Fecal Microbiota Transplantation for the Treatment of Primary Sclerosing Cholangitis.
Phase: PHASE1
Conditions: Sclerosing Cholangitis
Sponsor: Brigham and Women's Hospital

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Fecal Microbiota Transplantation for the Treatment of Primary Sclerosing 
Cholangitis.  
 
Jessica R. Allegretti MD,MPH and Joshua R. Korzenik MD 
 
Version Date: 7/3/17 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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I. 
Background and Significance:  
Primary sclerosing cholangitis (PSC) is a progressive, chronic cholestatic liver disease 
characterized by inflammatory and fibrotic destruction of the intrahepatic and/or 
extrahepatic bile ducts. PSC will progress to biliary cirrhosis, portal hypertension and 
liver failure (1) . It is a common indication for liver transplantation. In up to 90% of 
patients, ulcerative colitis or Crohn’s disease will also be present (2) . Medications used 
for the treatment of ulcerative colitis such as sulfasalazine, corticosteroids and 
azathioprine or 6-mercaptopurine have not been effective in reducing inflammation or 
bringing about remission in PSC (3) . A number of studies of other anti-inflammatory 
agents have failed to demonstrate any benefit. In standard dosing, ursodeoxycholic acid 
(UDCA) may be of benefit in delaying the progression of disease, although a recent study 
showed that high dose UDCA was not only ineffective, it may also be harmful (4) .  
Currently there is no medical therapy that has been shown to be effective in PSC and no 
therapy has won FDA approval for this indication. 
 
It has been postulated that bacterial components may stimulate an aberrant immune 
response resulting in the perpetuation of the biliary inflammation seen in PSC. Bacteria 
gain access to the liver and biliary tree through translocation across an abnormal and 
inflamed intestinal mucosa into the portal venous system (5) . Studies have shown an 
increased risk of portal venous bacteremia in patients with PSC. Animal models have 
demonstrated that enteric dysbiosis can lead to hepatobiliary inflammation with various 
features of PSC (6) . The pathways through which bacteria might then induce the 
pathology characteristic of PSC are speculative.  
 
Bacteria might cause direct injury through colonization, though studies have not 
identified any particular pathogen or a consistent set of bacteria. Another potential 
pathway may be that a certain set of bacteria generate secondary bile acids, such as 
deoxycholic acid and lithocholic acid, which are injurious to the biliary system (7) . We 
recently found an altered serum bile acid composition in patients with PSC compared to 
non-cholestatic controls. Treatment with UDCA in PSC patients decreases the 
concentration of the toxic primary bile acid chenodeoxycholic acid but also increased the 
toxic secondary bile acid lithocholic acid (Abstract DDW 2014). Alteration of the gut 
microbiota may minimize or eliminate this injury.  
 
There is limited experience in the use of antibiotics in treating PSC. Metronidazole has 
been shown to result in improvement in liver function tests (8) . Oral vancomycin has 
also been advanced as a potentially promising therapy (9) . An initial report of three 
pediatric patients and a subsequent small, uncontrolled series of oral vancomycin in 14 
children showed improvement in liver tests and symptoms (10, 11) . We recently 
completed a study of oral vancomycin was given to 10 adults with PSC found mild 
improvement in serum alkaline phosphatase levels (Abstract DDW 2011).   
 
Fecal Biotherapy (FBT) also known as fecal transplantation or fecal microbiota 
transplant—involves the transfer of a donor’s fecal flora (bacteria) to a recipient’s colon. 
It has become widely accepted as the standard of care for recurrent Clostridium difficile 

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infection, with a cumulative cure rate of >90% and minimal adverse events (12) . In C. 
diff infection, prior exposure to antibiotics diminishes the normal colonic flora, allowing 
C. diff organism to proliferate and release toxin (13) . This bacterial environment is 
similar to the major shifts in microbial diversity seen in patients with IBD. Interestingly, 
when patients with IBD receive FBT for C. diff. infections, their outcomes are excellent, 
reinforcing the notion that the enteric flora have a strong influence in the enteric immune 
system (14) . We currently have a robust FMT clinical program for recurrent and 
refractory c.difficle infections with a cure rate > 90%. We have also recently participated 
in an open label clinical trial for the use of FMT in crohn’s disease. 
 
We hypothesize that for patients with PSC, fecal microbiota transplantation will correct a 
dysbiosis that has led to hepatobiliary inflammation leading to improvement in LFTs and 
slow progression to cirrhosis.  
 
II. 
Specific Aims:  
Specific Aim 1: Determine the impact of fecal microbiota transplantation on the 
intestinal microbiome of patients with primary sclerosis cholangitis with and without 
inflammatory bowel disease via 16s ribosomal RNA sequencing comparing delivery 
modalities (colonoscopy and capsules).  
Hypothesis: Fecal microbiota transplantation will result in a sustained repopulation of 
the patient’s microbiome that corresponds to the bacteria from the donor stool.  
 
Specific Aim 2: Assess for clinical response in patients with PSC receiving FMT 
comparing delivery modalities (colonoscopy and capsules).  
Hypothesis: Fecal microbiota transplantation will lead to a 50% reduction in liver 
biochemistries in patients with PSC.  
 
Specific Aim 3: Assess bile salt metabolomics as a therapeutic biomarker for clinical 
response to fecal microbiota transplantation.  
Hypothesis: A decrease in the production of toxic secondary bile acids (lithocholic and 
deoxycholic acid) will correlate with clinical response to fecal microbiota therapy 
 
III. 
Subject Selection 
This is an open-label single-arm pilot study to measure the microbiological and clinical 
impacts of FMT in patients with PSC. We will prospectively enroll 16 PSC patients Stage 
1-4. Donor Stool will be obtained from OpenBiome. OpenBiome is a nonprofit 501(c)(3) 
organization that provides hospitals with screened, filtered, and frozen material ready for 
clinical use (See Attachments for OpenBiome Quality and Saftey Program as well as 
donor screening examples).  
Donors:  
OpenBiome donors are rigorously assessed and monitored. 
1. Donor candidates are screened with comprehensive evaluation of medical 
histories, behavioral risks, and current health status. 

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2. Laboratory Screening: Donor candidates are screened for 20 stool and 
serological tests at a CLIA-certified laboratory. Less than 20% of those screened 
become qualified donors 
3. Continuous Requalification: Qualified donors are under medical monitoring 
through the entire donation window and are fully rescreened every 60 days 
4. Quarantine Procedure: Prior to release, donated material is quarantined for 60 
days in between two full panel screens at a CLIA certified laboratory. After 
passing a first battery of tests, a donor may donate specimens for a 60-day 
window. All material made from these specimens is held in quarantine until a 
second battery of tests is administered. The material from this 60-day window is 
release only if and when the donor passes this second battery of tests. 
Patients: 
Patient enrollment will be done via referral of appropriate patients from the GI clinic. 
Patients with PSC evaluated at Brigham and Women’s Hospital and the Massachusetts 
General Hospital will be enrolled in this protocol. All study procedures will take place at 
Brigham and Women’s Hospital.  
 
Inclusion criteria:  
1. Age 18 or older  
2. Confirmed diagnosis of PSC (with or without a concurrent diagnosis of 
inflammatory bowel disease) characterized by a cholestatic liver condition of 
greater than 6 months duration with confirmatory cholangiographic findings, as 
well as an elevation of Liver Function Tests of greater than 1.5 times the upper 
limit of normal.  
 
Exclusion Criteria:  
1. Decompensated liver disease  
2. Patients who were pregnant or breastfeeding  
3. Use of concomitant immune modulators including methotrexate, mycophenolate 
mofetil, tacrolimus, cyclosporine, thalidomide, Interleukin-10, or Interleukin-11 
within 4 weeks prior to receiving the FMT 
4. Patients who are unable to give informed consent 
5. Patients who are unable or unwilling to undergo colonoscopy with moderate 
sedation (>ASA class II) 
6. Patients who have previously undergone FMT Patients who have a confirmed 
malignancy or cancer 
7. Patients who are immunocompromised 
8. Treatment within last 8 weeks with infliximab, adalimumab, certolizumab, 
natalizumab, vedolizumab or thalidomide 
9. Antibiotic use within 2-months of start date 
10. Participation in a clinical trial in the preceding 30 days or simultaneously during 
this trial  
11. Probiotic use within 30 days of start date 
12.  Congenital or acquired immunodeficiencies 
13. Other comorbidities including:Diabetes mellitus, cancer, systemic lupus, must be 
able to tolerate conscious sedation with colonoscopy 

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14. Chronic kidney disease as defined by a GFR <60mL/min/1.73m2 44 
15. History of rheumatic heart disease, endocarditis, or valvular disease due to risk of 
bacteremia from colonoscopy 
16. Steroid dose >20mg/day 
17. Ursodeoxycholic Acid within 4 weeks prior to receiving the FMT 
18. 25. Patients with allergies to ingredients Generally Recognized As Safe (GRAS): 
glycerol, sodium chloride, hypromellose, gellan gum, titanium dioxide, cocoa 
butter 
19. 26. Dysphagia: oropharyngeal, esophageal, functional, neuromuscular (e.g. stroke, 
multiple sclerosis, ALS) 
20. 27. History of aspiration 
21. 28. History of severe gastroparesis 
 
 
 
Subject Withdrawal Criteria: Patients will be withdrawn under the following 
circumstances: 
 
Patients – patients will be withdrawn under the following circumstances: 
 
For patients in the colonoscopy Group:  
1. Colonoscopy cannot be completed for technical reasons due to inability by 
endoscopist to reach terminal ileum, or patient intolerance of procedure.  
a. These patients will only be followed-up for week 2 adverse event 
screening, as they will not have received FMT. These subjects will be 
replaced, as they will not be considered “treated”. 
 
For patients in the capsule group 
2. Patient is unable to successfully perform capsule test swallow. 
3. These above patients will only be followed-up for week 2 adverse event 
screening, as they will not have received FMT. These subjects will be replaced, as 
they will not be considered “treated” 
 
For all Patients  
4. Patient withdraws their consent for follow-up visits or contacts. 
 
 
IV. 
Subject Enrollment   
Recruitment Procedures:  
BWH or MGH gastroenterologists, including attendings and fellows, will be informed of 
the study’s aims and inclusion criteria. These doctors will inform the principal 
investigator of patients who meet the study criteria and who may be good candidates for 

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the study. The treating gastroenterologist will introduce the study to the potential patient 
and request the patient’s permission to be approached by study staff.  We will not utilize 
advertisement material or other informational materials for patients beyond the consent 
form. 
Patients will be given as much time as they need to decide.  They will be given a copy of 
the consent form to take home, read, and consider, and they will be encouraged to discuss 
participation with family members and health care providers.  Patients will receive 
parking vouchers at each visit to cover the cost of parking.   
 
Consent Procedures:  
The treating gastroenterologist will introduce the study to the potential patient and 
request the patient’s permission to be approached by study staff.  With the treating 
gastroenterologist’s permission, either a physician investigator or study coordinator will 
describe the research study in detail, including participation and risks and alternative 
courses of treatment, and answer any questions or concerns that the patient may have.  
Patients will be given as much time as they need to consider participation before signing 
the consent form.   
 
Subjects will be drawn from the investigators own practice. In order to avoid coercion, 
study staff will reinforce that participation is voluntary and that their decision will not 
affect the medical care that they receive now or in the future.  If patients seek more time 
to consider participation, they will be given a copy of the consent form and encouraged to 
discuss the study with family, friends, PCP, or others.  Study staff will follow-up to see if 
any questions or concerns have not been addressed. A physician investigator will obtain 
informed consent signatures.   
 
 
V. 
Study Procedures  
Donor Procedures (OpenBiome): 
Prior to enrollment, donors (age >18), receive informed consent with oversight from 
MIT’s IRB and COUHES. Donors are interviewed by a healthcare professional to 
determine whether they meet the following exclusion criteria: 
1. Infectious risk factors: 
a. Known HIV, Hepatitis B or C infections or exposure within previous 12 months 
b. High risk sexual behaviors 
c. Use of illicit drugs 
d. Tattoo or body piercing within previous 6 months 
e. Incarceration or history of incarceration 
f. Known current communicable disease 
g. Risk factors for variant Creutzfeldt-Jakob disease 
h. Travel within previous 3 months to countries where risk of infectious diarrhea is 
elevated 
2. Gastrointestinal and systemic comorbidities: 
a. History of IBD, irritable bowel syndrome, chronic constipation or chronic diarrhea 

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b. History of gastrointestinal malignancy or known polyposis 
c. Antibiotic use within the previous 3 months 
d. Immunosuppressive state or use of immunosuppressive medications 
e. History of major gastrointestinal surgery (e.g., gastric bypass) 
f. Metabolic syndrome with BMI >30 
g. Systemic autoimmunity, e.g., multiple sclerosis, connective tissue disease 
h. Atopic diseases including asthma and eczema, eosinophilic disorders of the 
gastrointestinal tract 
i. Chronic pain syndromes, e.g., chronic fatigue syndrome, fibromyalgia 
 
B. Donor Testing 
Prospective donors that do not meet any of the exclusion criteria outlined above will then 
be subjected to a battery of serological and stool-based assays to determine whether 
common infectious agents are present. All tests will be outsourced to third party Clinical 
Laboratory Improvement Amendments (CLIA) certified testing facilities. As a condition 
for participation in this program, donors are required to submit written authorization for 
the disclosure of the results of these tests to the Microbiome Health Research Institute, in 
compliance with the Health Insurance Portability and Accountability Act (HIPAA). We 
will redact all personal identifying information from each report when we receive it. We 
will share copies of these raw diagnostic reports with our clinical partners. In the event 
that material from multiple donors is provided in a single shipment, results will be 
provided for all samples along with a file indicating which samples correspond to which 
donor screens. Documentation will be provided for the battery of tests prior to enrollment 
of a donor and for tests performed at the end of the collection window. Positive results 
for any of the following assays will be treated as exclusion criteria for all materials. 
 
1. Serologic testing: 
a. HIV antibody, type 1 and 2 
b. Hepatitis A (IgM) 
c. Hepatitis B panel (HBsAg & HBc [IgM]) 
d. Hepatitis C (HCV antibody) 
e. Treponema pallidum screening cascade (EIA with reflex to RPR) 
f. Liver function panel 
g. Complete blood count 
h. C-reactive protein assay 
i. HTLV 1 and 2 antibodies 
2. Stool testing: 
a. EIA assay for Clostridium difficile toxins A and B 
b. Culture-based assays for common enteric pathogens (including Salmonella, Shigella, E. 
coli, Campylobacter and Vibrio) 
c. Fecal Giardia antigen EIA 
d. Fecal Cryptosporidium antigen EIA 
e. Ova and parasites exam 
f. Tri-chrome stain for Isospora 
g. Cyclospora smear test 
h. H. pylori EIA 

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C. Collection Window and Donor Monitoring 
Donors that meet the above criteria are enrolled to provide material for FMT. Donor 
material is collected for up to 60 days following the initial screening. During this 
collection window donors must not violate any of the risk factors identified in Part A 
above. During a collection window, all material is quarantined until the donor has passed 
a second battery of serological and stool tests as described in Part B above. Material will 
be released for clinical use only after the donor has successfully completed both sets of 
assays (before and after the collection window). 
 
In the event that a donor is recruited to provide additional material beyond an initial 60 
day collection window, additional testing will be performed at 60 day intervals. Repeat 
donors that have not been tested within 60 days will be treated as new donors subject to 
the same screenings described in Parts A and B above. This ensures that all donors (even 
long-term participants) are subject to regular health evaluation. 
 
In the event that the donor passes a loose stool or has other symptoms of disease, donors 
will immediately meet with a healthcare professional to evaluate their continued 
suitability for participation in our program. If the clinician determines that the donor is 
not healthy,the donor will be un-enrolled from the program. In the event of such a 
diagnosis, all material contributed during the preceding collection window will be 
destroyed. In addition to this qualitative exclusion by clinician’s discretion, we will also 
treat three or more loose stools passed in a 24-hour period as an absolute exclusion 
criterion, and all material from the affected donor’s collection window will be destroyed, 
regardless of clinical evaluation. Although less frequent passage of loose stool is not 
medically indicated as a disease and is common among healthy individuals, in the 
interests of caution we will also destroy material collected near any loose stool movement. 
All material collected from within 48 hours of two loose stools will be destroyed. All 
material collected from within 24 hours of a single loose stool will similarly be destroyed. 
 
D. Production and Process Controls 
1. The donor deposits stool in a commode, seals the lid, and places the collection 
container in a plastic bag to serve as secondary containment. Donors receive training to 
ensure that samples are not contaminated during the collection process. 
2. After passage, the sealed sample collection container is immediately transferred from 
the donor to a qualified technician to process the sample. 
3. Samples are transferred to a UV-sterilized biosafety hood as quickly as possible, not to 
exceed 60 minutes from the time of collection. 
4. Within the biosafety hood, the stool is transferred to a sterile filter bag. The filter bag 
fits around the collection commode entirely, 
so there is no risk of material escaping during this transfer process. All stool material is 
added to the same side of the membrane in the filter bag. 
5. An autoclaved dilutant consisting of 12.5% glycerol and a normal saline buffer (0.90% 
w/v NaCl in water) is added to the filter bag. 
6. The sample solution sealed inside the filter bag is then introduced to a homogenizer 
blender for 60 seconds to mix the materials. 

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7. Samples are then aliquoted into sterile bottles using sterile, disposable serological 
pipettes. 
8. The bottles are then capped, sealed and frozen immediately at -80°C. Any samples not 
fully processed and frozen within 120 minutes of passage will be destroyed. 
9. Samples are sealed with a tamper evident shrink band as an additional level of 
containment and to ensure samples are not contaminated or tampered with during storage 
and distribution. 
10. Samples will be delivered to clinicians on dry ice, in double-containment vessels, 
with temperature indicators to ensure that samples have not thawed during transportation. 
 
 
Recipient Procedures 
 
Overview. This is an open-label pilot study to assess the safety of FMT in patients with 
PSC. Additionally, the study will measure the microbiological and clinical impacts of 
FMT in patients with PSC. We will prospectively enroll 16 adults with PSC after 
providing written informed consent. If a subject qualifies for the study, they will be asked 
to stop taking their current PSC medications,which include azathioprine, methotrexate, 
and ursodeoxycholic acid for 4 weeks before starting the study.  This “washout period” 
allows regular medications to leave the body before subjects begin taking the study drug.   
The first 10 study participants will receive a single FMT via colonoscopy. The last 6 
patients will receive induction followed by monthly maintenance oral capsules for 6 
months. Donor Stool and placebo material will be obtained from OpenBiome. 
OpenBiome, with whom we have previously collaborated with, is a nonprofit 501(c)(3) 
organization that provides hospitals with screened, filtered, and frozen material ready for 
clinical use. 
 
For Colonoscopy Group:  
Week -2: Screening – potential subjects will undergo the following screening procedures 
one to two weeks prior to FMT to determine if they meet the recipient selection criteria; 
1. Medical record review to confirm diagnosis and treatment history  
2. Symptom assessment and physical exam by study physician  
3. Harvey Bradshaw Index (HBI) score for patients with Crohn’s and the Simple 
Clinical Colitis Activity Scale for patient with Ulcerative Colitis to determine 
disease activity if IBD is present 
4. Mayo Risk Score 
5. PBC 40 Quality of Life evaluation. This is a QoL scale for PBC that has been 
validated in PSC(15).  
6. stool sample to exclude current infections (bacterial culture, ova & parasites, 
Clostridum difficule toxin)  
7. Stool will also be sent for bile salt metabolomics  
8. Blood tests (CBC, LFTs, Renal profile, CRP, ESR, bile salt metabolomics) 
9. Urine Pregnancy Test 
10. Review of MRCPs done for clinical care.  

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Week -1: Baseline Microbiome – a stool sample will be taken for baseline microbiome 
profiling. 
 
Week 0: Fecal Transplant - the following baseline assessments will be made in enrolled 
subjects on day of scheduled FMT; 
1. Urine pregnancy test (HCG) for female patients.  
2. Disease activity score will be assessed (HBI) 
3. PBC 40 
4. Stool transplant via colonoscopy 
5. Tolerability questionnaire 
Weeks 1, 4, 8, 12, 24, 52: Follow-up assessment of clinical scores and adverse event 
screening 
Weeks 1, 4, 8 and 12, 24: stool sample for microbiome analysis and bile salt 
metabolomics, blood tests for (CBC, LFTs, Renal profile, CRP, ESR, bile salt 
metabolomics) 
 
Week 52: Final Study Phone Call.  
1. Final assessment of outcome of the FMT will be made; disease activity score will 
be assessed (HBI, PBC 40) 
2. Outpatient MRCP will be scheduled.  
Week 52: Patient obligations in the study will end at week 52 however the patient’s 
medical record will be followed prospectively for evaluation of LFTs, MRCP and ERCPs 
done for clinical care through year 5 post-enrollment.  
For Capsule Group:  
 
Week -2: Screening – potential subjects will undergo the following screening procedures 
one to two weeks prior to FMT to determine if they meet the recipient selection criteria; 
11. Medical record review to confirm diagnosis and treatment history  
12. Symptom assessment and physical exam by study physician  
13. Harvey Bradshaw Index (HBI) score for patients with Crohn’s and the Simple 
Clinical Colitis Activity Scale for patient with Ulcerative Colitis to determine 
disease activity if IBD is present 
14. Mayo Risk Score 
15. PBC 40 Quality of Life evaluation. This is a QoL scale for PBC that has been 
validated in PSC(15).  
16. stool sample to exclude current infections (bacterial culture, ova & parasites, 
Clostridum difficule toxin)  
17. Stool will also be sent for bile salt metabolomics  
18. Blood tests (CBC, LFTs, Renal profile, CRP, ESR, bile salt metabolomics) 
19. Urine Pregnancy Test 
20. Review of MRCPs done for clinical care.  

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21. Test swallow of an empty capsule  
 
Week -1: Baseline Microbiome – a stool sample will be taken for baseline microbiome 
profiling. 
 
Week 0: Fecal Transplant - the following baseline assessments will be made in enrolled 
subjects on day of scheduled FMT; 
1. Urine pregnancy test (HCG) for female patients.  
2. Disease activity score will be assessed (HBI) 
3. PBC 40 
4. Stool transplant via capsule (30 capsule dose) 
5. Tolerability questionnaire 
Weeks 1:  
1. Follow-up assessment of clinical scores and adverse event screening 
2. stool sample for microbiome analysis and bile salt metabolomics, blood tests for 
(CBC, LFTs, Renal profile, CRP, ESR, bile salt metabolomics) 
Weeks 4, 8 and 12, 16, 20: 
1. 5 Monthly maintance capsule dosing will be done in the clinic under direct 
observation  
2. Follow-up assessment of clinical scores and adverse event screening 
3. stool sample for microbiome analysis and bile salt metabolomics, blood tests for 
(CBC, LFTs, Renal profile, CRP, ESR, bile salt metabolomics) 
Week 24:  
1. Follow-up assessment of clinical scores and adverse event screening 
2. stool sample for microbiome analysis and bile salt metabolomics, blood tests for 
(CBC, LFTs, Renal profile, CRP, ESR, bile salt metabolomics) 
Week 52: Final Study Phone Call.  
3. Final assessment of outcome of the FMT will be made; disease activity score will 
be assessed (HBI, PBC 40) 
4. Outpatient MRCP will be scheduled.  
Week 52: Patient obligations in the study will end at week 52 however the patient’s 
medical record will be followed prospectively for evaluation of LFTs, MRCP and ERCPs 
done for clinical care through year 5 post-enrollment.  
 
 
Primary Physiological Endpoint: 

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1. Recipient’s fecal microbial diversity at 12 weeks after FMT, when compared to 
baseline using 16s ribosomal RNA. 
 
Primary Clinical Endpoint 
1.  The primary study end point is them mean change serum liver biochemistries after 3 
months of treatment as compared with baseline.  Treatment success was defined as an 
improvement in serum alkaline phosphatase, total bilirubin, alanine aminotransferase 
(ALT), or aspartate aminotransferase (AST) by 50 % or greater.  
 
 
Secondary Endpoints 
Metabolomics: Bile salt profiles of the samples and associated community structure of 
the fecal microbiome will be assessed as a measure of the interplay between host and gut 
microbiota. Stool and Serum will be analyzed using the metabolomics platform at the 
Broad Institute, targeting bile acids. Samples will be sent to the Broad Institute where we 
will use liquid chromatography tandem mass spectrometry (LC-MS) to measure 
endogenous bile salts and their metabolite levels in fecal supernatant. Water soluble 
metabolites will be extracted from feces as described by Saric et al while lipids will be 
extracted from lypophilized samples using isopropanol. Water soluble metabolites will be 
measured using ion pairing chromatography and hydrophilic interaction chromatography 
methods, and lipids and bile acids will be measured using C4 and C18 reversed phase 
chromatography methods. MultiQuant software (AB SCIEX) will be used for automated 
peak integration and manual review of peak quality prior to statistical analyses. The 
GenePattern (Broad Institute) and IPA (Ingenuity Systems) software will be used to 
analyze and visualize results.   
 
 Clinical Endpoints: 
1) Mean change in Harvey Bradshaw Index (HBI) and PBC 40 score between week 
0 and week 1, 4, 8, and 12. Percentage of patients in clinical remission (those with 
an HBI score at week 12 <5)  
2) Mean change in Mayo Risk Score at week 12 compared to baseline. The Mayo 
Risk Score (MRS) for PSC is calculated based using the following formula: risk = 
(0.0295 * (age in years)) + (0.5373 * LN(total bilirubin in mg/dL)) - (0.8389 * 
(serum albumin in g/dL)) + (0.5380 * LN(AST in IU/L) + (1.2426 * (points for 
variceal bleeding)) 
  If your Mayo Risk Score  is less than or equal to 0 then you are in the "low" 
risk group. 
  If your Mayo Risk Score  is greater than 0 but less than 2 then you are in the 
"intermediate" risk group. 
  If your Mayo Risk Score  is greater than 2 then you are in the "high" risk 
group. 
Safety Endpoints: Number and nature of adverse events at week 1, 4, 8, 12 and 24 
 
Treatment with FMT vial colonoscopy: 

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The treatment for this trial will be a filtered solution of donor fecal microbiota (50 g) 
homogenized with sterile saline 90 mL.  This will be administered as a single topical 
treatment administered via colonoscopy to the ileo-colonic mucosa. Follow-up after 
administration will be at 1,4,8,12,24 and 52 weeks 
 
Trial Treatment with FMT via Capsule:  
The treatment for this trial will be administration of an induction dose of 30 FMT capsules 
ingested orally. Treatment will occur after screening. 
 
Subsequent FMT administration will be maintenance capsules of frozen FMT material 
ingested orally every 4 weeks (30 capsules). All ingestions will be undertaken in the clinic 
under supervision. A follow-up phone call will be undertaken 4 hours after each ingestion 
visit to screen for adverse events.  
 
1. Initial dose - filtered solution of donor stool in 30 gelatin capsules at Day 0 
(16500µl total). 
2. Maintenance dose – thirty capsules of fecal material taken every 4 weeks (550µl 
of fecal material in each size 00 gelatin capsule)  
 
Capsule preparations are delivered to clinical investigators in double containment 
shipping vessels packed with dry ice, as with non-encapsulated placebo preparations. 
Packaging is labeled with the same information included on non-encapsulated 
preparations, with the addition of a clause instructing clinicians to administer the material 
to patients within 90 minutes of removal from frozen storage. Patient instructions listed in 
Appendix 6.  
 
Packaging 
Enscapsulated fecal material in freezer safe bottles will be stored in Styrofoam boxes from 
the Microbiome Health Research Institute at Massachusetts Institute of Technology, as 
described in their Drug Master File (15543). 
 
Adverse Event Reporting 
For this trial, an adverse event (AE) is defined as any untoward medical occurrence in a 
patient or clinical investigation patient administered a biologic product; such an 
occurrence does not necessarily have to have a causal relationship with this treatment. An 
AE can be any unfavorable and unintended sign, symptom, or disease temporally 
associated with the use of a medicinal product whether or not considered related to the 
medicinal product. A serious adverse event (SAE) is defined as any untoward medical 
occurrence that results in death, is life threatening, requires hospitalization or 
prolongation of existing hospitalization, results in persistent or significant 
disability/incapacity, is a congenital anomaly/birth defect, is an important medical event 
that may not be immediately life threatening or result in death or hospitalization but may 
jeopardize the patient or may require intervention to prevent one of the other outcomes 
previously mentioned. Adverse events will be determined by a toxicity grading scale. 
 
The internal DSMB (Appendix 6) will include the following individuals: Dr. Ryou 

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(Gastroenterology- BWH), Dr. Walter Chan (Gastroenterology – BWH), and Dr. Andrew 
Courtwright (Pulmonary Critical Care). All events will be reported directly to the DSMB 
and the Institutional Review Board (IRB) in accordance with Harvard University policy: 
Investigators will promptly report to the IRB all unanticipated problems involving risks 
to human subjects or others under Title 21 of the Code of Federal Regulations (21 CFR) 
part 56 (Institutional Review Boards), part 312 (Investigational New Drug Application), 
and part 812 (Investigational Device Exemptions). Harvard Medical School policy is 
consistent with guidance set forth by the Office for Human Research Protections (OHRP) 
(presented January 15, 2007)  
http://www.hhs.gov/ohrp/policy/AdvEvntGuid.htm and the FDA (presented January 14, 
2009) 
http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126572.pdf when 
determining what related events require review by the Institutional Review Board.  
Any serious AEs also will be evaluated by the DSMB for review and determination of 
whether the trial should continue. 
All subjects will be followed for an additional six months following the end of their 
treatment. Subjects that did not experience a AEs or SAEs will receive a telephone call to 
monitor their current symptoms and quality of life. For subjects that did experience a AE 
or SAE that was found to be connected to the FMT treatment, we ask that they return to 
our medical center for an exam with their gastroenterologist. All AEs will be followed to 
resolution or stabilization by the study physician. 
 
Stopping Criteria 
Adverse events will be monitored at 0, 1, 4, 8, 12, 24 and 52. 12  weeks after FMT by 
symptom diaries and direct patient interviews. A data safety and monitoring board 
(DSMB, will review all patient data to ensure optimal patient safety and precautions for 
subjects with CD treated with FMT. A severity grade for adverse events (see Appendix) 
and subject symptom diary used (See Appendix). The DSMB will meet a minimum of 3 
times: after treatment of the first 5 subjects and after treatment of 10 subjects and then 
after the first 3 capsule patients. Study will be stopped under the following 
circumstances: 
1. Detection of new pathogenic intestinal infection in stool samples in any patient 
treated. 
2. Any unexpected serious adverse event that that DSMB determines is of 
significant clinical impact, and probably related to FMT. 
Accountability Procedures for the Investigational Product 
The location, volume and number of FMT donor solutions will be maintained in a log by 
the research team. The principal investigator will be responsible for accurate record and 
tracking of all FMT solutions.  
 
Medications Permitted 
During the follow-up period after FMT, subjects may remain on their co-existing 
medications at stable doses. Rescue pathway for IBD subjects with worsening disease 
during the study period to be determined by the clinician investigator and based on 
standard of clinical practice.  

15 
 
This may include, but is not limited to the following; 
i. 
Oral steroids (if not already receiving them or failing them)  
ii. 
Rectal therapy (5-ASA or steroids)  
iii. IV steroids  
iv. Hospitalization  
v. 
Anti-TNF therapy  
vi. Surgery  
 
 
VI. 
 Biostatistical Analysis:  
Spontaneous biochemical normalization occurs in less than 5% of patients with PSC. A 
response by natural history would be 0/5. This is an exploratory study as relatively little 
is known about the microbiomes of PSC patients. Thus, an objective of our study will be 
to characterize variability in PSC microbiomes to aid in estimating effect sizes for 
designing larger studies powered to detect differences between the microbiomes of PSC 
patients or to find associations between microbiome data and bile acid profiles. 
 
Preliminary data from the colonoscopy cohort revealed that global engraftment in several 
patients decline during the first month post-FMT. While all patients' microbiomes 
increased in diversity and similarity to the donor at one week post-FMT, diversity 
declined in 4 out of 7 patients between one and four weeks post-FMT. Three of these 
patients also showed a decrease in microbiome similarity to the donor community 
between one and four weeks post-FMT. For this reason we have decided to test 
maintenance dosing as well at monthly intervals with capsules prior to a placebo 
controlled RCT.  
 
VII. 
Risks and Discomforts:  
Fecal Microbial Therapy: 
Known Risks of FMT 
• Altered bowel pattern (diarrhea, constipation) 
• Cramping 
• Belching 
 
Potential Risks of FMT 
• Transmission of pathogenic bacteria, viruses, fungi 
• Transmission of allergens 
• Alteration in intestinal metabolism 
 
Privacy and Confidentiality:  
This study involves the collection of personal health information.  Accidental release of 
personal health information is a risk of participation in this study.  Measures will be taken 
to protect the confidentiality of all subjects’ information.  These measures include 
keeping all information collected about the subjects’ confidential, keeping information in 
locked rooms, and having physicians who are directly involved with a subject’s clinical 
care involved in the study. 
 

16 
 
Colonoscopy: 
Standard potential risks of the endoscopy procedure include discomfort, gastrointestinal 
bleeding either related or unrelated to biopsies, intestinal perforation, altered bowel habit. 
Complications of IV conscious sedation during the procedure include respiratory arrest, 
medication reactions, and aspiration. 
 
Venipuncture: 
Risks of having blood drawn include pain, bruising, or infection.   
 
Pregnancy 
The risks to fetuses and women who are pregnant are unknown.  
 
VIII. Potential Benefits:  
The potential benefits include:  
• Restoration of fecal diversity 
• Reduction in intestinal inflammation 
• Improvement in clinical symptom scores 
 
As this is a pilot study, it is difficult to quantify the expected benefits.  
 
IX. 
Monitoring and Quality Assurance:  
The Principal Investigator, Dr. Joshua Korzenik, will assure the validity and integrity of 
the data and adherence to the IRB-approved protocol.   
 
Study staff will review completed CRF’s before each visit to ensure completeness of 
previous entries.  Entries that need clarification will be reviewed by the PI, and the 
subject and/or treating gastroenterologist will be consulted if needed.   
 
 
Appendix 1. 
Harvey-Bradshaw Index for Crohn’s disease 
 
Harvey-Bradshaw Index 
General Well-Being (0=very well, 1=below par, 2=poor, 3=very poor, 
4=terrible) 
Abdominal Pain (0=none, 1=mild, 2=moderate, 3=severe) 
Number of Liquid Stools per Day 
Abdominal Mass (0=none, 1=dubious, 2=definite, 3=definite & tender) 
Complications (1 per item) 
Arthralgia 
Uveitis 
Erythema Nodosum 
Apthous ulcers 
Pyoderma Gangrenosum 
Anal fissue 

17 
 
New Fistula 
Abscess 
TOTAL SCORE 
Appendix 2: Simple Clinical Colitis Activity Index: 
 
Ulcerative Colitis (SCCAI): 
1) Bowel frequency (day) 
⓿   
1 to 3  
①  
4 to 6  
②  
7 to 9  
③  
 more than 9  
2) Bowel frequency (night) 
⓿  
 
None -->0 
②  
1 to 3 
③  
4 to 6 
3)  Urgency of defecation 
⓿  
 
None 
①  
Hurry 
②  
 
Immediately 
③  
Incontinence 
4)  Blood in the stool 
⓿  
 
None 
①  
 
Trace 
②  
Occasionally Frank 
③  
 Usually Frank 
5) General wellbeing 
⓿  
Very well 
①  
Slightly below par 
②  
Poor 
③  
Very poor 
④  
Terrible 
6)  Extraintestinal manifestations of IBD (check all that apply; 1point for each): 
□ Arthralgia 
□Erythema nodosum 
□ Uveitis 
□ Pyoderma gangrenosum 
 
Appendix 3. Mayo Risk Score: 
Mayo Risk Score (MRS) for PSC is calculated based using the following formula: risk = 
(0.0295 * (age in years)) + (0.5373 * LN(total bilirubin in mg/dL)) - (0.8389 * (serum 
albumin in g/dL)) + (0.5380 * LN(AST in IU/L) + (1.2426 * (points for variceal 
bleeding)). 
 
 
Appendix 4: 

18 
 
Grading and Attribution Methods for Adverse Events 
 
 
Grading Scale 
0 
No adverse event or within normal limits 
1 
Mild adverse event – did not require treatment 
2 
Moderate adverse event – resolved with treatment 
3 
Severe adverse event – resulted in inability to carry on normal activities 
and required professional medical attention 
4 
Life threatening or disabling adverse event 
5 
Fatal adverse event 
 
Attribution Scale 
Definite: 
The adverse event is clearly related to the study drug 
Probable: 
The adverse event is likely related to the study drug 
Possible: 
The adverse event may be related to the study drug 
Unlikely:  
The adverse event is doubtfully related to the study drug 
Unrelated: 
The adverse event is clearly not related to the study drug 
 
 
Appendix 5: Record of Side Effects 
 
Fecal Microbiota Transplantation - 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 record one entry 1-week 
prior and on the day of the transplant.  You will then complete one entry per day 
for the first week following the treatment and then once a week thereafter for 12-
weeks.   
❖ 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 7 days after the 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 first 7 days after the 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. 
 

19 
 
Continue to record any problem up to 6 months after the transplant. 
 
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. 
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. 
 
 
Subject ID:_____________________ 
 
Date:____/____/______ 
 
   Check here is no side effects present: 
                  
Highest temperature of the day:______oF 
              Total 
Number 
of 
Stools:__________ 
 
Check if 
symptom 
present 
Event 
Date 
of 
Onset 
Intensity 
Action 
taken 
Medications 
Date 
Resolved 
 
 
Fever 
 
 
 
 
 
 
 
Abdominal Pain/ 
Stomachache 
 
 
 
 
 
 
 
Abdominal 
distension 
/bloating 
 
 
 
 
 
 
 
 

20 
 
 
 
Flatulence/  
excess gassiness 
 
 
 
 
 
 
 
Diarrhea 
 
 
 
 
 
 
 
Nausea/Vomiting 
 
 
 
 
 
 
 
Blood in Stool 
 
 
 
 
 
 
 
Other 1 
 
 
 
 
 
 
 
Other 2 
 
 
 
 
 
 
 
Other 3 
 
 
 
 
 
 
 
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. 
 
 
 
Appendix 6:  
Charter, Data and Safety Monitoring Board for  
Fecal Microbiota Transplantation (FMT) for the treatment of Primary Sclerosis 
Cholangitis 
Version Date: January 2015 
 
1. Introduction 
This Charter is for the Data and Safety Monitoring Board (DSMB) for the study “Fecal 
Microbiota Transplantation (FMT) for the treatment of Primary Sclerosis Cholangitis” 
 
The DSMB will consist of a team of clinical researchers who are unaffiliated with this 
project.  
These individuals will not be investigators in this study and will be experienced in 
conducting and interpreting clinical trials; they will review the efficacy and safety 
endpoints at the below stated time points. There will be 3 members on the DSMB 
consisting of at least two gastroenterologists and one infectious disease specialist.  The 
members of the DSMB are: 
 
 
 
 
 
 
 
 

21 
 
Dr Walter Chan (Gastroenterology- BWH)  
Dr. Marvin Ryou (Gastroenterology – BWH) 
Dr. Andrew Courtwright (Pulmonary/Critical Care- BWH) (Chair)  
 
The Charter is intended to be a living document.  The DSMB may wish to review it at 
regular intervals to determine whether any changes in procedure are needed.  
 
2. Responsibilities of the DSMB 
 
The DSMB is responsible for safeguarding the interests of study participants, assessing 
the safety and efficacy of study procedures, and for monitoring the overall conduct of the 
study.   
 
The DSMB is an independent group advisory and is required to provide 
recommendations about starting, continuing, and stopping the study.  In addition, the 
DSMB is asked to make recommendations, as appropriate, to the about: 
• Selection, recruitment, and retention of participants 
• Adherence to protocol requirements 
• Completeness, quality, and analysis of measurements  
• Amendments to the study protocol and consent forms 
• Participant safety 
• Notification of and referral for abnormal findings  
 
 
3.  Scheduling, Timing, and Organization of Meetings 
Data and Safety Monitoring Meetings 
The DSMB will meet a minimum of 3 times: after treatment of the first 5 subjects, after 
treatment of 10 subjects and then after the first 3 capsule patients. In addition the DSMB 
may convene additional meetings if necessary to ensure the ongoing monitoring and 
safety of the subjects treated with FMT. Any serious AEs also will be evaluated by the 
DSMB for review and determination of whether the trial should continue. An example of 
the DSMB meeting minutes are at the end of this document. The study will not proceed at 
each of these time points until the DSMB gives approval to continue.  
 
Safety Reporting 
In accordance with applicable policies of the BWH Institutional Review Board (IRB), the 
investigator-sponsor will report, to the IRB, any observed or volunteered Unanticipated 
Problem that is determined to be 1) unexpected); 2) related or at least possibly related to 
study participation; and 3) suggests that the research places subjects or others at a risk of 
unknown harm or addition/increased frequency of harms (including physical, 
psychological, economic, legal, or social harm) than was previously known or recognized. 
Unanticipated problems may be adverse events, protocol deviations, noncompliance or 
other types of problems, but MUST meet all of the criteria listed above. Unanticipated 
problem reports will be submitted to the IRB in accordance with the respective IRB 
procedures.  

22 
 
Applicable unanticipated problems will be reported to the IRB as soon as possible 
and, in no event, later than 10 calendar days following the investigator-sponsor’s receipt 
of the respective information.  For Internal Fatal/Life-Threatening Unanticipated 
Problems, the PI should notify the IRB Chair by phone immediately and consider 
voluntarily halting subject enrollment. 
Follow-up information to reported adverse event will be submitted to the IRB as 
soon as the relevant information is available.  If the results of the investigator’s follow-up 
investigation show that an adverse event that was initially determined to not require 
reporting to the IRB does, in fact, meet the requirements for reporting; the investigator 
will report the unanticipated problem to the IRB as soon as possible, but in no event later 
than 10 calendar days, after the determination was made. 
 
 
4. Grading and Attribution Methods for Adverse Events 
 
 
Grading Scale 
6 
No adverse event or within normal limits 
7 
Mild adverse event – did not require treatment 
8 
Moderate adverse event – resolved with treatment 
9 
Severe adverse event – resulted in inability to carry on normal activities 
and required professional medical attention 
10 
Life threatening or disabling adverse event 
11 
Fatal adverse event 
 
Attribution Scale 
Definite: 
The adverse event is clearly related to the study drug 
Probable: 
The adverse event is likely related to the study drug 
Possible: 
The adverse event may be related to the study drug 
Unlikely:  
The adverse event is doubtfully related to the study drug 
Unrelated: 
The adverse event is clearly not related to the study drug 
 
 
Data and Safety Monitoring Meeting Minutes 
 
Date:  
 
Title of Protocol/IRB Number:  
 
Principal Investigator/Designee:   
 
Recommendations: 
 
□ Continue the trial without modification 
 
□ Accrual: 
□ Recommend study be closed because of slow accrual 

23 
 
□ Continue to monitor study, but consider closure because of slow accrual 
 
□ Recommend study is amended/changed: 
□ For patient safety reasons 
□ Rate of adverse events 
□ Early stopping of inferior therapy 
□ To extend accrual because of an event rate slower than expected 
 
□ Other: _________________________________________________________ 
 
Signature/Principal Investigator or Designee:  
 
_______________________________________________ 
DSMB meetings will be held at the Brigham and Women’s Hospital. The purpose of the 
first meeting is to review and discuss this charter and process.  
 
  The DSMB also will review adverse event data, other safety data, quality and 
completeness of study data, and enrollment data at each meeting to ensure proper trial 
conduct.  At intervals, as noted above, the DSMB will also review formal interim 
analyses of the primary end point. 
 
 
5.  
Reports of DSMB Deliberations 
 
• Initial summary:  The Director or designee will review this summary and approve 
or disapprove the recommendation(s), or request additional information.  The 
recommendations will then be sent to the DCC, and the clinical investigators.   
 
• Action plan:  If the DSMB’s recommendations require significant changes or 
follow-up, the BWH IRB staff will prepare an action plan outlining the steps 
required to implement the recommendations. 
 
• Formal minutes:  The DSMB Chair is responsible within 30 days of the meeting 
or call to present minutes to the IRB.  These minutes are subject to FOIA requests 
and are prepared accordingly to summarize the key points of the discussion and 
debate, requests for additional information, response of the investigators to 
previous recommendations, and the recommendations from the current meeting.  
These minutes will be reviewed by IRB staff, key study personnel before being 
forwarded to the DSMB Chair for final review and approval.  The DSMB Chair 
may sign the minutes or indicate approval electronically via email.  Then, the 
minutes are sent to the BWH IRB for approval. Subsequently, the minutes are 
sent back to the IRB and the relevant investigators, and included in the materials 
for the subsequent DSMB meeting to be approved by voice vote at that meeting.  
Once they have been voted and approved by the Board, they are considered Final. 
 

24 
 
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