Investigational Microbiota Restoration Therapeutic for Hepatic Encephalopathy

Study Overview
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Brief Summary
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Individuals with cirrhosis are likely to develop overt hepatic encephalopathy for which diagnostic modalities and treatment options are limited. The purpose of this study is to determine if individuals with cirrhosis who experience hepatic encephalopathy would benefit from investigational microbiota restoration therapy due to their inherent cognitive alterations. Analysis for a correlation between changes in microbiome composition and specific blood biomarkers could allow for earlier diagnosis of HE which could then be treated earlier and with novel treatments.

Detailed Description
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The investigators hypothesize that changes in an individual's cognition due to HE-related liver cirrhosis can be stabilized and/or improved through investigational microbiota restoration therapeutic treatment. The main objective of this study is to determine if investigational microbiota restoration therapeutic treatment alters the cognitive function in individuals with cirrhosis who have been previously diagnosed with overt hepatic encephalopathy (HE). Once individuals have one HE episode, they are more likely to experience additional episodes, even after complying with standard of care. The number of HE episodes each study group experiences during the post-treatment follow-up will be compared among treatment groups. It is also anticipated that cognitive improvement will correlate with specific changes in the intestinal microbiota composition of these individuals likely shifting their microbiome away from baseline samples and becoming more like donor samples. Novel blood biomarkers potentially related to episodes of HE will be assessed in individuals before and after treatment.

Official Title
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Assessment of Cognitive Ability and the Intestinal Microbiome in Individuals With Liver Disease Before and After Investigational Microbiota Restoration Therapeutic

Conditions
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Hepatic Encephalopathy, Cirrhosis, Liver

Intervention / Treatment
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* Biological: RBX7455
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Individuals who are male or female and are between the ages of 18 and 70 years. Individuals with a current diagnosis of liver cirrhosis as evidenced by one or more of the following: a. Liver Biopsy OR a clinical suspicion of cirrhosis based on the presence of one or more of the following criteria: 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 Elastography (i.e. Fibroscan) Individuals must have at least one previously documented episode of HE. Individuals must be able to read and write in the English language. Individuals must be able and willing to utilize the electronic device necessary to measure cognitive function without assistance from outside individuals once the training phase has been completed. Individuals must be able to provide valid informed consent prior to any study related procedures. Exclusion Criteria Individuals who are color-blind. Individuals actively using psychotropic substances including alcohol. Individuals who are pregnant, breastfeeding, or unwilling to practice birth control during participation in the study. Study individuals are expected to attest to this fact during their participation time. Females who are not surgically sterile or having undergone greater than one year of menopause will receive urine pregnancy tests at screening and initial drug dosing. Presence of TIPS (transjugular intrahepatic portosystemic shunt). Individuals with an active bacterial infection and are taking antibiotics for those infections at time of consent. Individuals with ANC <800 (neutropenia). Individuals with MELD >17. Individuals with platelet count <35,000/mm3. Individuals who are immunocompromised due any of the following reasons: HIV infection (CD4 count <200/mm3) or AIDS diagnosis Inherited/primary immunodeficiency disorders Treatment with any anti-neoplastic agent within the last 3 months (excluding locoregional therapy for hepatocellular carcinoma) Treatment with any immunosuppressant medications [including but not limited to monoclonal antibodies to B cells or T cells, anti-TNF agents, glucocorticoids, antimetabolites (azathioprine, 6-mercaptopurine), calcineurin inhibitors (tacrolimus, cyclosporine), mycophenolate mofetil] within the last 3 months Individuals who have previously undergone FMT. Individuals with a history of colorectal cancer (all stages). Individuals with a history of chronic intrinsic GI diseases such as inflammatory bowel disease (ulcerative colitis, Crohn's disease or microscopic colitis), eosinophilic gastroenteritis, celiac disease or irritable bowel syndrome as determined by Rome III criteria. Individuals with a history of colectomy, major gastro-intestinal surgery, or intra-abdominal surgery. Individuals with a history of Clostridium difficile infection six months prior to study enrollment. Individuals with a history of chronic diarrhea. Individuals currently participating in a research trial that involves drug or device intervention. Individuals who are unable to fulfill all study criteria. Individuals that the PI determines are not capable of participating in the research study.

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: Study individuals will be placed into one of four study treatment groups: High dose investigational microbiota restoration therapeutic RBX7455 group, Low dose investigational microbiota restoration therapeutic RBX7455 group, or a pill quantity-matched Placebo group. Individuals will be randomized in a 1:1:1/2:1/2 manner. It is anticipated of the 75 potentially enrolled individuals, 50 will receive active treatment (high or low dose investigational microbiota restoration therapeutic) and 25 will receive placebo.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: High dose<br>Capsules of active drug will be supplied in 8-capsule blister packets to be taken twice per week for four weeks. Blood and stool samples and cognitive assessments will be collected before treatment and at 1, 3, 6, and 12 months after treatment. | Biological: RBX7455<br>* RBX7455 is a preparation of live intestinal microorganisms (active drug) purified from stool donations obtained from healthy, screened donors, mixed with preservative, lyophilized, and put into capsules. The capsules are taken orally (i.e., by mouth). After ingestion, these freeze-dried microorganisms can reconstitute and proliferate in the gut.<br>* Other names: Microbiota Restoration Therapy;|
| Experimental: Low dose<br>Capsules of active drug will be supplied in 4-capsule blister packets to be taken twice per week for four weeks. Blood and stool samples and cognitive assessments will be collected before treatment and at 1, 3, 6, and 12 months after treatment. | Biological: RBX7455<br>* RBX7455 is a preparation of live intestinal microorganisms (active drug) purified from stool donations obtained from healthy, screened donors, mixed with preservative, lyophilized, and put into capsules. The capsules are taken orally (i.e., by mouth). After ingestion, these freeze-dried microorganisms can reconstitute and proliferate in the gut.<br>* Other names: Microbiota Restoration Therapy;|
| Placebo Comparator: pill quantity-matched Placebo<br>Capsules of inactive compound will be supplied in 8- or 4-capsule blister packets to be taken twice per week for four weeks. Blood and stool samples and cognitive assessments will be collected before treatment and at 1, 3, 6, and 12 months after treatment. | Biological: Placebo<br>* Capsule with cellulose filler<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in cognitive function at 1 month post-FMT as measured by change in response times on EncephalApp (Stroop test) | Determine whether microbiota restoration therapy improves cognition 1 month after treatment by measuring differences in time scores from EncephalApp. The app times participants in seconds (s) in variations of the Stroop Test. The average (s) across all trials will be reported as well as the difference in (s) between (trial 1)-(trial 5). Longer completion times indicate greater cognitive impairment, while a decrease in completion time from trial 1 to trial 5 indicates learning (cognitive improvement). The scale for this measure is theoretically 0s-500s. | 1 month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of HE episodes | Once individuals have one HE episode, they are more likely to experience additional ones, even after complying with standard of care. The number of HE episodes each study group experiences during the post-treatment follow-up will be compared among treatment groups. | 1 month to 12 months | 
| Engraftment of FMT as assessed by change in type and abundance of gut microbiota following shotgun sequencing | It is anticipated that with treatment, changes in the intestinal microbiota composition of these individuals will likely shift their microbiome to contain different species. Microbiome analyses will measure, at the family and genus level, which bacteria are present and their relative abundance. Samples from the same individual at different time points will be compared as well as differences between treatment groups at each time point. | 1 month to 12 months | 
| Change in cognitive function at 3, 6 and 12 months post-FMT as measured by change in response times on EncephalApp (Stroop test) | Determine whether microbiota restoration therapy improves cognition 3, 6, and 12 months after treatment by measuring differences in time scores from EncephalApp. The app times participants in seconds (s) in variations of the Stroop Test. The average (s) across all trials will be reported as well as the difference in (s) between (trial 1)-(trial 5). Longer completion times indicate greater cognitive impairment, while a decrease in completion time from trial 1 to trial 5 indicates learning (cognitive improvement). | 3 to 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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encephalopathy