Clinical trial NCT04155099: Investigational Microbiota Restoration Therapeutic for Hepatic Encephalopathy
Official title: Assessment of Cognitive Ability and the Intestinal Microbiome in Individuals With Liver Disease Before and After Investigational Microbiota Restoration Therapeutic
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Hepatic Encephalopathy
Cirrhosis, Liver
Keywords: encephalopathy
Lead sponsor: Ochsner Health System
Sponsor class: OTHER
Collaborators: name: Rebiotix Inc.
First posted: 2019-11-07
Enrollment: 5
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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.
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Change in cognitive function at 1 month post-FMT as measured by change in response times on EncephalApp (Stroop test)
timeFrame: 1 month
Secondary outcomes:
measure: Number of HE episodes
timeFrame: 1 month to 12 months
measure: Engraftment of FMT as assessed by change in type and abundance of gut microbiota following shotgun sequencing
timeFrame: 1 month to 12 months
measure: Change in cognitive function at 3, 6 and 12 months post-FMT as measured by change in response times on EncephalApp (Stroop test)
timeFrame: 3 to 12 months
Other outcomes:
measure: Correlations of clinical variables with primary and secondary outcomes
timeFrame: Duration of the study (0 days to 12 months)
Locations:
city: Jefferson
country: United States
facility: Ochsner Medical Center
state: Louisiana
Study officials:
affiliation: Ochsner Health System
name: Julia Garcia-Diaz, MD
role: PRINCIPAL_INVESTIGATOR
References: