Oral Fecal Transplant in Cirrhosis

Sponsor

Virginia Commonwealth University (Other)

Overall Status

Completed

CT.gov ID

NCT03152188

Collaborator

OpenBiome (Industry), Medical College of Wisconsin (Other), Hunter Holmes McGuire VA Medical Center (U.S. Fed), National Institutes of Health (NIH) (NIH)

Enrollment

Locations

Arms

Actual Duration (Months)

Patients Per Site

0.6

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

To evaluate the safety and tolerability of oral fecal transplant in patients with cirrhosis and hepatic encephalopathy

Condition or Disease	Intervention/Treatment	Phase
Hepatic Encephalopathy Cirrhosis, Liver	Drug: FMT Other: Placebo	Phase 1

Detailed Description

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

20 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Placebo-controlled single-blind randomized trialPlacebo-controlled single-blind randomized trial

Masking:

Double (Participant, Outcomes Assessor)

Masking Description:

Single-blind study in which subjects will not be aware whether they will be on placebo or FMT capsulres

Primary Purpose:

Prevention

Official Title:

Modulation of Gut-Brain Axis Using Fecal Transplant Capsules in Cirrhosis

Actual Study Start Date :

Jun 12, 2017

Actual Primary Completion Date :

Nov 12, 2018

Actual Study Completion Date :

Nov 12, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: FMT Fecal Microbiota Transplantation (FMT) capsules	Drug: FMT Fifteen FMT Openbiome capsules administered at the same time
Placebo Comparator: Placebo Placebo capsules	Other: Placebo Fifteen placebo capsules administered at the same time

Arm

Intervention/Treatment

Experimental: FMT

Fecal Microbiota Transplantation (FMT) capsules

Drug: FMT

Fifteen FMT Openbiome capsules administered at the same time

Placebo Comparator: Placebo

Placebo capsules

Other: Placebo

Fifteen placebo capsules administered at the same time

Outcome Measures

Primary Outcome Measures

Serious Adverse events related to FMT [5 months]
Safety

Secondary Outcome Measures

Frequency, severity and relatedness of solicited and unsolicited AEs [5 months]
Safety
Occurrence of new potentially transmitted infections in the FMT group [5 months]
Safety
Occurrence of new onset or significant worsening of chronic medical conditions post-FMT [5 months]
Safety
changes in microbiota composition of the stool, duodenal and sigmoid colonic mucosa after oral FMT compared to pre-FMT baseline and donor compared to placebo post-FMT [30 days]
Mechanism
mucosal defenses by studying antimicrobial peptides, inflammatory cytokine expression and barrier protein expression compared to pre-FMT baseline and compared to placebo [30 days]
Mechanism
cognitive function after oral FMT compared to pre-FMT baseline and compared to placebo [30 days]
Mechanism

Eligibility Criteria

Criteria

Ages Eligible for Study:

21 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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