Fecal Microbiota Transplant as Treatment of Hepatic Encephalopathy

Study Overview
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Brief Summary
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A common complication of advanced liver disease is a condition called hepatic encephalopathy, which leads to confusion. The current treatment options cause side effects, are costly, and do not always work. An abnormal population of bacteria in the intestines may be causing this condition, and transplanting bacteria from the colon of a healthy person may treat it. In this research study, the investigators will first find two healthy stool donors whose stool donation improves the gut bacteria of patients with advanced liver disease and helps them think more clearly. Then, in a randomized controlled trial, the investigators will compare the ability of stool donation from these two best donors versus a placebo to improve the neurological function of patients with advanced liver disease. If the investigators find the expected results, there will be a new effective therapy for patients with advanced liver disease and the very troublesome complication of hepatic encephalopathy.

Detailed Description
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Decades of investigation demonstrate that hepatic encephalopathy (HE), a common complication of cirrhosis characterized by impaired cognition, develops as a consequence of intestinal microbial products reaching the brain. Recent investigation has found that cirrhotic patients, especially those who have developed HE, have intestinal dysbiosis compared to normal controls. Several plausible mechanisms explain how intestinal dysbiosis could lead to HE. There is limited prior literature on the efficacy of FMT in cirrhosis. The largest documented study of 10 cirrhotic patients receiving a single FMT enema found no significant change in microbiome diversity as assessed by 16S rRNA sequencing. The investigators hypothesize that aggressive manipulation of the microbial composition with fecal microbiota transplant (FMT) will improve neurological function in patients with a history of cirrhosis and HE. The investigators additionally hypothesize that five oral FMT capsule administrations from a previously efficacious stool donor will significantly change the intestinal microbiome composition of a cirrhotic patient. The study will consist of a 10-patient open-label pilot study to identify efficacious stool donors, defined as donors who precipitate the largest improvement in recipient neurological function and microbiome composition. The two most efficacious pilot study stool donors will be selected to donate stool for the randomized controlled trial (RCT). The 20-patient RCT will investigate the effect of FMT on neurological outcomes in patients with cirrhosis and a history of HE. Subjects will be randomized to receive 5 doses of oral FMT capsules or placebo capsules over 21 days. Cognitive testing and stool collections will occur at 4 time points, to assess for changes in neurological function and microbiome composition. The primary outcome is change in neurological function after FMT. The main secondary outcome is change in microbiome composition after FMT. This study could provide valuable information about the ability of FMT to improve intestinal dysbiosis in cirrhosis and treat HE.

Official Title
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Fecal Microbiota Transplant as Treatment of Hepatic Encephalopathy

Conditions
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Hepatic Encephalopathy

Intervention / Treatment
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* Drug: Fecal Microbiota Transplant (FMT) oral capsules
* Drug: Placebo oral capsule


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of cirrhosis: Based on liver biopsy or clinical assessment of a hepatologist based on history, exam, laboratory and radiographic evidence History of at least one episode of overt HE, defined by West Haven Criteria Grades II to IV; episodes of HE that were precipitated by gastrointestinal hemorrhage requiring transfusion of at least 2 units of blood, by medication use, by renal failure requiring dialysis, or by injury to the central nervous system will not be counted as previous HE episodes Compliant with lactulose and rifaximin treatment (lactulose: at least one dose at least 5 days per week; rifaximin: at least one dose at least 5 days per week) Exclusion Criteria: Current episode of overt HE as defined by West Haven Criteria Grades II to IV Expectation of liver transplantation within two months of the screening visit Current infection Variceal bleeding in the last 4 weeks Gut-absorbable or intravenous antibiotic therapy (including ciprofloxacin for SBP prophylaxis) in the last 3 months Alcohol or illicit drug intake within 3 months, by history and available serum testing; alcohol use will be characterized as >1 alcoholic drink / month PSC as etiology of liver disease, as prior literature has suggested these individuals have a unique microbiome History of Roux-en-Y Gastric bypass On immunosuppressive medications Positive C. difficile test Scoring above a threshold cut-off on the Psychometric Hepatic Encephalopathy Score (PHES) MELD > 17 History of spontaneous bacterial peritonitis History of low ascites protein ( ≤ 1g/dL) in the last year Hemodialysis in the last 30 days Other significant laboratory abnormalities: serum creatinine > 2.0 mg/dL, hemoglobin < 8 g/dL, serum sodium < 125 mmol/L, serum calcium > 11.0 mg/dL, serum potassium < 2.5 mmol/L Placement of a portosystemic shunt or transjugular intrahepatic portosystemic shunt Unstable doses of opiates, benzodiazepines or other sedating medication Unable to provide consent; a. If MMSE is < 18 or the patient is deemed to not have capacity by an investigator, a legally authorized representative (surrogate) will be allowed to provide consent

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is a two part study. The first part is a 10-patient pilot study, used to find 2 stool donors who precipitate the largest improvement in recipient neurological function and microbiome composition. The second part is a 20-patient RCT, where patients will be randomized to FMT or placebo.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Fecal Microbiota Transplant (FMT) oral capsules<br>Subjects will receive 15 oral capsules of FMT on days 1, 2, 7, 14, and 21. | Drug: Fecal Microbiota Transplant (FMT) oral capsules<br>* Donors will be healthy individuals, selected through a previously published, rigorous screening process. Elizabeth Hohmann M.D. of MGH has demonstrated the safety and therapeutic efficacy of oral frozen FMT capsules in Clostridium difficile infection, and her lab will produce the capsules for this study.<br>|
| Placebo Comparator: Placebo capsules<br>Subjects will receive placebo capsules on the same schedule as the experimental arm (days 1, 2, 7, 14, and 21). | Drug: Placebo oral capsule<br>* Oral placebo capsules filled with glycerol and cocoa powder. These capsules are identical in appearance to FMT capsules.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Psychometric Hepatic Encephalopathy Score (PHES) | The PHES is a validated assessment tool specifically designed for HE trials to test cognitive and psychomotor processing speed and visuomotor coordination. The PHES is a battery of 5 pencil-paper tests, completed in 15-20 minutes. The primary outcome is the change in PHES score from immediately before FMT to 1 week after the last dose of FMT. | Before the first administration of FMT (day 0) and one week after the last administration of FMT (day 28) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events | Adverse events will be graded based on CTCAE V.4.03. | Adverse event reporting will take place on day 2, 4, 7, 14, 21, then 1, 4 weeks after the last FMT administration. | 
| Stroop Test | The Stroop Test evaluates psychomotor speed and cognitive flexibility by the interference between recognition reaction time to a colored field and a written color name. A smartphone application software called EncephalApp Stroop Test will be used, validated to identify cognitive dysfunction in cirrhosis and screen for covert hepatic encephalopathy. | Before the first administration of FMT (day 0) and one week after the last administration of FMT (day 28) | 
| 36-Item Short Form Health Survey (SF-36) | The SF-36 is a highly utilized quality of life questionnaire. There are 8 health concepts assessed by the survey, which includes physical functioning, bodily pain, role limitations due to physical health problems, role limitations due to personal or emotional problems, emotional well-being, social functioning, energy/fatigue, and general health perceptions. Each of these health concepts is scored on a scale from 0 to 100. 0 is considered the worst outcome and 100 is considered the most favorable health state on each subscale. There will be no total or summed score. | Before the first administration of FMT (day 0) and one week after the last administration of FMT (day 28) | 
| Ammonia level | Ammonia is a serology with a known association with hepatic encephalopathy. | Before the first administration of FMT (day 0) and one week after the last administration of FMT (day 28) | 
| Microbiome engraftment | Sequence-based microbiome surveys will be carried out using metagenomic sequencing. Computational analyses will investigate donor microbiota colonization by comparing single-nucleotide variants in strain level data between the donor and recipient. | Before the first administration of FMT (day 0), after 3 FMT administrations (day 14), one week after the last administration of FMT (day 28) and 4 weeks after the last administration of FMT. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Microbiome, Fecal Microbiota Transplant