VE303 for Treatment of Hepatic Encephalopathy (HE)

• ClinicalTrials.gov Identifier: NCT04899115
• Recruitment Status: Completed
• First Posted: May 24, 2021
• Results First Posted: May 7, 2024
• Last Update Posted: May 7, 2024
• Sponsor: Patricia Bloom
• Collaborators: Vedanta Biosciences, Inc.; American College of Gastroenterology; American Association for the Study of Liver Diseases
• Information provided by (Responsible Party): Patricia Bloom, University of Michigan

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Cirrhosis; Hepatic Encephalopathy	Drug: Placebo; Drug: VE303; Drug: oral vancomycin	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 19 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment

Intervention 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 (Participant, Investigator)
• Masking Description: Study staff will remain blinded to subject randomization until the study period is over.
• Primary Purpose: Treatment
• Official Title: A Randomized Controlled Trial of VE303 to Treat Hepatic Encephalopathy
• Actual Study Start Date: August 6, 2021
• Actual Primary Completion Date: April 10, 2023
• Actual Study Completion Date: August 30, 2023

Arms and Interventions

Arm	Intervention/treatment
Placebo Comparator: Placebo	Drug: Placebo; 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.; Drug: oral vancomycin; All enrolled subjects will receive 5 days of oral vancomycin 125 mg four times a day (q.i.d).
Experimental: VE303; VE303 is a live biotherapeutic product comprising 8 nonpathogenic commensal strains of Clostridia.	Drug: VE303; 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.; Drug: oral vancomycin; All enrolled subjects will receive 5 days of oral vancomycin 125 mg four times a day (q.i.d).

Outcome Measures

Primary Outcome Measures :

1. Number of Participants Who Experienced Serious Adverse Events up to Week 6 [ Time Frame: Week 6 ]
   An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view of the investigator, it results in any of the following outcomes: death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect.
2. Change in Psychometric Hepatic Encephalopathy Score (PHES) as a Measure of Cognitive Function From Pre-vancomycin to Week 6 [ Time Frame: baseline (pre-vancomycin), 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, where +6 is the best function and -18 is worst function.

Secondary Outcome Measures :

1. Number of Hospitalizations for Overt Hepatic Encephalopathy (OHE) up to Week 26 [ Time Frame: up to week 26 ]
2. Adverse Events up to Week 26 [ Time Frame: up to week 26 ]
3. Change in Patient Reported Outcome Measurement Information System (PROMIS) Global Health Reported From Pre-vancomycin to Week 26 [ Time Frame: baseline (pre-vancomycin), 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.
4. Time to Overt HE [ Time Frame: up to 26 weeks ]
5. Change in Microbiome Composition From Pre-vancomycin to Week 26 [ Time Frame: baseline (pre-vancomycin), week 26 ]
   This will be calculated by beta diversity between stool collection timepoints and will have metagenomic sequencing on stool to assess this.
6. Change in Serum and Stool Biomarkers From Pre-vancomycin to Week 26 [ Time Frame: baseline (pre-vancomycin), week 26 ]
7. PHES From Pre-vancomycin to Week 26 [ Time Frame: pre-vancomycin up 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.

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

United States, Michigan

University of Michigan

Ann Arbor, Michigan, United States, 48109

Sponsors and Collaborators

Patricia Bloom

Vedanta Biosciences, Inc.

American College of Gastroenterology

American Association for the Study of Liver Diseases

Investigators

• Principal Investigator: Patricia Bloom, MD; University of Michigan

  Study Documents (Full-Text)

Documents provided by Patricia Bloom, University of Michigan:

Study Protocol and Statistical Analysis Plan  [PDF] February 16, 2023

More Information

• Responsible Party: Patricia Bloom, Clinical Lecturer in Internal Medicine, University of Michigan
• ClinicalTrials.gov Identifier: NCT04899115
• Other Study ID Numbers: HUM00194437
• First Posted: May 24, 2021
• Results First Posted: May 7, 2024
• Last Update Posted: May 7, 2024
• Last Verified: April 2024

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Hepatic Encephalopathy; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Liver Failure; Hepatic Insufficiency; Liver Diseases; Digestive System Diseases; Brain Diseases, Metabolic; Metabolic Diseases; Vancomycin; Anti-Bacterial Agents; Anti-Infective Agents