FMT in Cirrhosis and Hepatic Encephalopathy
FMT in Cirrhosis and Hepatic Encephalopathy
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 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.
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 (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 cirrhotic patients with 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.
Inclusion Criteria:

 -  Cirrhosis diagnosed by either of the following in a patient with chronic liver disease

 -  Liver Biopsy

 -  Radiologic evidence of varices, cirrhosis or portal hypertension

 -  Laboratory evidence of platelet count <100,000 or AST/ALT ratio>1

 -  Endoscopic evidence of varices or portal gastropathy

 -  Fibroscan values suggestive of cirrhosis

 -  On treatment for hepatic encephalopathy (patient can be on lactulose and rifaximin)

 -  Able to give written, informed consent (demonstrated by mini-mental status exam>25 at
 the time of consenting)

 -  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

 -  Negative pregnancy test in women of childbearing age

 Exclusion Criteria:

 -  MELD score >22

 -  WBC count <1000 cells/mm3

 -  Platelet count<25,000/mm3

 -  TIPS in place for less than a month

 -  Currently on antibiotics apart from rifaximin

 -  Infection at the time of the FMT (diagnosed by blood culture positivity, urinalysis,
 paracentesis as needed)

 -  Hospitalization for any non-elective cause within the last 1 month

 -  Patients who are aged >75 years

 -  Patients who are pregnant or nursing (will be checked using a urine pregnancy test)

 -  Patients who are incarcerated

 -  Patients who are incapable of giving their own informed consent

 -  Patients who are immuno-compromised due to the following reasons:

 -  HIV infection (any CD4 count)

 -  Inherited/primary immune disorders

 -  Current or recent (<3 mos) treatment with anti-neoplastic agent

 -  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

 -  Patients on renal replacement therapy

 -  Patients with untreated, in-situ colorectal cancer

 -  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

 -  Major gastro-intestinal or intra-abdominal surgery in the last three months

 Other Exclusion Criteria:

 -  Enema-related

 -  Platelet count<25,000

 -  Grade IV hemorrhoids

 -  Safety-related:

 -  Dysphagia

 -  History of aspiration, gastroparesis, intestinal obstruction

 -  Ongoing antibiotic use (except for Rifaximin)

 -  Severe anaphylactic food allergy

 -  Allergy to ingredients Generally Recognized As Safe in the FMT capsules
 (glycerol, sodium chloride, hypromellose, gellan gum, titanium dioxide, theobroma
 oil)

 -  Adverse event attributable to prior FMT

 -  ASA Class IV or V

 -  Pregnant or nursing patients

 -  Acute illness or fever within 48 hours of the day of planned FMT

 -  Immunocompromised due to medical conditions

 -  Probiotics use within the last 48 hours of the day of planned FMT

 -  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