Conditions: Cirrhosis Hepatic Encephalopathy
Keywords: fecal microbial transplant cirrhosis hepatic encephalopathy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 60
Healthy volunteers: no

Brief summary:
Patients with end stage of liver disease or cirrhosis can develop confusion due to high ammonia and inflammation. This confusion is brought upon by changes in the bacteria in the bowels and may not respond to current standard of care treatments. Repeated episodes of confusion can make it difficult for patients to function and may result in multiple admissions to the hospital and burden on the family. The investigators have studied using a healthy person's stool to replace the bowel bacteria, called fecal microbial transplant, in small studies with good results. In this trial the investigators propose to perform these procedures using an upper and lower route in Veterans who suffer from this condition and follow them for safety and HE and related hospitalizations over 6 months. The investigators will compare this to placebo treatments and hope that this intervention can improve the health and daily functioning of affected patients.

Detailed description:
Indication: Cirrhosis and hepatic encephalopathy

Study Objectives: To evaluate the safety and tolerability of fecal transplant in patients with cirrhosis and hepatic encephalopathy

Rationale and Supporting Evidence:

Hepatic encephalopathy affects 30-45% of patients with cirrhosis and adversely affects survival in these patients. The mainstay of treatment for hepatic encephalopathy (HE) has long been the manipulation of the gut flora through antibiotics, prebiotics or probiotics. The current first and second line therapies for HE in the US are lactulose and rifaximin respectively that uniquely act within the confines of the gut lumen with encouraging clinical results. However, there is a subset of patients with HE that continues to recur despite being on both treatments. This patient group is at a higher risk of poor outcomes because HE has now been removed from liver transplant priority and multiple episodes of HE can result in cumulative brain injury which may be irreversible. Therefore, the prevention of recurrent HE is an important therapeutic goal.

The investigators' group and other reports have shown that patients with HE and cirrhosis are more likely to have overgrowth of potentially pathogenic bacterial taxa such as Enterobacteriaceae and reduction of autochthonous species such as Lachnospiraceae and Ruminococcaceae in the stool and the colonic mucosa. This has been linked to poor performance on cognitive tests that are a hallmark of HE and with increased systemic inflammation in these patients.

Therefore, a gut-based therapeutic option that can potentially improve the recurrence rate and the overall prognosis is needed. Fecal transplant has been shown to be effective in conditions with predominant gut-bacterial overgrowth or alteration such as recurrent Clostridium difficile and inflammatory bowel disease. Safe protocols have been developed across the world and studies are being performed in the US under FDA-monitored INDs. Limitations to performing fecal transplant include identifying and screening appropriate donors, which is time consuming and costly, with the cost typically falling to the patient or donor as the required screening is generally not covered by insurance.

The investigators' preliminary data suggest that a one-time administration of an FMT-enema using a rationally-selected donor is safe in patients with cirrhosis and recurrent HE. However, given the small bowel overgrowth and the predominantly small bowel location for bacterial translocation in cirrhosis, which is out of the reach of an enema, an upper GI route for FMT needs to be explored. In the investigators' published experience, a single enema from a rationally-derived donor was associated with significantly lower total and HE-related hospitalizations compared to patients who were randomized to standard of care, with a stable long-term course over \>1 year. The investigators' data show that FMT was associated with favorable changes in fecal bile acid (BA) profile with a decrease in proportions of fecal secondary BAs, conjugated BAs and increase in sulfated BAs, indicating a healthier milieu. The investigators also have preliminary data defining the safety of oral FMT capsules in patients with cirrhosis and HE in a current trial led by us. The use of combined oral and rectal routes of FMT, which can potentially alleviate both small bowel and colonic translocation are likely to be better than either alone.

Overall aim: To determine the effect of dual oral and rectal administration of FMT from a rational donor on clinical outcomes (HE and related hospitalizations, brain function, quality of life) and host-microbiota interactions (microbial composition and bile acid composition with systemic and intestinal inflammation), compared to single route of administration and placebo, along with a second oral capsular FMT vs placebo administration in patients with cirrhosis and HE using a randomized, phase II clinical trial.

Design overview: Four groups of outpatients with cirrhosis will be randomized using random sequence generator into placebo and FMT groups and followed for 6 months under an FDA IND double-blind clinical trial.

Arms:
arm 1: Oral and rectal placebo at visit 2 Oral placebo at day 30 arm 2: Oral placebo and rectal FMT at visit 2 Oral placebo at day 30 arm 3: Oral FMT and rectal placebo at visit 2 Oral FMT at day 30 arm 4: Dual Oral and rectal FMT at visit 2 Oral FMT at day 30

Interventions: intervention 1: Fecal Microbial transplant Capsules intervention 2: Fecal Microbial Transplant Enema intervention 3: Placebo
Intervention descriptions: intervention 1: Oral capsules of FMT intervention 2: FMT enema intervention 3: Placebo

Protocol document:
Prot_SAP_000.pdf: 
 
Sponsor-Investigator:  
Jasmohan S Bajaj, MD, MS 
Associate Professor, Virginia Commonwealth University and McGuire VA 
Medical Center,  
1201 Broad Rock Boulevard,  
Richmond, Virginia 23249 
Telephone: (804) 675 5802 
Fax: (804) 675 5816 
Email: Jasmohan@gmail.com 
 
Study Title:  
Fecal MicrobiotaTransplantation in Cirrhosis and Hepatic Encephalopathy 
IND #18578 
Date:  October 14, 2020 
Amendment 4 
 
Protocol Number: BAJAJ0024 
Product:  Fecal Microbiota Preparations vs Placebo From Molecular and Cellular 
Therapeutics (GMP) facility at the University of Minnesota. 
Proposed Indication: Cirrhosis and Hepatic Encephalopathy 
 


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SCIENTIFIC BACKGROUND 
 
Indication: Cirrhosis and hepatic encephalopathy 
 
 
Study Objectives: To evaluate the safety and tolerability of fecal transplant in patients 
with cirrhosis and hepatic encephalopathy 
 
Rationale and Supporting Evidence: 
Hepatic encephalopathy affects 30-45% of patients with cirrhosis and adversely affects 
survival in these patients1. The mainstay of treatment for hepatic encephalopathy (HE) 
has long been the manipulation of the gut flora through antibiotics, prebiotics or 
probiotics2. The current first and second line therapies for HE in the US are lactulose 
and rifaximin respectively that uniquely act within the confines of the gut lumen with 
encouraging clinical results. However, there is a subset of patients with HE that 
continues to recur despite being on both treatments3. This patient group is at a higher 
risk of poor outcomes because HE has now been removed from liver transplant priority 
and multiple episodes of HE can result in cumulative brain injury which may be 
irreversible4. Therefore, the prevention of recurrent HE is an important therapeutic goal. 
Our group and other reports have shown that patients with HE and cirrhosis are more 
likely to have overgrowth of potentially pathogenic bacterial taxa such as 
Enterobacteriaceae and reduction of autochthonous species such as Lachnospiraceae 
and Ruminococcaceae in the stool and the colonic mucosa5-8. This has been linked to 
poor performance on cognitive tests that are a hallmark of HE and with increased 
systemic inflammation in these patients6, 7.  
Therefore, a gut-based therapeutic option that can potentially improve the recurrence 
rate and the overall prognosis is needed. Fecal transplant has been shown to be 


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effective in conditions with predominant gut-bacterial overgrowth or alteration such as 
recurrent Clostridium difficile and inflammatory bowel disease9. Safe protocols have 
been developed across the world and studies are being performed in the US under 
FDA-monitored INDs. Limitations to performing fecal transplant include identifying and 
screening appropriate donors, which is time consuming and costly, with the cost 
typically falling to the patient or donor as the required screening is generally not 
covered by insurance. For this reason, we had worked with OpenBiome and have now 
partnered with Molecular and Cellular Therapeutics (GMP) facility at the University of 
Minnesota, whose protocols are used by OpenBiome. We have obtained their 
collaboration towards performing this FMT by cross-referencing of their DMF (Drug 
Master File). 
 
Our preliminary data suggest that a one-time administration of an FMT-enema using a 
rationally-selected donor is safe in patients with cirrhosis and recurrent HE. However, 
given the small bowel overgrowth and the predominantly small bowel location for 
bacterial translocation in cirrhosis, which is out of the reach of an enema, an upper GI 
route for FMT needs to be explored. The FMT capsule supplied by Molecular and 
Cellular Therapeutics (GMP) facility at the University of Minnesota acts on the small 
and large intestine and is available for C. difficile. It is potentially more acceptable to 
patients for repeated administrations and in cirrhosis has the advantage of acting on 
the small bowel in addition to the large bowel. We will be using fecal material from all 
available donors in the University of Minnesota donor pool, in consultation with facility 
scientists, and as noted in cross-referenced IND #15071. All of their donor have high 
relative abundance of taxa in their stool such as Lachnospiraceae and 


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Ruminococcaceae. In our published experience, a single enema from a rationally-
derived donor was associated with significantly lower total and HE-related 
hospitalizations compared to patients who were randomized to standard of care, with a 
stable long-term course over >1 year10. Our data show that FMT was associated with 
favorable changes in fecal bile acid (BA) profile with a decrease in proportions of fecal 
secondary BAs, conjugated BAs and increase in sulfated BAs, indicating a healthier 
milieu. We also have preliminary data defining the safety of oral FMT capsules in 
patients with cirrhosis and HE in a current trial led by us11.  The use of combined oral 
and rectal routes of FMT, which can potentially alleviate both small bowel and colonic 
translocation are likely to be better than either alone. 
Details of the team’s experience with FMT in cirrhosis using enema10:  
In the trial conducted by us under IND 16452, we have recruited 20 subjects with 
cirrhosis and recurrent HE (the same population proposed for this trial). All subjects 
completed the 5-month follow-up without SAEs that were associated with FMT. The 
baseline subject characteristics are: 
 
No-FMT group 
(n=10) 
FMT group 
(n=10) 
P value 
Age 
62.9±9.8 
64.5±5.1 
0.65 
Gender (Men/Women) 
10/0 
10/0 
1.0 
Race (Caucasian, African-
American, Hispanic, others) 
6/3/1/0 
7/2/1/0 
0.9 
MELD score  
13.2±3.7 
12.0±2.9 
0.36 
 
None of the subjects reached a grade of 3 or change in >2 of any of their GI symptoms 
throughout the study. Similarly, none of the subjects developed clinically relevant 
hepatic encephalopathy or significant changes in liver chemistries or labs (WBC 


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>12,000 or <1000/ml, MELD >8 increase, AST/ALT/ALK>10 times ULN). As shown in 
the table below, there was a significant improvement (reduction in the MELD score) in 
the FMT group compared to the no-FMT group at day 1 post-FMT (day 6) and day 30 
post-FMT (day 35) compared to baseline. No changes in the WBC count were 
observed. 
 
 
There was a significant reduction in hospitalizations and improvement in brain function 
in patients randomized to FMT+ antibiotics compared to those randomized to SOC10. 
 
Effect of FMT on antibiotic-associated microbial diversity and function 
collapse12: 
Since the trial above had antibiotics followed by FMT, we could study the impact of 
antibiotics on the microbial function (bile acid metabolism, short-chain fatty acid 
production) and microbiota diversity. There was a collapse of microbial diversity post-
antibiotics that recovered after the FMT. In addition, after antibiotics, there was a 
reduction in deconjugation, desulfation and conversion of primary to secondary bile 
acids in the stool. These were reversed with FMT. Most importantly, the collapse in 
beneficial short-chain fatty acid production was reversed by one FMT in this population. 
 
Experience with oral FMT in C. difficile and in cirrhosis: 
 
In studies of capsules and nasojejunal/nasogastric infusion of the fecal contents in C. 
difficile, there was an excellent safety profile without serious adverse events 
 
No-FMT group 
(n=10) 
FMT group 
(n=10) 
P value 
MELD score 
 
 
 
Day 0 minus day 6 
0.6±1.4 
-1.5±1.4 
0.004 
Day 0 minus day 12 
0.4±1.3 
-0.2±1.3 
0.3 
Day 0 minus day 35 
1.2±2.4 
-0.9±1.7 
0.04 
Serum WBC count 
 
 
 
Day 0 minus day 6 
-0.1±0.6 
0.1±1.2 
0.60 
Day 0 minus day 12 
-0.53±0.9 
0.2±1.0 
0.10 
Day 0 minus day 35 
0.22±0.5 
0.2±0.9 
0.95 


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(Youngster et al JAMA 2014, Youngster et al Clin Infect Dis 2014). A pooled analysis of 
data from trials comparing oral vs. colonoscopic administration showed that both routes 
were safe and effective for C. difficile (Postigo et al Infection 2012). 
 
There has been one study in the literature of nasojejunal infusion of fecal transplant 
from several donors in patients with severe alcoholic hepatitis, most of whom have 
cirrhosis. This case series also demonstrated a good safety profile and was able to 
show a survival benefit compared to historical controls (Phillips et al Clin Gastroenterol 
Hep 2016). 
 
The team’s experience with FMT in cirrhosis using capsules:  
Fecal transplant using the oral capsule route is safe: In a current ongoing safety trial, 
which is powered for 20 individuals (10 in placebo and 10 with FMT capsules using a 
rational donor) under FDA IND, we have currently enrolled all 20 patients (10 in 
placebo and 10 to FMT)11. All 10 FMT patients have tolerated the procedures and do 
not have any safety signal compared to the ones in placebo group. They have all safely 
undergone safety capsule testing, swallowed all the oral capsules required for placebo 
or FMT without any issues11. This study is being performed under an approved FDA 
IND 17239 and is a phase I study of capsules. There is good background information 
that this will be safe and well-tolerated, but we will aggressively monitor every patient 
as outlined below. 
 
Concentration of bacteria in capsules and enemas in the oral and enema 
preparations used for the studies above: 
 
CFUs per mL of Capsules G3 Microbial Emulsion Matrix  
Mean 
St Dev 
Aerobes 
Fresh 
2.53E+05 1.76E+05 
1 freeze-thaw 
4.30E+05 4.43E+05 
Anaerobes Fresh 
5.80E+07 3.96E+07 
1 freeze-thaw 
6.20E+07 5.29E+06 
  CFUs per mL of stool homogenized 1:1 (w/v) with buffer containing 12.5% glycerol and 0.9% saline, 
after one freeze-thaw cycle  
per mL 
Aerobes 
4.53E+06 
Anaerobes 
1.47E+09 
Spores 
2.00E+06 
 
These concentrations will be used for the upcoming trial to ensure that the material 
concentrations in our older trials are expanded. 


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• We anticipate providing 5 capsules at a time for the oral FMT and 60ml of the 
FMT enema.  
• The placebo for the oral FMT will be made using identical capsules as the active 
drug, except it will contain 10%/weight trehalose (the cryoprotectant used in 
preparation of freeze-dried microbiota) and the rest carboxymethylcellulose.  
Since the capsules are not transparent and have no specific smell or taste, there 
should be no difficulty in maintaining double blinding.  
• The placebo for the liquid formulation is non-bacteriostatic, sterile phosphate 
buffered saline containing 10% USP grade glycerol.  Each dose will be 
packaged in individual cryobags, just as the active drug.  
 


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Study Design 
Overall objective: To determine the effect of dual oral and rectal administration of 
FMT from a rational donor on clinical outcomes (hospitalizations, brain function, quality 
of life) and host-microbiota interactions (microbial composition and bile acid 
composition with systemic and intestinal inflammation), compared to single route of 
administration and placebo, along with a second oral capsular FMT vs placebo 
administration in patients with cirrhosis and HE using a randomized, phase II clinical 
trial. 
 
 
Design overview:  
Four groups of outpatients with cirrhosis will be randomized using random sequence 
generator into placebo and FMT groups and followed for 6 months under an FDA IND 
double-blind clinical trial. 
 
Group 1: Dual oral and rectal FMT,  
Group 2: Oral FMT and rectal placebo,  
Group 3: Oral placebo and rectal FMT and 
Group 4: Oral and rectal placebo 
  
A repeat oral capsular FMT vs placebo based on the group assignments above will be provided 
to every subject in at day 30. 
 
The primary aim is: To evaluate the safety and tolerability of fecal transplant through 
rectal and oral capsular routes in cirrhosis and HE from a liver disease and symptom 
standpoint using analysis of serious adverse events, especially HE recurrence, in a 
placebo-controlled trial. 
 
Secondary aims are between the groups: 
1. Safety and tolerability of FMT compared to placebo 
a.  Frequency, severity and relatedness of solicited and unsolicited AEs 
through day 30 
b. Occurrence of new potentially transmitted infections through six-months 
post FMT 
c. Occurrence of new onset or significant worsening of chronic medical 
conditions post-FMT 
2. To define the changes in microbiota composition and function of the stool 
microbiota after FMT compared to pre-FMT baseline and donor compared to 
placebo 


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3. To evaluate changes in systemic inflammatory cytokines and endotoxin, quality 
of life and cognitive function compared to pre-FMT baseline and compared to 
placebo 
4. To determine occurrence of new onset or significant worsening of chronic 
medical conditions through six months post-FMT and compared to placebo 
5. To evaluate the changes in the microbiota after the second oral FMT vs. 
placebo compared to baseline values 
 
Inclusion/Exclusion Criteria: 
Inclusion criteria: 
A. Cirrhosis diagnosed by either of the following in a patient with chronic liver 
disease 
a. Liver Biopsy 
b. Radiologic evidence of varices, cirrhosis or portal hypertension 
c. Laboratory evidence of platelet count <100,000 or AST/ALT ratio>1 
d. Endoscopic evidence of varices or portal gastropathy 
e. Fibroscan values suggestive of cirrhosis 
B. On treatment for hepatic encephalopathy (patient can be on lactulose and 
rifaximin) 
C. Age: at least 21 years of age 
D. Able to give written, informed consent (demonstrated by mini-mental status 
exam>25 at the time of consenting) 
E. Women of child bearing potential must agree to use effective contraception for 
the duration of the study and for 10 days prior and 30 days after the study  
F. Negative pregnancy test in women of childbearing age 
Exclusion criteria: 
A. MELD score >22 
B. WBC count <1000 cells/mm3 
C. Platelet count < 25,000/mm3 
D. TIPS in place for less than a month 
E. Currently on antibiotics apart from rifaximin 
F. Infection at the time of the FMT (diagnosed by blood culture positivity, urinalysis, 
paracentesis as needed) 
G. Hospitalization for any non-elective cause within the last 1 month 
H. Patients who are aged >75 years  
I. Patients who are pregnant or nursing (will be checked using a urine pregnancy 
test) 
J. Patients who are incarcerated  
K. Patients who are incapable of giving their own informed consent  


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L. Patients who are immuno-compromised due to the following reasons:  
a. HIV infection (any CD4 count)  
b. Inherited/primary immune disorders  
c. Current or recent (<3 mos) treatment with anti-neoplastic agent  
d. Current or recent (<3 mos) treatment with any immunosuppressant 
medications [including but not limited to monoclonal antibodies to B 
and T cells, anti-TNF agents, glucocorticoids, antimetabolites 
(azathioprine, 6-mercaptopurine), calcineurin inhibitors (tacrolimus, 
cyclosporine), mycophenolate mofetil]. Subjects who are otherwise 
immunocompetent and have discontinued any immunosuppressant 
medications 3 or more months prior to enrollment may be eligible to 
enroll.  
M. Patients on renal replacement therapy 
N. Patients with untreated, in-situ colorectal cancer  
O. Patients with a history of chronic intrinsic GI diseases such as inflammatory 
bowel disease (ulcerative colitis, Crohn’s disease or microscopic colitis), 
eosinophilic gastroenteritis or celiac disease  
P. Major gastro-intestinal or intra-abdominal surgery in the last three months 
Q. Patients who have received FMT within last 6 months 
 
Other Exclusion Criteria: 
 
Enema-related   
(1) Platelet count<25,000  
(2) Grade IV hemorrhoids 
 
Safety-related:  
(1) Dysphagia  
(2) History of aspiration, gastroparesis, intestinal obstruction  
(3) Ongoing antibiotic use (except for Rifaximin)  
(4) Severe anaphylactic food allergy  
(5) Allergy to ingredients Generally Recognized As Safe in the FMT capsules (glycerol, 
sodium chloride, hypromellose, gellan gum, titanium dioxide, theobroma oil)  
(6) Adverse event attributable to prior FMT 
 (7) ASA Class IV or V  
(8) Pregnant or nursing patients  
(9) Acute illness or fever within 48 hours of the day of planned FMT  
(10) Immunocompromised due to medical conditions 
(11) Probiotics use within the last 48 hours of the day of planned FMT  
(12) Any condition that the physician investigators deem unsafe, including other 
conditions or medications that the investigator determines puts the participant at 
greater risk from FMT 


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Intervention  
 
Dosage:   
FMT Procedure #1 
5 FMT capsules or 5 placebo capsules and 
60 ml FMT enema vs 60 ml placebo 
FMT Procedure #2 
5 FMT capsules or 5 placebo capsules 
 
Route of Administration: Oral and enema for baseline, and oral only for Day 30 
 
Timing of administration: Twice (at baseline and Day 30) 
 
Procedures:  
Once patients are randomized 1:1:1:1 into Group 1: Dual oral and rectal FMT, Group 2: 
Oral FMT and rectal placebo, Group 3: Oral placebo and Rectal FMT and Group 4: 
Oral and rectal placebo, both will be followed over 6 months with intensive follow-up in 
the first 30 days. 
 
At the end of one month, we will provide another oral-route FMT or placebo to all 
subjects based on their initial assignment (Groups 1 and 2 will get oral FMT 5 capsules 
again, and Groups 3 and 4 will get 5 capsules of placebo again). All subjects will be 
followed with monthly visits till 6 months to assess SAEs. 
 
An overview is shown below in Figure 1 (extended through 6 months) 
 
 
 
 


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Procedures:  
Visit 1: After initial review of the medical record is completed and informed consent is 
obtained, potentially eligible patients will be interviewed and their questions about the 
study will be answered by the study team. Vital signs (including heart rate, blood 
pressure, respiratory rate, temperature) and weight will be measured. Physical exam 
will be performed. We will administer the Mini-mental status exam (MMSE)13 4. For 
those <25, we will deem them not able to give consent and their clinicians will be 
notified. For the rest we will obtain blood and urine for further confirming eligibility 
(MELD score and complete blood count for platelet count/ANC). Patients will also be 
administered a safety test capsule orally to ensure they can swallow it without any 
issues. If the subject is eligible and can swallow the capsules and otherwise fits criteria, 
they will be randomized into one of the four groups (Groups 1-4, Table 2) and a date 
for visit 2 will be generated.  A dietary recall will be performed and the patients will be 
asked to stay on the same diet throughout the trial. We will perform the validated 
lactulose/mannitol testing at baseline. Patients will undergo brain function tests and 
quality of life assessment during this visit to establish their baseline. Patients will be 
given a Stool Collection Kit to bring in the day of the baseline visit (Visit 2). They will 
also be given a symptom diary and instructions to complete it. 
 
 
Visit 2 After re-confirming eligibility, the patient will 
be seen within 3±5 days of visit 1. Vital signs and 
weight will be measured. Targeted physical exam 
will be done based on any symptoms. 
Their symptom diaries and dietary recall will be 
examined. Stool, blood and urine will be collected 
and processed (see section below), including urine 
pregnancy testing for women of child-bearing potential. After this we will administer the 
assigned intervention by enema and oral capsules. This has been tolerated without any 
issues in our current protocols. These will be dispensed from our VAMC Investigational 
Pharmacy, which has been handling these for our prior and current FMT trials. The 
Table 2: Patient Groups 
Group 1: Oral and enema FMT, 
Group 2: Oral FMT+ enema 
placebo, Group 3: Oral placebo + 
enema FMT, Group 4: Both 
placebo 


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following will be recorded in all FMTs (dose, Unit ID/Lot# of each treatment, Expiration 
Date and storage condition) The patient will be observed for a further 1 hour and then 
given another stool kit to bring back 10±5 days from this visit (Visit 3). All subjects will 
be given contact information for the study team to call in case any issues arise. 
 
Optionally, subjects may elect to combine Visits 1 and 2 to minimize potential COVID 
exposure. In this case, stool collection kit would be mailed to subject before visit, and 
the staff would provide further instructions to subject on their use. The subject may 
determine whether he/she will collect a stool sample to bring to the study clinic visit. In 
the event the subject decides not to participate in the study, the stool collection kit 
would be discarded. 
 
Visit 3: We will see the patient in the McGuire VAMC at day 15, at which point, dietary 
recall will again be performed along with changes in GI or other adverse events using 
interview and review of the symptom diaries. If no adverse event (AE) or serious 
adverse events (SAE) occur (standard definitions and in the human subjects protection 
section per FDA specifications), the subject will continue in the study. Vital signs and 
weight will be measured. Targeted physical exam will be done based on any 
symptoms. The stool sample, blood and urine will be collected for microbiota and 
safety analysis. Changes in blood counts that prompt attention (MELD score increase 
by 8, WBC count change to >13,000 or <2,000) will be monitored. If all is well, then 
subjects will be discharged with another stool kit and instructions for the last visit 15±3 
days later (visit 4). 
 
Visit 4: All procedures as in visit 2 will be performed again, including dietary recall, 
targeted physical exam, and sample collection. All subjects will also get another oral 
FMT/placebo dose of 5 capsules each depending on their original assignment. All 
subjects in the study will get this intervention unless (a) they refuse the intervention (b) 
have undergone a liver transplant or have died/discharged to hospice (c) developed an 
infection or an SAE that was adjudicated to be related to FMT in the interim or (d) are 
currently undergoing antibiotic therapy for an infection that is not related to FMT. 


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For those who are infected due to an FMT-unrelated infection, we will approach the 
patients 2 days after the completion of the assigned antibiotic course. For those 
initiated on SBP (Spontaneous Bacterial Peritonitis) prophylaxis, we will provide the 
intervention after the initial SBP episode is treated. This may require delaying the 
intervention from day 30 to up to day 45 but this will still be counted as the second 
FMT.  
 
All other subjects will be given the intervention and the blind will still be maintained. 
The brain function tests and QOL will be performed again. Groups 1 and 2 will get 
active FMT and groups 3 and 4 will get placebo FMT. No enemas will be given. The 
subjects will then be sent home. 
 
Follow-up visits every month: The subjects will be followed monthly in person, or by 
phone or videoconference at Months 3, 4, 5 to evaluate dietary and medication 
changes and for safety analysis (hospitalizations, AEs or SAEs), targeted physical 
exam and for collection of samples at each study clinic visit. Mail-in kits for collection of 
stool, and urine will be provided along with instructions for use if visit is performed 
remotely. We will also perform the cognitive tests and QOL assessment at one month 
post-second intervention and at 6 months. We will continue to follow every patient for 6 
months regardless of whether they developed an SAE or hospitalization in between. 
Only reasons not to follow them up for 6 months would be death, liver transplantation 
or patient withdrawal of consent.  
 
End-of-Study visit: Per FDA mandates for FMT studies, we will see the patients at six 
months and we will evaluate AEs, interim hospitalizations, dietary recall, and perform 
targeted physical exam, QOL and brain function studies, and collect serum, and stool 
again. At this point the participation of the patient will end. 
 
Preparation and handling of FMT material 
For enema material (60 ml) 


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As per University of Minnesota guidelines 
1. Frozen material will thaw for up to 4 hours in an ice bath. After thawing, material 
should be kept refrigerated/on ice for up to additional 8 hours. 
2. Standard protocol for handling bio-hazardous material will be employed in order to 
avoid contamination and risk to healthcare handlers. Sterile microbiological technique 
will be employed during material transfer peri-procedure. 
 
At that point we will provide 60 ml of the fecal material using universal precautions 
through a rectal tube. The procedure will be completed by a trained Registered Nurse, 
Nurse practitioner, or physician in an outpatient clinic, endoscopy recovery area, or 
standard endoscopy unit.  We will ensure that patients are able to hold the enema for 
at least 30 minutes after the administration. This will be ensured by positioning patients 
in the left lateral decubitus position, and asked periodically to rotate 180 degrees to a 
right lateral position and back to the left lateral position, to promote movement of the 
FMT material throughout the colon. We can cut it down to 60ml in case the patient is 
uncomfortable with more volume although we do not expect that. The total retention 
time will be recorded. 
 
The following will be recorded in all FMTs 
- 
Dose 
- 
Unit ID/Lot# of each treatment 
- 
Expiration Date 
- 
Storage Condition 
- 
FMT retention time (in minutes) 
 
 
For capsules: As per University of Minnesota guidelines (5 capsules) 
 
1. Long-term storage of capsules can be done in -80oC or -20oC laboratory freezer 
(without automatic freeze-thaw cycles). Once thawed, the capsules may be kept at 4oC 
for up to one month and may be kept at room temperature for up to 24 hours. If 
capsules are removed from frozen storage during an occasion in which they will not be 
administered to a patient, they must be returned to frozen storage within 10 minutes to 


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continue long-term storage or transferred to a refrigerator (4oC) for temporary storage. 
The goal is to avoid repeat freeze-thaw cycles. Any product that has gone through 
more than one freeze-thaw cycle after its original release should be discarded. 
2. Standard protocol for handling bio-hazardous material will be employed in order to 
avoid contamination and risk to healthcare handlers. Sterile microbiological technique 
will be employed during material transfer peri-procedure. 
3. The following will be recorded in all interventions (dose, Unit ID/Lot# of each 
treatment, Expiration Date and storage condition)  
 
Number of interventions: One administration of rectal placebo or FMT and two 
administrations of oral FMT or placebo 
 
We will ensure that each subject receiving active FMT will receive material (oral/rectal) 
from the same donor. 
 
 
Duration of Follow-up after FMT: 6 months 
 
Samples collected at baseline (before FMT), and at the visits specified above will be: 
a. Stool (microbiome, bile acid profile, metagenomics, metabolomics) 
b. Blood (CBC, Basic metabolic panel, LFTs, INR, endotoxin, and storage 
for circulating microbiome, systemic inflammatory markers, bile acids and 
metabolomics) 
c. Urine for metabolomics 
 
Sample processing will be done using standard precautions at the McGuire VA Medical 
Center and samples will be stored for analysis of the secondary endpoints. Microbiota 
analysis will be performed at George Mason University and University of Minnesota, 
and metabolomics will be performed at the UC Davis NIH West Coast Metabolomics 
Center or Metabolon. We will perform the bile acid analysis at the McGuire VA Medical 
Center laboratories. Additional analyses at the Institute of Hepatology, London, UK, 


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BAJAJ0024 - Amend 4 
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and the University of North Carolina at Chapel Hill. We may also use other referral 
laboratories as needed. 
 
 
Statistical analysis: These will be performed using ANOVA of delta changes after 
intervention/follow-up using Chi-square and Fisher exact for non-parametric 
(hospitalizations, HE episodes, covert hepatic encephalopathy etc.), for continuous 
variables, and specialized bio-informatics analyses for the microbiota (see details 
below). These will be adjusted for age, gender, MELD score and alcoholic etiology of 
cirrhosis. 
 
Sample size: Based on the published study with rectal FMT10, we found that standard 
of care patients had an 80% chance of hospitalization at 6 months, while FMT had a 
20% hospitalization rate. Given that we had used antibiotics for this study, we will 
assume that rectal FMT alone will have a 30% chance of hospitalization rate without 
antibiotics. We will also assume that oral FMT alone will have a similar hospitalization 
rate, and their combination will have a 10% hospitalization rate. Using a significance 
level of α=0.05, a sample size of 25 per group will provide a power of 100% between 
groups, 20 per group will give a power of 98% to define differences between the 
groups, while a sample size of 15 patients per group will give a power of 94% between 
the groups. Therefore, we will enroll 100 patients (25 in each group) for this trial. This 
sample size calculation will also be valid when we include the second oral FMT with a 
sample of 10 per group giving 88% power, 15 per group giving 97% power and 25 
giving 99% power.  
 
Specialized analyses: 
Inflammatory milieu: We will perform the analysis for endotoxemia using the validated 
Limulus amebocyte lysate (LAL) assay and serum inflammatory cytokines (IL-6, TNF, 
IL-1b) using ELISA at Dr. Bajaj and Pandak’s laboratory at the McGuire VAMC or at 
Assaygate14.  
 
 
 


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Microbial Analysis: Bacterial community composition in stool will be characterized 
using OTU counts generated as described above. OTU counts will be converted to 
measures of relative abundance to account for variation in sequencing coverage 
between samples and compared to the donor sequence. Statistical analysis will be 
carried out using the statistical software package R. Alpha (α) diversity (richness and 
evenness of taxa within a population) will be reported using the Shannon Index15 and 
Chao1 richness estimator16. Changes in abundance of individual taxa will also be 
analyzed using traditional univariate statistical methods. We will use LEfSe (Linear 
discriminant analysis Effect Size) to determine the features most likely to explain 
differences. All comparisons will be performed between treatment arms, to gauge 
donor engraftment in the three FMT-assigned arms, as well as within groups to 
compare to their baseline microbial composition17. These will be performed at George 
Mason University and University of Minnesota. Functional analysis using bile acids, 
SCFA and metabolomics will also be performed. 
 
Brain function: These will be administered at visit 1, visit 4 (one month after the 
second FMT), and end-of-study by Dr. Bajaj and the coordinator/research assistant. 
Two validated testing strategies, Psychometric Hepatic Encephalopathy Score (PHES) 
and EncephalApp Stroop Test, which have norms for the Virginia population will be 
used18. The PI and his team are well-published in this field and have been 
administering these for several years to cirrhotic patients. Both these tests showed 
benefit in the FMT enema trial published by our group in HE10. PHES is a 
recommended battery that defines brain dysfunction in cirrhosis19. It consists of 5 paper 
and pencil tests (number connection tests A and B, digit symbol test, line tracing test 
and serial dotting tests), which form a composite score of standard deviations below an 
age/education-matched community healthy population. This gives a score ranging 
between -15 and +4. In addition to this continuous score, covert hepatic 
encephalopathy can be diagnosed with a score <-4 for our population18. This test 
battery takes 15 minutes to complete. EncephalApp Stroop18, 20 is a freely available 
computerized test which consists of an easier “Off” state and a more difficult “On” state. 
The OffTime+OnTime is the output, which is the time taken to complete 5 correct runs 
in the Off and On states. The output here can be continuous (seconds in the 


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BAJAJ0024 - Amend 4 
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OffTime+OnTime) or covert hepatic encephalopathy percentage based on local 
norms18. This takes 5-7 minutes to complete.  
 
Quality of Life: This will also be administered at Visit 1, Visit 4, one month after the 
second FMT, and End-of-Study visit. The Sickness Impact Profile (SIP)21 is a validated 
profile for QOL in cirrhosis that the PI and his team have had several years of 
published experience22-24. SIP consists of 136 questions that pertain to any issues that 
patients have experienced in the last 24 hours. It has a composite score, two 
dimensions (physical and psycho-social) and twelve individual domains that are 
calculated based on norms. A higher score indicates a worse quality of life. This gives 
only a continuous score as the output. A copy is shown in the Appendix. Dr. Bajaj and 
the coordinator/research assistant will perform these. 
 
Endpoints and Plan of Analysis: 
Primary Endpoint: FMT-related SAEs including HE recurrence within 6 months 
 
 
 
 
Secondary Endpoints (details below): 
1. Safety-related (at 6 months): Liver-related hospitalizations, other serious adverse 
events (SAE) and adverse events related to interventions.  
2. Microbiota composition: Stool 16SrRNA sequencing and engraftment of donor into 
recipients. 
3. Inflammatory milieu: Endotoxemia (LAL), Systemic inflammatory cytokines (IL-6, 
TNF, IL-1b using ELISA) 
4. Bile acid profile and gut-liver mediators expression: Bile acid profile using LC/MS in 
stool and serum and serum C4 (7α-Hydroxy-4-cholesten-3-one). 
5. Urinary metabolomics to evaluate gut-microbial markers 
6. Brain function: Two validated testing strategies, PHES and EncephalApp Stroop 
Test, and Quality of Life: Sickness Impact Profile (a validated profile for health-
related quality of life in cirrhosis)  


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Adjudication: Data and safety monitoring for this study will be provided by the Clinical 
Science Research & Development (CSR&D) centralized Data Monitoring Committee 
(DMC).  The DMC is provided by CSR&D to ensure independent oversight of the safety 
and integrity of the project. The DMC is an independent multidisciplinary group, whose 
members have collectively – through research, education, training, experience, and 
expertise – the requisite knowledge pertinent to the subject areas to be reviewed.  
Membership details are available on the CSRD website.  The DMC will provide an 
ongoing independent evaluation of this study focused on safety and feasibility, 
including participant accrual and retention, adverse events monitoring, and data 
analyses.  Meetings will be held three times per year at which recommendations will be 
made to the Director of CSR&D for endorsement. These recommendations will range 
from approval to continue (unconditionally or with conditions to be addressed) to 
probation or possibly termination, if there are problems with enrollment or safety 
concerns 
All outcomes will be compared between groups as well as post-intervention to 
baseline. 
 
Visits at VCU and VAMC: 
None of the Veterans included in this study will have any visits at VCU. Non-Veterans 
will be recruited according the approved VCU protocol and will sign the VCU consent. 
These potential participants will also be shown the approved VA Consent form in order 
to provide them the full scope of the study. These non-Veterans will have a choice to 
perform all subsequent studies at VAMC or only the 2 treatment visits, which are visits 
2 and 4. When they first arrive at the VAMC for their in-person visits, they will be asked 
to sign the VA IRB approved consent form before proceeding. Neither of the treatment 
visits will be performed at VCU even if the enrollee is a non-Veteran. 
Dr Bajaj, who is the PI at both sites, will ensure that subjects meet criteria for 
enrollment and reporting to both IRBs as necessary. An MOU will be signed. 
 
Safety and hospitalization analysis: 


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Using detailed FDA-approved protocols, patients will be adjudged based on adverse 
events and serious adverse events at every visit and during the 6-month follow-up. Any 
SAEs or deaths in an FMT-randomized group will require the DMC to define the 
“relatedness” of the event to the FMT. If the DMC votes that this is related to the FMT, 
then this will be sent to the FDA, and Molecular and Cellular Therapeutics (GMP) 
facility at the University of Minnesota to invoke stopping rules as detailed below. The 
safety endpoints will be all-cause hospitalizations, defined as unplanned, non-elective 
hospitalizations within the 6-month period. The reason for the hospitalization will be 
analyzed by the investigating team and divided into liver-related, liver-unrelated, 
planned or elective. The latter two categories will not count towards the study but the 
first two will be analyzed by the team and submitted to the DMC.  Other SAEs will be 
analyzed per FDA definitions. AEs that do not meet the standards of SAE will be 
evaluated at each visit and be compiled to define trends in one group compared to the 
other. 
 
Reasonably foreseeable significant risks: 
Physical risks:  
1. 
Infection or bruising during blood draw 
2. 
Procedure-related adverse events from enema (e.g. perforation, bleeding etc) 
3. 
Pill-associated dysphagia  
4. 
FMT material-related adverse events (e.g. transmissible infection, allergic 
reaction) 
Psychological/Social risks:  
(b) 
Very small risk of loss of confidentiality and privacy 
 
Specific issues to be captured will be 
1. Study procedure-related adverse events from enema (e.g. perforation, bleeding, 
etc.) 
2. FMT material-related adverse events (e.g. transmissible infection, allergic reaction) 
3. Capsule ingestion-related adverse events (pill-associated dysphagia) 


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4. Short-term safety: Both solicited and unsolicited adverse events will be recorded by, 
clinical assessment at all in-person visits. The subjects will have the ability to telephone 
the study team at any point during the study.  
5. Long-term safety: follow-up monthly till 6 months to evaluate for SAEs (listed below). 
 
Solicited AEs throughout the trial will be  
(a) fever:  
(b) diarrhea  
(c) vomiting  
(d) constipation 
(e) GI bleeding 
(f) abdominal cramping and pain  
(g) Development of HE (confusion/altered mental status):  
(h) Development of infections, specifically spontaneous bacterial peritonitis  
(i) New onset or significant worsening of chronic medical conditions 
(j) New potentially transmitted infections 
 
We do not expect the infections to occur at a higher rate than the natural history of 
cirrhosis at this stage. This is borne out by our enema study, in which the FMT group 
had no infections. Also, a nasojejunal study performed by Phillip et al in severe 
alcoholic hepatitis, whose MELD scores were much higher than our proposed patients, 
did not reveal a poor safety profile. We will monitor for all infections and specifically for 
spontaneous bacterial peritonitis (SBP). 
 
All safety assessments in FMT will be compared to placebo groups given the 
advanced nature of the cirrhosis and the association of several of these 
symptoms in the natural history of the disease 
 
 
 
Stop-points or reportable adverse events  


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BAJAJ0024 - Amend 4 
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Any hospitalization or event that is life-threatening will be deemed a serious adverse 
event in the FMT group and reported to the IRB, FDA, DMC and Molecular and Cellular 
Therapeutics (GMP) facility at the University of Minnesota within 72 hours (per usual 
protocol). 
This will include the development of an infection that is gut-based/not gut-based: 
Gut-Related 
- 
Spontaneous Bacterial peritonitis 
- 
Infectious diarrheal illnesses 
 
Others 
- 
UTI 
- 
Respiratory 
- 
Skin/soft-tissue 
- 
Bacteremia 
 
Overall Study Halting Rules 
Specific safety findings will result in temporarily suspending enrollment until a safety 
review is convened, the objective of which is to determine whether the study should 
continue per protocol, proceed with caution, be further investigated, be discontinued, or 
be modified and then proceed. Suspension of enrollment is another potential outcome 
of a safety review. This will be done if the assigned infection is in the FMT group since 
this patient population is prone to infections. 
Subsequent review of serious, unexpected, and related AEs by the Data and Safety 
Monitoring Board, IRB, the PI, or the FDA or relevant local regulatory authorities may 
also result in suspension of further trial interventions/administration of FMT at a site. 
The FDA and PI retain the authority to suspend additional enrollment and study 
interventions/administration of FMT for the entire study, as applicable. The PI and the 
adjudication panel will make the initial decision. The subsequent safety review by the 
IRB and FDA will then decide if the study can resume. 
Findings that will trigger a safety review are  
Findings that will trigger a safety review are  
o Death related to FMT material or study procedures in any subject; 
o New potentially transmitted infection in five or more subjects assigned 
to FMT -  i. e., cannot exclude transmission and/or attribution is 


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BAJAJ0024 - Amend 4 
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pending investigation/Data Monitoring Committee (DMC) 
adjudication; 
o Any single potential transmitted infection assessed as possibly, 
probably, or definitely related to FMT by the investigator and DMC. 
o One or more subjects assigned to FMT has a serious, unexpected AE 
assessed as possibly, probably, or definitely related to FMT by the 
investigator and DMC; Five or more subjects (per assigned group) 
develop a new diagnosis of a medical condition or immune-mediated 
disease considered probably, or definitely related to FMT. 
o Five or more severe AEs of a similar nature occurring in different 
subjects and assessed as definite, possible or probable relatedness 
to study product in groups assigned to FMT (per assigned group) 
 
FDA/CBER will be notified by phone or fax within 72 hours if the study is halted for 
review.  
 
Individual study halting rules 
(1) patient’s choice  
(2) change in GI adverse events with a magnitude of 3 increase over baseline  
(3) fever and signs of infection (including WBC count >12,000/ml)  
(4) SAE development including cirrhosis complications (OHE) and hospitalizations for 
any cause including bleeding, nausea, vomiting, or other GI conditions 
(5) increase in MELD score by 8 or more 
(6) Increase in AST, ALT or Alkaline phosphatase to 10X ULN 
(7) Non-elective Hospitalization  
Even if the subject is withdrawn before 30 days, they will still be followed till 6 months 
for safety. 
 
Health risks (please see adverse events table attached): 
Adverse events will be both for the FMT material, placebo as well as for the procedures. 
These risks are listed in the Risk Section of the informed consent. 
 
These possible adverse events will be: 


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BAJAJ0024 - Amend 4 
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(a) Fever: yes or no answer with grading based on actual temperature on 
examination 
(b) diarrhea (will be asked to grade them from 0-4 compared to baseline) 
(c) abdominal cramping and pain (will be asked to grade them from 0-4 
compared to baseline) 
(d) vomiting (will be asked to grade them from 0-4 compared to baseline) 
(e) Development of HE (Altered mental status) in every group: will be 
monitored by clinical examination through the West-Haven Criteria25. We 
will be closely monitoring all subjects for this development, including a 
clinical examination by a gastroenterologist at every visit.  
(f) Development of infections specifically spontaneous bacterial peritonitis  
- Fever will be reconfirmed by measuring by the study nurse and if it is confirmed, a 
detailed investigation into the cause of the fever will be performed as part of standard 
clinical care and the patient will be withdrawn from the study. 
- Vomiting, constipation, GI bleeding, abdominal cramps and diarrhea: If the patient’s 
diarrhea and abdominal cramps change in a magnitude of 3 over their baseline values 
per the AE chart (patients with cirrhosis often have these symptoms at baseline), they 
will be withdrawn from the study. 
 
-Infections that occur in the FMT group will be thoroughly investigated according to 
standard clinical care to prove whether they were associated with the FMT.  


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Adverse Event Grading Chart  
 
Volunteer Study ID:_________________Date:________ Time: _____ 
Study Start Date:________ Current Visit number:_________________ 
 
*Volunteer’s responses will be marked on grading sheet by circling the appropriate grade or indicating no 
symptoms. 
PARAMETER 
COMPARED TO 
BASELINE 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
ESTIMATING SEVERITY GRADE 
 
Symptoms with minimal 
change from baseline 
causing no or minimal 
interference with usual 
social & functional 
activities 
Symptoms with 
moderate change from 
baseline causing greater 
than minimal 
interference with usual 
social & functional 
activities 
Symptoms with severe 
change from baseline 
causing inability to 
perform usual social & 
functional activities 
Symptoms causing 
inability to perform basic 
self-care functions OR 
Medical or operative 
intervention indicated to 
prevent permanent 
impairment, persistent 
disability, or death  
SYMPTOM SPECIFIC SEVERITY GRADE 
Fever (oral)  
(99.9-100.5F) 
(100.6-101.5F) 
(101.6. -104F) 
> 104F 
Diarrhea 
Transient or intermittent 
episodes of unformed 
stools OR Increase of ≤ 
3 stools over baseline 
per 24-hour period 
Persistent episodes of 
unformed to watery 
stools OR Increase of 4 
– 6 stools over baseline 
per 24-hour period 
Bloody diarrhea OR 
Increase of ≥ 7 stools 
per 24-hour period OR 
IV fluid replacement 
indicated 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
Nausea 
Transient (< 24 hours) 
or intermittent nausea 
with no or minimal 
interference with oral 
intake 
Persistent nausea 
resulting in decreased 
oral intake for 24 – 48 
hours 
Persistent nausea 
resulting in minimal oral 
intake for > 48 hours 
OR Aggressive 
rehydration indicated 
(e.g., IV fluids) 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
Vomiting 
Transient or intermittent 
vomiting with no or 
minimal interference 
with oral intake 
Frequent episodes of 
vomiting with no or mild 
dehydration 
Persistent vomiting 
resulting in orthostatic 
hypotension OR 
Aggressive rehydration 
indicated (e.g., IV fluids) 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
Distension/bloating, 
abdominal 
discomfort 
Asymptomatic 
Symptomatic, but not 
interfering with GI 
function 
Symptomatic, interfering 
with GI function 
--- 
Abdominal Pain 
Symptoms causing no 
or minimal interference 
with usual social & 
functional activities 
Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities 
Symptoms causing 
inability to perform 
usual social & functional 
activities 
Disabling pain causing 
inability to perform basic 
self-care functions OR 
Life-threatening 
consequences (i.e. 
acute peritonitis) 


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BAJAJ0024 - Amend 4 
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PARAMETER 
COMPARED TO 
BASELINE 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Dehydration 
Increased oral fluids 
indicated; dry mucous 
membranes; diminished 
skin turgor 
IV fluids indicated <24 
hours 
IV fluids indicated >24 
hours 
Life-threatening 
consequences (e.g. 
hemodynamic collapse) 
Constipation 
NA 
Persistent 
constipation requiring 
regular use of dietary 
modifications, 
laxatives, or enemas 
Obstipation with 
manual 
evacuation 
indicated 
Life-threatening 
consequences 
(e.g., 
obstruction) 
Procedural Enema 
Rectal discomfort; 
minor bleeding <24 
hours on toilet paper 
Rectal discomfort; 
minor bleeding >24 
hours on toilet paper 
Gross hematochezia  
Bowel perforation 
Change in mental 
status (West-Haven 
Criteria) 
No change in 
orientation and no 
asterixis 
Disorientation to time, 
asterixis 
Disorientation to place 
or person, asterixis, 
lethargy and stupor 
Coma 
MELD score 
increase (includes 
INR, bilirubin and 
creatinine) 
<3 
3-7 
>8 
             NA 
Serum WBC 
NA 
NA 
>12,000/ml or <1000/ml 
NA 
AST 
NA 
≥ 5.0 to < 10.0 x ULN 
≥ 10.0 x ULN 
NA 
ALT 
NA 
≥ 5.0 to < 10.0 x ULN 
≥ 10.0 x ULN 
NA 
Alkaline 
phosphatase 
NA 
≥ 5.0 to < 10.0 x ULN 
≥ 10.0 x ULN 
NA 
 
Specific investigation of the infection related to the FMT in those assigned to the FMT 
group: 
1. Regular clinical care of the subject according to the infection developed will include 
the appropriate cultures and relevant antibiotics will be started 
2. Stool tests from the patient will be compared to the donor safety sample when a CLIA-
certified assay is available 
3. Contact will be made with the FMT suppliers to evaluate this batch of the 
donor. Specifically, the cross-referenced drug master file has the means to track 
down the lots and batches of the donors. In the event of a suspected adverse 
event related to the potential transmission of an infection, an immediate initial 
consultation will be held between the researchers and the Chief Medical Officer of 
Molecular and Cellular Therapeutics (GMP) facility at the University of Minnesota 
(Dr. Alexander Khoruts) to gather further information.  This will be followed by a 
detailed collaborative investigation as follows: 
The investigation will entail: 
a. Strict donor material quarantining during the investigation 


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BAJAJ0024 - Amend 4 
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b. Rescreening of the donor safety aliquot and the donor for infectious diseases 
as well as risk factors for the suspected infectious disease 
c. Consultation with external experts in infectious diseases and gastroenterology 
with extensive experience in FMT. 
d. Full Advisory board review at Molecular and Cellular Therapeutics (GMP) 
facility at the University of Minnesota to track the donors 
 
 
Laboratory: 
Lab values for WBC counts, serum AST, ALT, Alkaline phosphatase, serum bilirubin, 
INR and serum creatinine (all three are in MELD score) will be followed. 
These criteria will be graded per the chart as well.  
The lab values that will be followed from an adverse event perspective will be: 
 
- 
WBC count: a new >12,000/ml or <1000/ml in the presence of fever will 
necessitate investigation of an infectious source 
- 
Worsening of the MELD score by 8 or higher will be considered significant 
- 
Increase in AST, ALT and alkaline phosphatase >10 ULN will be considered 
significant although this change is not expected in cirrhotic subjects 
 
Dr. Bajaj asks subjects to allow him to keep a portion of their blood, urine and stool 
specimens collected during the study to be used for future testing. Subjects agreeing to 
this will have a portion of their blood, urine and stool specimens stored in a research 
laboratory at the McGuire DVAMC. The samples will be de-identified. This means that 
no information that can identify a subject will appear on the samples. Subjects do not 
have to agree to this in order to participate in the study. If at any time during or after the 
study, a subject decides they want their samples destroyed, the subject can contact Dr. 
Bajaj at 804-675-5021 and request that their samples be destroyed. 
 
 
Adverse Events Reporting 
Dr. Bajaj will function as both the Investigator and the Sponsor during the conduct of 
this study. Dr. Bajaj will be responsible for reporting all safety observations (adverse 
events and serious adverse events) to the FDA 
 
 


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BAJAJ0024 - Amend 4 
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A. Definitions  
1. Adverse Event (AE) 
An AE is any untoward medical occurrence in a patient or study subject administered 
FMT due to the material or procedure that does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a FMT, whether or not related to the FMT.  
• AEs may be new events or may be pre-existing conditions that have become 
aggravated or have worsened in severity or frequency.  
• AEs may be clinically significant changes from baseline in physical examination, 
laboratory tests, or other diagnostic investigation (e.g. laboratory results, radiographic 
findings).  
Pregnancy is not an AE; however, if a female subject becomes pregnant during the 
conduct of the study, the Investigator/Sponsor is responsible for notifying the FDA.  
 
2. Serious Adverse Event (SAE)  
A serious adverse event is any adverse experience occurring during or after FMT that 
results in any of the following outcomes:  
• Death 
• Life-threatening experience 
Note: An adverse event or suspected adverse reaction is considered “life-threatening” 
if, in the view of the Investigator/Sponsor, its occurrence places the patient or subject 
at immediate risk of death. It does not include an adverse event or suspected adverse 
reaction that, had it occurred in a more severe form, might have caused death.  
• Requires inpatient hospitalization or prolongation of existing hospitalization 
Note: Adverse events requiring hospital admissions that are less than 24 hours in 
duration do not meet this criterion. A scheduled hospitalization for a pre-existing 
condition that has not worsened during participation in the study does not meet this 
criterion. Pre-planned hospitalizations for an elective medical/surgical procedure or 
routine check-ups do not meet this criterion.  
• Results in persistent or significant disability or incapacity 


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BAJAJ0024 - Amend 4 
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• Results in a congenital anomaly or birth defect 
 
• Results in an important medical event 
Note: Important medical events are those that may not be immediately life threatening 
or result in death or hospitalization but may jeopardize the patient or may require 
intervention to prevent one of the outcomes listed in the definition above.  
 
 
3. Planned Hospitalization  
A hospitalization planned prior to intervention is to be considered a therapeutic 
intervention and not the result of a new SAE. If the hospitalization or procedure is 
executed as planned, it will be recorded in the subject’s medical history or procedures. 
However, if the event/condition worsens during the study, it must be reported as an AE.  
 
4. Adverse reaction 
An adverse reaction means any adverse event caused by FMT or placebo.  Adverse 
reactions are a subset of all suspected adverse events for which there is reason to 
conclude that FMT or placebo caused the event. 
 
5. Suspected Adverse Reaction  
Suspected adverse reaction means any adverse event for which there is a reasonable 
possibility that FMT caused the adverse event. For the purposes of IND safety 
reporting, ‘reasonable possibility’ means there is evidence to suggest a causal 
relationship between FMT and the adverse event. A suspected adverse reaction 
implies a lesser degree of certainty about causality than adverse reaction, which 
means any adverse event caused by a therapy. 
 
6. Unexpected 
An adverse event or suspected adverse reaction is considered “unexpected” if it is not 
listed in the Investigator brochure or is not listed at the specificity or severity that has 


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been observed; or is not consistent with the risk information described in the general 
investigational plan or elsewhere in the current application.  
 
Solicited Adverse Events 
According to the attached Adverse Event Grading Chart 
 
Monitoring of Adverse Events 
Each subject will be monitored for the occurrence of AEs, including SAEs. Each 
subject will be followed for safety monitoring at each follow-up interval and at the 6-
month phone call  
• Subjects will be questioned regarding stool patterns, abdominal pain, 
fevers, and subjective well-being. Subjects will be questioned about the 
possible occurrence of adverse events in a generalized way, such as, 
"How have you been feeling since your last visit?” Subsequent solicited 
questions and relevant details will be asked if there is a positive 
response. Site Investigators will be contacted by study representative if 
there is a suspected or reported AE 
• Subjects having AEs will be monitored with relevant clinical assessments 
and laboratory tests, as determined by the site Investigator 
• AEs, actions taken as a result of AEs, and follow-up results will be 
recorded as well as in the subject's source documentation. Follow-up 
laboratory results should be filed with the subject's source documentation  
• Subjects will be seen every month till 6 months post-enrollment to record 
any SAEs, new onset of potentially transmitted infections, new medical 
conditions, or changes in pre-existing medical conditions (New onset or 
significant worsening of chronic medical conditions including, but not 
limited to, autoimmune diseases, inflammatory bowel diseases, metabolic 
syndrome, cardiovascular disorders, and neuropsychiatric disorders.)   
 


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Assessment of Adverse Events 
1.  Assessment of Severity will be performed compared to baseline symptoms 
that the patient has at enrollment and according to the adverse event table The 
severity of AEs will be assessed according to the following definitions: 
•Mild (1 change): the AE is noticeable to the patient and/or the Investigator, but 
does not interfere with routine activity 
•Moderate (2 change): the AE interferes with routine activity, but responds to 
symptomatic therapy or rest 
•Severe (3 change): the AE significantly limits the patient’s ability to perform 
routine activities despite symptomatic therapy 
• Life threatening (4 change): Potentially life-threatening 
 
2.  Assessment of Causality 
The Investigator must assess the relationship of any AE (including SAEs) to 
FMT, as related or not related, based on clinical judgment and using all 
available information, and may include consideration of the following factors: 
• Possible alternative causes of the AE, including the disease under treatment, 
pre-existing conditions, concomitant use of other drugs, and presence of 
environmental or genetic factors 
• The temporal association between FMT exposure and onset of the AE 
• Whether the manifestations of the AE are consistent with known actions or 
theoretical toxicity of FMT 
 
The causal relationship between FMT and the AE will be assessed using one of 
the following categories: 
 
Not Related: An AE is not associated with FMT if: 
• Temporal relationship is lacking (e.g., the event did not occur within a 
reasonable time frame following administration of FMT); or 
• Other causative factors more likely explain the event (e.g. pre-existing 
condition, other concomitant treatments);  


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Related: An AE is attributed to FMT if: 
• There is a positive temporal relationship (e.g. the event occurred within a 
reasonable time frame following FMT); and 
• The AE is more likely explained by FMT than by another cause  
 
To aid this assessment, the Investigator/Sponsor will be helped by the VA 
Central DMC as mentioned above. 
 
All SAEs, possible transmission of infections, and new or worsening medical conditions 
possibly related to FMT will be referred to this panel, including ones elicited at the 
monthly visits. This panel will vote based on their analysis of the data regarding the 
“relatedness” of the AE. 
 
Reporting Safety Observations by the Investigator /Sponsor 
1.  Reporting of Non-serious AEs 
All AEs, regardless of seriousness, severity, or causal relationship to FMT, will 
be recorded in the AE section of the subject case report form. 
 
2.  Reporting of FMT Exposure during Pregnancy 
If a female subject becomes pregnant during the course of study, the 
Investigator/Sponsor is required to follow up on the pregnancy until it has 
completed. The outcome of the pregnancy and the status of the newborn (if 
applicable) will be reported to the local IRB within 24 hours of becoming aware.  
 
3. Reporting of Safety Observations by the Investigator/Sponsor 
Any occurrence of the following events or outcomes must be reported 
expeditiously by the Investigator/Sponsor to the local IRB (within 5 days of 
becoming aware) and will be responsible for reporting the event to the FDA:  
1. SAE related to FMT material 
2. Death of a subject related to FMT material  
 


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The site Investigator/Sponsor is to report any safety observations from the list 
above to the FDA within 72 hours of becoming aware of the event. Any 
observation that is also an AE will be recorded on the subject’s case report form 
along with any actions taken. If not all information is available at the time of 
initial report, follow up SAE reports will be completed and submitted.  
 
Any occurrence of the following events or outcomes must be reported by the 
Investigator/Sponsor to the local IRB and for reporting the event to the FDA:   
1. SAE unrelated to FMT material 
2. Death of subject unrelated to FMT material 
3. New or worsening medical condition, or new medications  
 
The Investigator is to report any safety observations from the list above to the 
Sponsor within 7 days of becoming aware of the event. The Sponsor will notify 
the FDA in its Annual Report. Any observation that is also an AE will be 
recorded on the subject’s case report form along with any actions taken. If not 
all information is available at the time of initial report, follow up SAE reports will 
be completed and submitted. The investigator will report all new onset of 
potentially transmitted infections and new onset or significant worsening of 
chronic medical conditions to FDA regardless of the assessment of causality 
and according to time frames outlined in 21 CFR 312.32 (within 7 days for 
deaths and life-threatening SAEs; others within 15 days). Similarly, deaths and 
SAEs related to FMT procedures (not only FMT material) will be reported to the 
FDA expeditiously (within 7 days for deaths and life-threatening SAEs; others 
within 15 days.  
 
The Investigator/Sponsor is to report any safety observations from the list above 
to the local IRB within 5 days of becoming aware of the event. The 
Investigator/Sponsor will notify the FDA in its Annual Report. Any observation 
that is also an AE will be recorded on the subject’s case report form along with 


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any actions taken. If not all information is available at the time of initial report, 
follow up SAE reports will be completed and submitted.  
The Investigator/Sponsor is required to follow SAEs until resolution, regardless 
of whether the subjects are still participating in the study. Resolution is defined 
as:  
• Resolved with or without residual effects 
• Return to baseline for a pre-existing condition 
• Fatal outcome; if autopsy is performed, the autopsy report must be 
provided to the Investigator/Sponsor. 
 
Monitoring the study database and submitting safety reports 
The Investigator/Sponsor will notify FDA of any unexpected fatal or life-
threatening suspected adverse reaction related to FMT material as soon as 
possible, but no later than 7 calendar days after the Investigator/Sponsor's initial 
receipt of the information.  The Investigator/Sponsor will notify the FDA in an 
IND safety report of potentially serious risks from this study as soon as possible, 
but no later than 15 calendar days after the Investigator/Sponsor receives the 
safety information and determines that the information qualifies for reporting.  In 
addition, the Investigator/Sponsor will identify in each IND safety report, all IND 
safety reports previously submitted to FDA concerning a similar suspected 
adverse reaction and will analyze the significance of the suspected adverse 
reaction in light of previous, similar reports or any other relevant information. 
The Investigator/Sponsor will evaluate a suspected adverse reaction in the 
context of other related reports or adverse events.  The Investigator/Sponsor will 
periodically review and analyze the entire safety database, for IND safety 
reporting purposes, and also to update Investigator brochures with new safety 
information. An IND safety report will be submitted when any of the following 
criteria are met:  
 
 


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A. Serious and unexpected suspected adverse reaction related to FMT 
material 
A serious and unexpected adverse reaction is a SAE as determined by the 
Investigator/Sponsor, as defined previously, in combination with unexpected, 
defined as not being listed in the Investigator Brochure. At the request of the 
FDA, it will also include any documented infectious disease, defined as a new 
onset infection in the recipient after FMT and the infection present in the safety 
aliquot, which is a sample of the exact specimen that was transferred to the 
patient.  
 
 
B. Findings from other sources  
The Investigator/Sponsor will also expeditiously report any findings from clinical, 
epidemiological, or pooled analysis of multiple studies or any findings that 
suggest a significant risk in humans exposed to FMT and thought related to the 
material. 
 
 
C. Increased occurrence of serious suspected adverse reactions related to 
FMT material 
The Investigator/Sponsor will report any clinically important increase in the rate 
of a serious suspected adverse reaction over that listed in the protocol. 
 
Minimizing Risks to Human Subjects 
Human Subjects Involvement, Characteristics and Design 
1. Approval will be obtained from the McGuire VAMC IRB and get the required FDA 
approval of IND. 
2. Subjects will be given informed consent using the standard consent process for 
enema. Additional theoretical risk for transmission of infectious agents, and other 
diseases and conditions will also be discussed. 
3. Protections against risk are provided in detail below. 
 


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Protection against Risks to Subjects  
Recruitment and informed consent 
-Participants will be recruited after they are determined to meet inclusion criteria, the 
clinician will introduce him/her to the research assistant, if applicable. The research 
staff or clinician will carefully explain all aspects of the study to a potential recruit, 
including the risks and benefits, and obtain participant’s written informed consent. 
-The research assistant or clinician will orally describe the material written in the 
informed consent document and answer any questions the participant may have. 
- Participants will be reminded that they are not required to participate in the study and 
that they will receive the standard care provided by their physician regardless of 
whether or not they choose to participate. Participants who give their consent will sign 
a copy of the document and will be given a signed copy of the informed consent 
document. 
-Recruits will be informed of the treatment commitment, amount and general types of 
assessments, the follow-up telephone interview procedures, and clinic visits. They will 
be given detailed descriptions of study procedures. They will also be told of the 
possibility of being randomized to the non-FMT arm or an arm that receives one 
placebo. 
 
Protection against risk 
Data and safety monitoring will take place to assure the safety of subjects. All 
participants will be reminded that their participation is voluntary and that they can 
withdraw at any time without penalty. 
Additionally, the risks described above will be minimized by the following procedures: 
1. We will minimize the risk of potential coercion by following standard procedures for 
obtaining informed consent from subjects. We will begin this process during the intake, 
where we will clarify the nature of the study and possible alternatives upfront. Prior to 
enrolling subjects in the research, we will fully explain the study procedures, risks, 
benefits, and alternatives, emphasizing that the subject’s participation has no impact 
on the other services they receive. Also, subjects who do not consent or who withdraw 
during the study period will continue to receive appropriate treatment if needed. All 


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subjects will be reminded that there is no penalty for those who choose to not 
participate or to withdraw from the study and that their decision to participate does not 
impact the standard services they receive through the hospital.  
 
2. We will minimize potential risks due to loss of confidentiality by having all information 
collected and handled by research staff trained to deal appropriately with sensitive 
clinical issues. All study information will be treated as confidential and will be available 
only to research staff. Hardcopies will be kept in locked file cabinets, and computer 
data files will be encrypted and available only to authorized personnel – with no 
storage of names or obvious identifying information. No participant will be identified in 
any report of the project. Further, when contacting participants for follow-up, no 
identifying information other than the first name of the research assistant will be used 
when leaving messages or speaking to anyone other than the participant him/herself. 
Written consent will be obtained to contact other persons for the purpose of locating 
the participant for follow-up and participants can refuse or revoke such 
consents. No information about participants will be released without their permission or 
where required by law. 
 
3. We will minimize the theoretical risks of infectious disease or other conditions by the 
following points: 
(a) Infection or bruising during blood draw: We will minimize these risks by having 
the experienced nurse coordinator or phlebotomist draw the blood 
      (b) Procedure-related adverse events from enema (e.g. perforation, bleeding, etc.): 
will be reduced by conducting these procedures and post-procedure monitoring in the 
accredited Richmond VA Medical Center by trained certified practitioners. Patients will 
be monitored per standard protocols 
(c) FMT pill-associated dysphagia: This will be minimized by using the safety 
capsule ingestion and also by excluding subjects who may be at risk for 
dysphagia. We can perform an endoscopy to retrieve any stuck capsules if 
needed urgently. 


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(d) FMT material-related adverse events (e.g. transmissible infection, allergic 
reaction): Using one rational donor as the source of all the capsules will greatly 
reduce these risks. These will be minimized by aggressive monitoring using a 
dedicated adverse event chart. 
 
Data Monitoring Plan 
Data will be collected using standardized paper forms and will only be identified with 
the study’s ID of the subject. The codes that link the name of the subject and the study 
ID will be kept confidential by the PI in a secured cabinet. Data will be entered in the 
computer database independently by trained data entry staff, and discrepancies will be 
corrected by the PI, based on source documents. 
Data quality will be monitored once per month by random inspection of the completed 
forms by the PI. 
 
 


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