outside of the normal range will be repeated as judged appropriate to ensure the 
validity of the abnormal result. The investigator will document all laboratory values on the relevant page 
of the CRF and will assess the etiology of the clinically relevant abnormal laboratory values.  
Clinically relevant abnormal laboratory values are only documented on the AE form of the CRF, if the 
study patient is discontinued, hospitalized, or, in the investigator’s opinion, it should be considered as 
an AE. 
Abnormal laboratory results caused by ulcerative colitis should not be reported on the AE form. 

 
34 
16. WITHDRAWAL CRITERIA 
• Criteria in individual cases 
Any study patient can withdraw from the study at any time without personal disadvantages and without 
having to give a reason. The time of withdrawal, the results available up to that time, and, if known, the 
reason for withdrawal must be documented on the CRF. 
The investigator can also discontinue the study after considering the risk-to-benefit ratio, if he/she no 
longer considers the further participation of the study patient justifiable. The date of and the primary 
reason for the withdrawal as well as the observations available at the time of withdrawal are to be 
documented on the CRF. 
Reasons leading to the withdrawal of a study patient can include the following (primary reason must be 
determined): 
• Development of a SAE that is thought to be likely secondary to study drug or study 
intervention. 
• Development of an AE with ≥ grade 3 toxicity, using the FDA toxicity grading scale for 
preventive vaccines ( 
If the PI or DSMB believes it is no longer in the subject’s best interest to continue participation in the 
study.  Examples include: 
• A serious or unexpected adverse event 
• Serious inter-current illness, or 
• Progression of disease that requires alternative treatment. 
• The subject no longer meets the inclusion criteria. 
• Lack of compliance with study procedures or study treatment, as determined by the PI. 
 
In all study patients who finish the study prematurely, a withdrawal examination should be carried out 
within 3 weeks after the last application of the study medication. The withdrawal examination must be 
conducted as a final examination and documented in the CRF. It is most important to calculate at least 
the final mPDAI score for each study patient. If possible, an endoscopy with biopsies according to the 
protocol should be performed and blood samples for hematology and serum chemistry should be taken. 
The investigator will continue to observe study patients withdrawn from the study because of intolerable 
AEs until the findings have been clarified. 
• Criteria for the termination of the whole study 
If serious safety concerns arise, the coordinating investigator can terminate or interrupt the study by 
agreement with the sponsor and the DSMB. If new information on the risk-to-benefit ratio of the drug 
or on the treatment methods used in the study is obtained in the meantime, the coordinating investigator 
reserves the right to interrupt or terminate the project by agreement with the sponsor. Premature 
termination is also possible if the coordinating investigator, or the investigators and the sponsor if study 
patient recruitment is insufficient and cannot be expedited by appropriate measures.  
The study should also be stopped or paused until thorough review of all safety data by the DSMB for 
the following: 
• An SAE occurs in at least one subject in which the SAE is determined to be possibly, 
probably, or definitely related to test treatment. 

 
35 
• The same grade 3 or higher AE assessed as possibly, probably, or definitively related, 
occurring in two or more subjects, using the FDA toxicity grading scale for preventive 
vaccines. 
 
 
17. DATA SAFETY MONITORING BOARD (DSMB) AND SAFETY OFFICER 
The DSMB will consist of at least external 3 members. Additionally one independent medical safety 
officer will monitor the study.  On a monthly basis, the Data Management Center (DMC) will issue 
standard safety reports (enumerated by event and category, both by total and by type) as well as a 
cumulative report of all Adverse Events (AEs) to include Event Code, Dates of Onset/Resolution, Grade, 
and Outcome to the an independent safety officer. In addition, these standard safety reports will be 
presented to the DSMB at each conference.  The DSMB will review these data and make appropriate 
safety decisions based on these events. Participants will be monitored for potential AEs, including signs 
or symptoms related or unrelated to the condition under study, any clinically significant laboratory 
abnormality, or any abnormality detected during physical examination. 
  
18. RANDOMIZATION, DATA MANAGEMENT AND DATA MONITORING 
The randomization of the study patients and the processing and analysis of the data will be carried out 
by the Biostatistics core of the Center for Gastrointestinal Biology and Disease at UNC Chapel Hill.  
Study data for this study will be collected and stored using electronic records.  Data captured will be 
entered in real time at each clinical site using web forms developed to replicate paper case report forms.  
All data will be created, modified, maintained, archived, retrieved and distributed by a computer system.  
The use of electronic records will increase the speed of data collection and exchange.  This will reduce 
the manpower necessary to perform double-data entry from paper forms and transcription error.  In 
addition, electronic records permit economical storage of study data and ease of accessibility and 
analysis. Data management and data quality systems will be built into the system.   
Data quality using electronic records will ensure that data are attributable, legible, contemporaneous and 
original.   
The DMC at the CGIBD at the University of North Carolina will track the data collection, provide data 
security, control for confidentiality of study data, maintain computer backups to protect data until study 
closure and archive study data according to FDA requirements (21 CFR 11).  Electronic signatures will 
be linked to each entry.   
All computer systems and programs will be password protected, and all electronic communications of 
study and other confidential information will be encrypted. Personnel at the CGIBD have extensive 
training and experience using electronic data systems.  Good computer security practice (restricting 
physical access to machines, prohibition of password sharing, and logging off computers after work 
hours or when away from the machine) will be required of all study personnel.  
Standard Operating Procedures exist for users of the DMC.  Only authorized persons are authorized for 
data entry and access.  Data security systems require password protected identification codes for data 
entry and provide protection against data manipulation.  The database is located on a server protected by 
firewalls.  Access to the database server will not be allowed by users on computers outside of the firewall-

 
36 
protected zone.  Virus protection software is installed on each study machine. System access to computer 
systems will be audited.  Redundant backups and off-site backup storage will allow for quick restoration 
of data in the unlikely event that a hardware failure, disaster, or security breach should occur.  Servers 
and backups will be located in a secured location with access limited to authorized personnel. 
Data cleaning will include range and edit checks, cross form edit checks, query generating and tracking 
and periodic data status reports.  Any data errors or inconsistencies detected after data entry will be 
automatically tracked, communicated and resolved using a web-based application.  An audit trail of all 
data changes over the life of the study will be maintained.  All study raw data, forms, documents, 
software programs, software applications and computer data files will be indexed and archived routinely.  
Strict version control of documents and software applications will be instituted.  Retention of study 
documentation after study completion will conform to FDA and NIH requirements. 
Standardized study management reports will be generated monthly during the recruitment phase of the 
study.  These reports will be used to track study progress including study patient enrollment, 
randomization, compliance, study patient status changes, and study events.  The data will be reported 
for each Study Center individually and summarized for the study as a whole.  Every six months, a 
standardized report will also be generated for the DSMB meeting.  This report will include additional 
information on clinical events and adverse events that is coded by blinded treatment group.  Other than 
the study statistician and statistical analyst, no study personnel will see this report.  
19. MODIFIED POUCHITIS DISEASE ACTIVITY INDEX (PDAI) 
The Pouchitis Disease Activity Index (PDAI) was developed by Sandborn et al for diagnosing active 
pouchitis and quantifying the severity of pouchitis 66. Shen et al. later on modified the index (mPDAI) 
and showed that similar outcomes can be measured after omitting the evaluation of histology, thus 
omitting the biopsy and histology costs.67 The PDAI or the modified PDAI has been used in a number 
of clinical studies where it appears quite useful in discriminating between subjects with and without 
pouchitis and in quantifying the severity of pouchitis 20, 22, 25, 27-29, 68-70 
•  Subject Data Collected via Diary Card 
Subjects will be instructed to complete the diary at the same time each night before going to bed.  The 
following information will be collected daily using a subject completed diary card: 
• Current daily stool number via the question, “During the past 24 hours how many bowel 
movements did you have?” (Provide number) 
• Rectal bleeding via the question, “During the past 24 hours, what percentage of your bowel 
movements contained blood?” a. 0% (none); b. <20% (rare); c.>20% (usual) 
• Fecal urgency/abdominal cramps via the question, “During the past 24 hours what percentage 
of your bowel movements were preceded with abdominal cramps or an urgent need to go to the 
bathroom?” a. 0% (none); b. <50% (occasional); c. >50% (usual) 
• Fever defined as temperature >37.8oC via the question, “During the past 24 hours have you 
experienced a fever higher than 37.8oC (100.0oF)  (Yes/No) 
 
Please note that responses to the rectal bleeding and fecal urgency questions are each associated with a 
word in parentheses.  These words are the ratings that are used on the mPDAI.  For example, if on a 
given day a subject responds that their percentage of bowel movements that had blood present was <20% 
and the percentage of bowel movements that were preceded by abdominal cramps was 0%, then their 

 
37 
rectal bleeding and fecal urgency/abdominal cramps mPDAI ratings would be “rare” and “none”, 
respectively. 
Diary cards will be distributed to pouchitis subjects only at the screening visit and week 0 visit and 
should be reviewed with the study patient at visit week 0 and week 4, respectively, to ensure that all 
headers are completed and that entries for all questions are made for each day of the study period.  
Subjects should not be asked to provide answers retrospectively to unanswered diary questions but can 
be counselled on the importance of providing answers to all questions on each study day during the 
treatment period. 
 
• Calculating the mPDAI 
At the screening visit subjects will be questioned regarding their post-IPAA daily stool frequency. This 
number will represent a subject’s “normal” stool frequency after undergoing IPAA. Current stool frequency 
as well as current symptoms of stool blood, fecal urgency and cramps, and fever will be determined from 
the subjects’ daily diaries.  To calculate the subjects’ baseline mPDAI scores, symptom data recorded in the 
subjects’ diaries from the three days prior to Visit week 0 will be used. To calculate their mPDAI score, the 
investigator will question the subject on their stool frequency, percentage of stools with blood, percentage 
of bowel movements associated with urgency and cramping, and fever, over the three days prior to their 
visit.  Their responses to these questions will be used to calculate the clinical subscore of the mPDAI.  To 
calculate the Month 1 mPDAI scores symptom data recorded in the subjects’ diaries from the three days 
prior to Visit week 4 will be used. If a subject fails to provide symptom responses for one of more days of 
the three days prior to Visit the three days prior and closest to the visit date for which symptom data was 
recorded will be used to calculate the clinical subscore of the mPDAI. Active pouchitis is defined as a total 
mPDAI score > 5 points. 
 
Pouchoscopy 
During the endoscopic examination of the pouch, the presence or absence of the following endoscopic 
findings will be noted: edema; granularity; friability; loss of vascular pattern; mucous exudate; and 
ulceration. No biopsies will be taken in the context of the study. 
 
Stool frequency 
The mean stool frequency will be calculated for the three evaluation days. The subject’s “normal” stool 
frequency will be subtracted from the mean stool frequency and the result will be evaluated against the 
stool frequency categories on the mPDAI. The appropriate mPDAI stool frequency score will be 
assigned. 
Rectal bleeding 
The rectal bleeding frequency will be calculated for the three evaluation days. The relative frequency for 
rectal bleeding will be calculated based on the total number of stools passed over the same three 
evaluation days ((total #stools with blood/total #stools)*100). The relative frequency will be evaluated 
against the following categories: 
0% (none) < 20% (rare) > 20% (present daily) 
Please note that the words, “none”, “rare”, and “present daily” in parentheses, correspond to the rectal 
bleeding categories on the mPDAI. These categories will be used to assign a mPDAI score for rectal 
bleeding. 

 
38 
Fecal urgency/abdominal cramping 
The fecal urgency/abdominal cramping frequency will be calculated for the three evaluation days. The 
relative frequency for fecal urgency/abdominal cramping will be calculated based on the total number 
of stools for the same three evaluation days ((total #stools with cramping or urgency/total #stools)*100). 
The relative frequency will be evaluated against the following categories: 
0% (none) < 50% (occasional) > 50% (frequent) 
As with rectal bleeding, the words, “none”, “occasional”, and “frequent” in parentheses, correspond to 
the fecal urgency/abdominal cramping categories on the mPDAI. These categories will be used to assign 
a mPDAI score for fecal urgency/abdominal cramping. 
Fever 
If a subject indicates that they had a fever on none of the three evaluation days, the mPDAI score for 
“absent” will be recorded. If a subject indicates that they had a fever on one or more of the three 
evaluation days, the mPDAI score for “present” will be recorded. 
 
20. STATISTICAL ANALYSIS 
The following endpoints will be assessed 
• Primary Endpoint:  
Safety and Tolerability of FMT 
• Number of study patients, who discontinued therapy 
• Adverse events grouped by body system  
• Changes in laboratory values 
•  Secondary Endpoints 
Clinical remission (mPDAI score ≤4 points and a 
decrease in the baseline mPDAI> 2 points) and no need for antibiotic therapy at week 
4. 
• Clinical remission (clinical mPDAI score ≤ 4) and no need for antibiotics at week 8*. 
• Clinical remission (clinical mPDAI score ≤ 4) and no need for antibiotics at week 16*. 
• Endoscopic improvement of active pouchitis (decrease from baseline in mPDAI 
endoscopic subscore > 2 points) at week 4. 
• Response: Symptomatic improvement of active pouchitis (decrease from baseline in 
mPDAI clinical subscore > 2 points) and no need for antibiotic therapy at week 4. 
• Response: Symptomatic improvement of active pouchitis (decrease from baseline in 
mPDAI clinical subscore > 2 points) and no need for antibiotic therapy at week 8*. 
• Response: Symptomatic improvement of active pouchitis (decrease from baseline in 
mPDAI clinical subscore > 2 points) and no need for antibiotic therapy at week 16*. 
 
*Only patients who do not continue in open label extension 
• Exploratory analyses (OL=Open label): 
• Endoscopic improvement of active pouchitis (decrease from baseline in mPDAI 
endoscopic subscore > 2 points) at in open label extension week 8. 

 
39 
• Clinical remission (mPDAI score ≤4 points and a decrease in the baseline mPDAI> 2 
points) and no need for antibiotic therapy at week 10 OL. 
• Clinical remission (clinical mPDAI score ≤ 4) and no need for antibiotics at week 14 
OL. 
• Clinical remission (clinical mPDAI score ≤ 4) and no need for antibiotics at week 22 
OL. 
• Response: Symptomatic improvement of active pouchitis (decrease from baseline in 
mPDAI clinical subscore > 2 points) and no need for antibiotic therapy at week 10 OL. 
• Response: Symptomatic improvement of active pouchitis (decrease from baseline in 
mPDAI clinical subscore > 2 points) and no need for antibiotic therapy at week 14 OL. 
• Response: Symptomatic improvement of active pouchitis (decrease from baseline in 
mPDAI clinical subscore > 2 points) and no need for antibiotic therapy at week 22 OL. 
• Symptomatic worsening of active pouchitis (decrease from baseline in mPDAI clinical 
subscore > 2 points) from FMT week 0 – week 16 
• Quantitative changes in mPDAI from baseline values 
• Quantitative changes of calprotectin from baseline 
• Alterations in stool microbiome after FMT 
• Engraftment of donor FMT 
 
Clinical analyses 
The primary endpoint is the evaluation of safety and tolerability of FMT in patients with ADP. Secondary 
endpoints are endoscopic and clinical remission at week 4 in conjunction with no need for antibiotic 
therapy, clinical response and remission and no need for antibiotics at week 4,8 and 16, endoscopic 
improvement of pouchitis and quantitative changes of calprotectin after the initial FMT. All subjects 
with missing data for determination of endpoint status will be considered as a non-responder in the 
intention-to-treat analysis. For dichotomous outcomes we will compute the percentage of subjects having 
the event along with a 95% confidence interval. For continuous outcomes we will compute the mean and 
a 95% confidence interval for the mean as well as descriptive statistics such as median, range and upper 
and lower quartiles. In addition to computing these measures for all 20 subjects, we will compute them 
for subgroups of interest (e.g. endoscopic active vs inactive ADP). These estimates can then be used in 
the planning of a larger, hypothesis-based study.  
 
• Sample size calculation 
This trial is designed as a proof-of-concept study of FMT therapy, not a definitive evaluation of FMT 
therapy in patients with ADP. The goal is to evaluate the safety and feasibility of such a trial, as well as 
to estimate the effect sizes in placebo and FMT therapy groups in order to accurately estimate the sample 
size needed for subsequent evaluation in a larger definitive trial. Nonetheless, we estimated the minimum 
effect size this pilot study can detect. We assume a placebo remission rate (defined as clinical remission 
and no need for antibiotics) of 10%. The low placebo response rate is based on the inclusion criterion, 
which selects only patients needing continuous or recurrent antibiotic therapy in the setting of ADP. 
With a follow-up of 16 weeks with the requirement of clinical remission without antibiotic therapy at 
end of follow-up, a placebo response rate beyond 10% is highly unlikely. The recent case series of 
Stallmach et al. suggests an antibiotic-free remission rate of 80% and a response rate of 100% in the 
setting of repeated FMT.49 With 20 patients (1:1 randomization), and a placebo response rate of 10%, 
we will have 80% power to detect an effect difference of 67.5%, that is, an antibiotic-free remission rate 

 
40 
of 77.5% in the treatment group (2-sided, alpha=0.05, Fisher-Irwin's exact conditional test). Thus, even 
with this small proof-of-concept design, we could observe a significant effect in the range of effect size 
reported in recent case series. 
 
Microbiome Analyses 
From each patient 1 stool sample will be collected before transplant and twice after the transplant (week 
3 and 4). Patients in remission will collect 2 more stool samples in week 8 and 16. Patients in the open 
label extension trial will collect stool samples after transplant in week 8, 10, 14 and 22. Assuming that 
9 patients enter remission in the placebo controlled phase (9x4= 36 samples) and 11 patients enter the 
open label extension (11x7=77 samples) a total of 116 samples will be analysed. All microbiome 
analyses will be conducted by OpenBiome, which will donate time and materials for the analyses. The 
gut microbiome of donors and patients will be analysed through deep sequencing of the 16S ribosomal 
RNA gene amplified from stool samples. Microbial engraftment will be operationalized through the 
donor similarity index (DSI) used to evaluate the degree of engraftment in FMT recipients over time 
(after 2,4,8 and16 weeks).61 We will measure DSI over time to elucidate the stability of engraftment and 
its relationship to clinical observations. In addition to 16S rRNA sequencing, we will save aliquots of 
stool for metabolomic characterization. In particular, given the potential role of butyrate in ameliorating 
inflammation, we’re especially interested in measuring short chain fatty acid levels in stool before and 
after FMT. We plan to collect stool samples for characterization at baseline and at 2, 4, 8 and 16 week 
intervals after treatment.  
 
 

21. STUDY VISITS CHART 
1.1  STUDY VISITS CHART PLACEBO CONTROLLED TRIAL SCREENING – WEEK 4 (SITE VISIT) 
Visit 
Screening 
1 
2 
3 
4 
5 
Early 
terminationg 
Type of visit 
Site 
Site 
Phone 
Site 
Phone 
Site 
Phone/site 
Day 
-14 
0 
7 
+/-1 
15 
+3 
26 
+/-1 
28 
+/-3 
 
Week 
-2 
0 
1 
2 
4 
4 
 
Medical History 
X 
 
 
 
 
 
 
mPDAI score 
 
X 
Xd 
Xd 
Xg(!) 
X 
X 
Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
Physical Exam 
X 
 
 
 
 
X 
X 
Blood Tests 
X 
 
 
 
 
X 
X 
Pregnancy Test (urine) 
X 
X 
 
 
 
 
 
Test FMT capsule 
X 
 
 
 
 
 
 
Dispense FMT capsules 
 
X 
 
 
 
 
 
10-14 day antibiotic therapy pre-
transplant 
X 
 
 
 
Xc 
Xc 
Xc 
Stool sample 
Xe 
 
 
Xf 
Xf 
Xg 
X 
Sigmoidoscopy (Pouchoscopy 
 
X 
 
 
 
Xa 
 
Endoscopic FMT 
 
X 
 
 
 
 
 
Distribute/Review Subject Diariesb 
X 
X 
X 
X 
X 
X 
X 
Distribute/Review Subject adverse 
events diaryb 
 
 
X 
X 
X 
X 
X 
 Study visits Chart for patients continuing in observation phase 
 

 
42 
 
Visit 
6 
7 
8 
9 
Early 
terminationg 
Type of visit 
Phone 
Site 
Site 
Phone 
Phone/site 
Day 
42 
+/-3 
56 
+/-5 
112 
+/-7 
168 
+/-10 
 
Week 
6 
8 
16 
24 
 
mPDAI score 
X 
Xd 
Xd 
 
X 
Concomitant Medication 
X 
X 
X 
 
X 
Adverse Events 
X 
X 
X 
XI 
X 
Physical Exam 
 
X 
 
 
X 
Blood Testsa 
 
X 
 
 
X 
Stool sample 
 
Xf 
Xf 
 
 
Sigmoidoscopy (Pouchoscopy 
 
 
 
 
 
Distribute/Review Subject Diariesb 
X 
X 
 
 
X 
Distribute/Review 
Subject 
adverse 
events diaryb 
X 
Xj 
 
 
X 
 
 
 

 
43 
1.2 STUDY VISITS CHART OPEN LABEL EXTENSION FOR PATIENTS WITH RESPONSE ONLY OR NO 
RESPONSE OR EARLY TERMINATION DUE TO FLARE IN PLACEBO-CONTROLLED TRIAL SECTION  
Visit 
6OL 
7OL 
8OL 
9OL 
10OL 
11OL 
12OL 
13OL 
Early 
terminationg 
Type of visit 
Site 
Phone 
Site 
Site 
Phone 
Site 
Site 
Phone 
Phone/site 
Day (post 2nd transplant) 
38 (0) 
46 (8) 
+/-1 
53 (15) 
+3 
66 (28) 
+/-3 
80 (42) 
+/-3 
94 (56) 
+/-5 
150 (112) 
+/-7 
206 (168) 
+/-10 
 
Week (post 2nd transplant) 
6 (0) 
7 (1) 
8 (2) 
10 (4) 
12 (6) 
14 (8) 
22 (16) 
30 (24) 
 
mPDAI score 
 
Xd 
Xd 
X 
X 
Xd 
Xd 
 
X 
Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
XI 
X 
Physical Exam 
X 
 
 
X 
 
X 
 
 
X 
Blood Tests 
 
 
 
X 
 
X 
 
 
X 
Pregnacy test (urine) 
X 
 
 
 
 
 
 
 
 
Dispense FMT capsules + 
omeprazole 
Xg 
 
 
 
 
 
 
 
 
Stool sample 
 
 
Xf 
Xf 
 
Xf 
Xf 
 
X 
Sigmoidoscopy 
(Pouchoscopy 
X 
 
 
X 
 
 
 
 
 
Endoscopic FMT  
X h 
 
 
 
 
 
 
 
 
Distribute/Review Subject 
PDAI Diaryb 
X 
X 
X 
X 
X 
X 
X 
 
X 
Distribute/Review Subject 
adverse events diaryb 
X 
X 
X 
X 
X 
Xj 
 
 
X 
 
 
 

 
44 
 
a Pouchoscopy visit 5 only in patients who are in remission (mPDAI<4) as assessed in visit 4 by phone or in patients with clinical active 
pouchitis, but not willing to participate in open label extension 
b There will be two subject diaries provided to the patient: One for the evaluation of the mPDAI will be provided at Screening. The study 
patient will complete this diary each day, beginning with the Screening visit, and ending with the Week 16 visit. Stool frequency, rectal 
bleeding, fecal urgency or abdominal cramps, and/or fever will be recorded. A minimum of three days of diary entries will be required during 
the week prior to randomization, Phone visit week 1 and 2 and Visit Week 4 and 8. The last three days of diary entries will be used to calculate 
stool frequency and fecal urgency/abdominal pain scores and clinical mPDAI subscores.  
The “adverse events diary” will assess for adverse events during the FMT phase (14 days) and daily for 28 days after the last day of oral FMT. 
c Visit 4: Start of pretransplant antibiotic therapy for 10-14 days only in patients qualifying for open label extension  
d Clinical mPDAI. 
e Stool samples for microbiome, calprotectin and C. diff analyses. 
f Stool samples for calprotectin and microbiome analyses. 
g between visit 1-5 or visit 6-8 or visit week 6OL-12OL 
h Endoscopic open label FMT followed by oral FMT only if no clinical remission according to mPDAI at visit 4 and study patients wants to 
continue in open label FMT. 
I Evaluation of serious adverse events occurring in the follow-up period 
j Collect adverse event diary 
 

22. APPENDIX B: STUDY FLOW CHART


  

          
           
          
         
 
                           
          
                                 
             
        
             
       
             
       
                                      
                                                               
                                                      
                                                          
              
              
                 
       
                  
       
               
                        
       
              
       
              
                
       
       
                    
       
       
                          
  
             
                       
                           
                
              
           
              
              
       
                  
        
                 
       
                         
                    
       
                      
        

 
47 
 
 

 
48 
 
23. APPENDIX C: MODIFIED POUCHITIS DISEASE ACTIVITY INDEX (MPDAI) 
According to Shen et al.; 2003 67 
 
Clinical Criteria 
 
 
 
Score 
Stool Frequency 
Usual post-op stool frequency  
 
0 
1-2 stools/day > post-op usual  
 
1 
3 or more stools/day > post-op usual  
2 
  
Rectal Bleeding 
None or rare 
 
 
 
 
0 
Present daily  
 
 
 
1 
  
Fecal Urgency / Abdominal Cramps 
None   
 
 
 
 
0 
Occasional 
 
 
 
 
1 
Usual  
 
 
 
 
2 
Fever (temperature> 100oF)  
Absent  
 
 
 
 
0 
Present  
 
 
 
 
1 
 
Endoscopic Criteria  
 
Edema  
 
 
 
 
1 
Granularity 
 
 
 
 
1 
Friability 
 
 
 
 
1 
Loss of vascular pattern 
 
 
1 
Mucus exudate 
 
 
 
1 
Ulceration 
 
 
 
 
1 
 

24. STUDY PATIENT STOOL DIARY 
Subject Diary for Pouchitis 
Instructions:  
Begin recording in your diary each night. You should record before going to bed and the answers should describe the preceding 24 hours. 
Date 
During the past 24 hours how 
many bowel movements did 
you have? 
(Please provide number) 
During the past 24 hours how 
many of your bowel 
movements contained blood? 
(Please provide number) 
During the past 24 hours how 
many of your bowel 
movements were preceeded 
by abdominal cramps or an 
urgent need to go to the 
bathroom? 
(Please provide number) 
During the past 24 hours did 
you experience fever higher 
than 37.8{C (100.0{F)? 
(Please mark “yes” or “No”) 
 
  
 
 
 
Yes 
No 
 
 
 
 
Yes 
No 
 
 
 
 
Yes 
No 
 
 
 
 
Yes 
No 
 
 
 
 
Yes 
No 
 
 
 
 
Yes 
No 
 
 
 
 
Yes 
No 

25. ADVERSE EVENT DIARY 
Front pages of diary 
 
Safety and efficacy of fecal microbiome transplantation (FMT) in the treatment of 
antibiotic dependent pouchitis (ADP) 
Record of Side Effects 
 
This diary is one way researchers will get information from you regarding any possible problems 
or side effects in this study. 
 
❖ What you are going to do is simple.  Just keep a record of any unpleasant thing that 
happens to you while you are in the study, before, during, and after we have completed 
the stool transplant.  We even want you to record things that do not seem to be part of 
the stool therapy, at all. 
❖ When do you start?  When do you end? You will complete one entry per day during 
the time of oral treatment with the FMT capsule (14 days) as well as daily for 28 days 
after the oral treatment stopped.  
❖ What do you look for?  What do you report?  Any symptom or problem whether or 
not it may be from the medicine, stool therapy.  This could include: fever, abdominal 
pain, a big belly, lots of gas, diarrhea, nosebleeds, and anything else you know is not 
quite right. 
❖ What will you do? In the first 42 days after the initial endoscopic transplant, you will 
report some of the specific things that have bothered you by checking the boxes in the 
diary (see below).  You can also write any other problems that you may have had during 
that time.  Additionally, you will record your temperature once for each day for the 
42 days after the initial endoscopic transplant, unless you feel hot.  If you feel hot, 
please take your temperature again.  Please make sure to record the highest 
temperature taken that day if you take it more than once. 
 
 
How will you record it?  Like this… 
EVENT 
DATE 
OF 
ONSET 
INTENSITY 
ACTION 
TAKEN 
MEDICATION 
DATE 
RESOLVED 
Fever 
3/1/12 
3 
Missed 
2 
days 
of 
school 
Tylenol-200mg 
3/3/12 
Sore throat 
3/5/12 
1 
None 
None 
3/6/12 
 
OTHER SYMPTOMS 
Record each symptom at its worst level for each day. 

 
51 
For example, a sore throat that starts at ‘Grade 1” but increases to ‘Grade 2’ should be recorded 
as ‘Grade 2”. 
 
Examples of Grades: 
Grade 1 – Mild: I noticed the symptom.  It did not keep me from doing my normal activities. 
Grade 2 – Moderate: I noticed the symptom and it kept me from doing some of my normal 
activities. 
Grade 3 – Severe: I really noticed the symptom and it kept me from doing activities that I 
wanted or needed to do. 
Grade 4 – Very severe: The symptom made me unable to perform basic self-care functions 
such as washing myself OR medical or surgical intervention was needed to prevent 
serious consequences. 
 
 

 
52 
Daily diary page day 0 (endoscopic FMT-day 42 after endoscopic FMT {day 28 after stop of oral FMT}) 
Day after transplant: _____________ 
 
Subject ID:_____________________ 
 
Date:____/____/______ 
              Check here is no side effects present:                   
Highest temperature of the day:____oF    
 
Check 
if 
symptom 
present 
Event 
Date of 
Onset 
Intensity 
Action 
taken 
Medications 
Date 
Resolved 
 
 
Fever 
 
 
 
 
 
 
 
Abdominal 
Pain 
 
 
 
 
 
 
 
 
Diarrhea 
 
 
 
 
 
 
 
Nausea/Vomiting 
 
 
 
 
 
 
 
Blood in Stool 
 
 
 
 
 
 
 
Other 1 
 
 
 
 
 
 
 
Other 2 
 
 
 
 
 
 
 
Other 3 
 
 
 
 
 
 
Other 4  
 
 
 
 
 
 
Grade 1 – Mild: I noticed the symptom.  It did not keep me from doing my normal activities. 
Grade 2 – Moderate: I noticed the symptom and it kept me from doing some of my normal activities. 
Grade 3 – Severe: I really noticed the symptom and it kept me from doing activities that I wanted or needed to do. 
Grade 4 – Very severe: The symptom made me unable to perform basic self-care functions such as washing myself OR medical or surgical 
intervention was needed to prevent serious consequences. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Completed by: ____________________ 
 

 
53 
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