Investigational Microbiota Restoration Therapeutic for Hepatic Encephalopathy

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

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.

Study Overview

• Status: Terminated
• Conditions: Hepatic Encephalopathy; Cirrhosis, Liver
• Intervention / Treatment: Biological: RBX7455; Biological: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 5
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Julia Garcia-Diaz, MD; Phone Number: 504-842-7617; Email: IDResearch@ochsner.org
• Study Contact Backup: Name: Amy Feehan, PhD; Email: IDResearch@ochsner.org

Study Locations

• United States
  • Louisiana
    • Jefferson, Louisiana, United States, 70121
      • Ochsner Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria

1. Individuals who are male or female and are between the ages of 18 and 70 years.

2. 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:

   1. Radiologic evidence of varices, cirrhosis or portal hypertension
   2. Laboratory evidence of platelet count <100,000 or AST/ALT ratio >1
   3. Endoscopic evidence of varices or portal gastropathy
   4. Elastography (i.e. Fibroscan)
3. Individuals must have at least one previously documented episode of HE.
4. Individuals must be able to read and write in the English language.
5. 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.
6. Individuals must be able to provide valid informed consent prior to any study related procedures.

Exclusion Criteria

1. Individuals who are color-blind.
2. Individuals actively using psychotropic substances including alcohol.
3. 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.
4. Presence of TIPS (transjugular intrahepatic portosystemic shunt).
5. Individuals with an active bacterial infection and are taking antibiotics for those infections at time of consent.
6. Individuals with ANC <800 (neutropenia).
7. Individuals with MELD >17.
8. Individuals with platelet count <35,000/mm3.

9. Individuals who are immunocompromised due any of the following reasons:

   1. HIV infection (CD4 count <200/mm3) or AIDS diagnosis
   2. Inherited/primary immunodeficiency disorders
   3. Treatment with any anti-neoplastic agent within the last 3 months (excluding locoregional therapy for hepatocellular carcinoma)
   4. 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
10. Individuals who have previously undergone FMT.
11. Individuals with a history of colorectal cancer (all stages).
12. 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.
13. Individuals with a history of colectomy, major gastro-intestinal surgery, or intra-abdominal surgery.
14. Individuals with a history of Clostridium difficile infection six months prior to study enrollment.
15. Individuals with a history of chronic diarrhea.
16. Individuals currently participating in a research trial that involves drug or device intervention.
17. Individuals who are unable to fulfill all study criteria.
18. Individuals that the PI determines are not capable of participating in the research study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: High dose; 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; 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.; Other Names: Microbiota Restoration Therapy
Experimental: Low dose; 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; 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.; Other Names: Microbiota Restoration Therapy
Placebo Comparator: pill quantity-matched Placebo; 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; Capsule with cellulose filler

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Correlations of clinical variables with primary and secondary outcomes	Other clinical outcome variables available from individuals' electronic medical records include age, liver-related diagnoses and disease progression, antibiotic usage history, number of previous hospitalizations, and mortality. This clinical data will be analyzed for significant correlations with the primary and secondary outcome variables.	Duration of the study (0 days to 12 months)

Collaborators and Investigators

• Sponsor: Ochsner Health System
• Collaborators: Rebiotix Inc.
• Investigators: Principal Investigator: Julia Garcia-Diaz, MD, Ochsner Health System

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2021
• Primary Completion (Actual): July 30, 2023
• Study Completion (Actual): July 30, 2023

Study Registration Dates

• First Submitted: August 21, 2019
• First Submitted That Met QC Criteria: November 4, 2019
• First Posted (Actual): November 7, 2019

Study Record Updates

• Last Update Posted (Actual): October 3, 2023
• Last Update Submitted That Met QC Criteria: September 29, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: encephalopathy
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Failure; Hepatic Insufficiency; Pathologic Processes; Metabolic Diseases; Central Nervous System Diseases; Nervous System Diseases; Liver Diseases; Fibrosis; Brain Diseases, Metabolic; Liver Cirrhosis; Hepatic Encephalopathy; Brain Diseases
• Other Study ID Numbers: 2019.193

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No