Oral Fecal Transplant in Cirrhosis

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 microbiota 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 study team's research 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. For this reason, the
study team is particularly interested in working with Openbiome and have obtained their
collaboration towards performing this Fecal Microbiota Transplantation (FMT) by
cross-referencing of their drug master file.

The preliminary data suggest that a one-time administration of an FMT-enema using a
rationally-selected donor via Openbiome 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 by Openbiome 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. The study will use a donor specifically selected from the
Openbiome pool whose microbial profile best fulfils the microbiota deficits related to
beneficial bacteria in HE patients, utilizing a "Precision Microbiome" approach.

Inclusion Criteria:

- 21-75 years of age

- 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

- At least two HE episodes, one within the last year but not within the last month
(patient can be on lactulose and rifaximin)

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

Exclusion Criteria:

Disease-related: (1) MELD score>17 (2) WBC count<1000 (3) TIPS, non-elective
hospitalization or HE within last month (4) on dialysis (5) known untreated, in-situ
luminal GI cancers (6) chronic intrinsic GI diseases (ulcerative colitis, Crohn's disease
or microscopic colitis, eosinophilic gastroenteritis and celiac disease) Endoscopy-related:
(1) Platelet count<50,000 (2) adverse reactions to sedation (3) lack of driver or other
contra-indications Safety-related: (1) Dysphagia (2) History of aspiration, gastroparesis,
intestinal obstruction (3) Ongoing absorbable antibiotic use (4) Severe anaphylactic food
allergy (5) allergy to ingredients Generally Recognized As Safe in the G3 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 on the day of planned FMT