FMT in Cirrhosis and Hepatic Encephalopathy

Sponsor

VA Office of Research and Development (U.S. Fed)

Overall Status

Recruiting

CT.gov ID

NCT03796598

Collaborator

(none)

Enrollment

Location

Arms

65.1

Anticipated Duration (Months)

0.9

Patients Per Site Per Month

Study Details

Study Description

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 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.

Condition or Disease	Intervention/Treatment	Phase
Cirrhosis Hepatic Encephalopathy	Drug: Fecal Microbial transplant Capsules Drug: Fecal Microbial Transplant Enema Other: Placebo	Phase 1/Phase 2

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 (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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

60 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Subjects will be divided into 4 groups via randomization 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 placeboSubjects will be divided into 4 groups via randomization 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

Masking:

Triple (Participant, Care Provider, Outcomes Assessor)

Primary Purpose:

Other

Official Title:

Fecal Microbiota Transplant in Veterans With Cirrhosis

Actual Study Start Date :

Jul 29, 2019

Anticipated Primary Completion Date :

Jun 24, 2024

Anticipated Study Completion Date :

Dec 31, 2024

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Oral and rectal placebo at visit 2 Oral placebo at day 30	Other: Placebo Placebo
Active Comparator: Group 3: Oral placebo and rectal FMT Oral placebo and rectal FMT at visit 2 Oral placebo at day 30	Drug: Fecal Microbial Transplant Enema FMT enema Other: Placebo Placebo
Active Comparator: Group 2: Oral FMT and rectal placebo Oral FMT and rectal placebo at visit 2 Oral FMT at day 30	Drug: Fecal Microbial transplant Capsules Oral capsules of FMT
Experimental: Group 1: Dual Oral and rectal FMT Dual Oral and rectal FMT at visit 2 Oral FMT at day 30	Drug: Fecal Microbial transplant Capsules Oral capsules of FMT Drug: Fecal Microbial Transplant Enema FMT enema

Outcome Measures

Primary Outcome Measures

Serious adverse events related to FMT [6 months]
Number of serious adverse events between groups related to FMT

Secondary Outcome Measures

Adverse events related to FMT [6 months]
Number of adverse events that do not fit the criteria of serious adverse events between groups related to FMT
Change in microbial diversity in stool [6 months]
Shannon diversity index compared to baseline and engraftment related to the donor at baseline, within 30 days and then monthly till 6 months. Ranges usually from 0-10
Sickness Impact Profile change [30 days and 6 months]
Quality of life assessment change defined by Sickness Impact Profile total score at 30 days and 6 months between groups. This is a percentage result ranges usually from 0-100
EncephalApp performance change [30 days, 60 days and 6 months]
Cognitive assessment change using the OffTime+OnTime in seconds between groups at 30 days, 60 days and 6 months
Psychometric hepatic encephalopathy score (PHES) change [30 days, 60 days and 6 months]
Cognitive assessment change using the total PHES score between groups at 30 days, 60 days and 6 months. This ranges from -15 to +5
Change in microbial diversity in saliva [6 months]
Shannon diversity index compared to baseline at 30 days and then monthly till 6 months. Ranges usually from 0-10

Eligibility Criteria

Criteria

Ages Eligible for Study:

21 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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