VE303 for Treatment of Hepatic Encephalopathy (HE)

Study Overview
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Brief Summary
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This research is studying the use of a new drug to learn about its safety and efficacy as a treatment for hepatic encephalopathy. Eligible participants will be enrolled and given oral antibiotics followed by 14 days of the study drug (placebo vs.VE303). There will be visits as well as other procedures to collect blood and stool samples, and have tests of your cognition (thinking) for this research study. The hypothesis is that VE303 will safely and effectively improve cognitive function in patients with a history of overt hepatic encephalopathy.

Official Title
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A Randomized Controlled Trial of VE303 to Treat Hepatic Encephalopathy

Conditions
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Cirrhosis, Hepatic Encephalopathy

Intervention / Treatment
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* Drug: Placebo
* Drug: VE303
* Drug: oral vancomycin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of cirrhosis based on liver biopsy, imaging, or evidence of clinical decompensation History of at least one episode of overt HE any time in the past Prescribed both lactulose and rifaximin, and compliant with this treatment Exclusion Criteria: Current episode of overt HE Variceal bleeding in the last 4 weeks Gut-absorbable or intravenous antibiotic therapy in the last 28 days Fecal microbiota transplant in the last 6 months Use of probiotics in the last 2 weeks Alcohol or illicit drug intake in the last 4 weeks Primary sclerosing cholangitis as etiology of liver disease History of inflammatory bowel disease, short gut, gastrointestinal tract fistulas, intestinal ischemia, or any form of ongoing colitis Prior diagnosis of dementia or other primary neurocognitive disorder Known hypersensitivity/allergy/intolerance to Vancomycin and any ingredients of VE303: sucrose, histidine, yeast extract, cysteine, metabisulfite, and microcrystalline cellulose History of Roux-en-Y Gastric bypass Any gastrointestinal surgery in the last year Substantial immune compromise/deficiency (e.g., uncontrolled human immunodeficiency virus, active immune suppressive therapy including high doses of corticosteroids or medications to prevent graft rejection, recent myeloablative therapy, sustained neutropenia) Pregnancy or breast feeding Model for end-stage liver disease (MELD) > 20 History of spontaneous bacterial peritonitis Hemodialysis in the last 28 days Placement of a portosystemic shunt or transjugular intrahepatic portosystemic shunt in the last 3 months (permissible if placed >3 months before enrollment) Unstable doses of opiates, benzodiazepines or other sedating medication Chronic methadone or low dose benzodiazepines (for example) is acceptable

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: Subjects will be randomized 2:1 to VE303 vs placebo. There will be no stratification. After the trial enrolls the first 9 patients, an interim analysis to evaluate safety of VE303 in this population will take place. If there is no concern for a higher rate of Serious adverse events (SAEs) in the VE303 group, enrollment will continue to reach a total of 18 patients.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Starting the last day of oral vancomycin (Day 1), subjects randomized to this arm will take 5 capsules of placebo for 14 days taken once daily.<br>Drug: oral vancomycin<br>* All enrolled subjects will receive 5 days of oral vancomycin 125 mg four times a day (q.i.d).<br>|
| Experimental: VE303<br>VE303 is a live biotherapeutic product comprising 8 nonpathogenic commensal strains of Clostridia. | Drug: VE303<br>* Starting the last day of oral vancomycin (Day 1), subjects randomized to this arm will take 5 capsules of VE303 taken daily for 14 days. The quantity of each strain is proportioned to assure a specific per-strain per-capsule titer. The 8 strains are blended together with a micro-crystalline cellulose flow agent and placed in enteric capsules.<br>Drug: oral vancomycin<br>* All enrolled subjects will receive 5 days of oral vancomycin 125 mg four times a day (q.i.d).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of serious adverse events up to week 6 |  | Week 6 | 
| Change in Psychometric Hepatic Encephalopathy Score (PHES) as a measure of cognitive function from pre-vancomycin to week 6 | This score is a battery of 5 paper-pencil tests that evaluate cognitive and psychomotor processing speed and visuomotor coordination. Scores on each subtest are assigned values based on age-related norms (1+ for scores better than 1 standard deviation (SD) above the normal mean to -3 for scores more than 3 SDs below the normal mean). Combined scores vary from +6 to -18. | baseline (pre-vancomycin), Week 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of hospitalizations for overt hepatic encephalopathy (OHE) up to week 26 |  | up to week 26 | 
| Adverse events up to week 26 |  | up to week 26 | 
| Change in Patient Reported Outcome Measurement Information System (PROMIS) Global Health reported from pre-vancomycin to week 26 | The PROMIS v 1.1 is a 10 question scale where participants select answers from (0) up to (10). Higher scores indicate better quality of life. | baseline (pre-vancomycin), week 26 | 
| Time to overt HE |  | up to 26 weeks | 
| Change in microbiome composition from pre-vancomycin to week 26 | This will be calculated by beta diversity between stool collection timepoints and will have metagenomic sequencing on stool to assess this. | baseline (pre-vancomycin), week 26 | 
| Change in serum and stool biomarkers from pre-vancomycin to week 26 |  | baseline (pre-vancomycin), week 26 | 
| PHES from pre-vancomycin to week 26 | This score is a battery of 5 paper-pencil tests that evaluate cognitive and psychomotor processing speed and visuomotor coordination. Scores on each subtest are assigned values based on age-related norms (1+ for scores better than 1 standard deviation (SD) above the normal mean to -3 for scores more than 3 SDs below the normal mean). Combined scores vary from +6 to -18. | pre-vancomycin up to week 26 |