Cirrhosis, Hepatic Encephalopathy
Conditions
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.
Interventions
DRUGPlacebo
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.
DRUGVE303
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.
DRUGoral vancomycin
All enrolled subjects will receive 5 days of oral vancomycin 125 mg four times a day (q.i.d).
Sponsors
Vedanta Biosciences, Inc.
American College of Gastroenterology
American Association for the Study of Liver Diseases
Patricia Bloom
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
Study staff will remain blinded to subject randomization until the study period is over.
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Psychometric Hepatic Encephalopathy Score (PHES) as a Measure of Cognitive Function From Pre-vancomycin to Week 6 | 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. |
| Number of Participants Who Experienced Serious Adverse Events up to Week 6 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Adverse Events up to Week 26 | up to week 26 | total number of AEs |
| Change in Patient Reported Outcome Measurement Information System (PROMIS) Global Health Reported From Pre-vancomycin to Week 26 | 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. Results are presented as change in scores pertaining to physical and mental health. |
| Change in Microbiome Composition From Pre-vancomycin to Week 26 | baseline (pre-vancomycin), week 26 | This will be calculated by alpha diversity between stool collection timepoints and will have metagenomic sequencing on stool to assess this. The Shannon index is a calculation used to measure the diversity of microbial species within a sample, taking into account both the number of different species present (richness) and how evenly distributed their abundances are (evenness). A higher Shannon index indicates a more diverse microbial community, meaning a wider variety of microbes present in roughly equal proportions. The Shannon index was calculated for each sample as part of metagenomic sequencing analysis performed with the tool MetaPhlAn (version 3.0). The minimum Shannon index value is 0 and it could theoretically go to infinity; however, typical values range more in the 1-4 range. Now, this outcome is measuring the CHANGE in Shannon index, therefore negative values are possible, if the diversity of specimens dropped from the pre-vancomycin to the week 26 samples. |
| PHES From Pre-vancomycin to Week 26 | 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. |
| Time to Overt HE | up to 26 weeks | This is the number of days from Day 1 of Vancomycin to the first OHE event or to the end of study, whichever came first. |
| Number of Hospitalizations for Overt Hepatic Encephalopathy (OHE) up to Week 26 | 26 weeks | Shown as a rate (# of episodes/ number of patients) = # per patient. |
Other
| Measure | Time frame |
|---|---|
| Change in Serum and Stool Biomarkers From Pre-vancomycin to Week 26 | baseline (pre-vancomycin), week 26 |
Countries
United States
Participant flow
Pre-assignment details
One patient was consented but then failed to meet eligibility criteria soon after enrollment. They did not initiate vancomycin and were not randomized.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo: Starting the last day of oral vancomycin (Day 1), participants randomized to this arm will take 5 capsules of placebo for 14 days taken once daily.
Oral vancomycin: All enrolled participants will receive 5 days of oral vancomycin 125 mg four times a day (q.i.d). | 6 |
| VE303 VE303 is a live biotherapeutic product comprising 8 nonpathogenic commensal strains of Clostridia.
VE303: Starting the last day of oral vancomycin (Day 1), participants 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.
Oral vancomycin: All enrolled participants will receive 5 days of oral vancomycin 125 mg four times a day (q.i.d). | 12 |
| Total | 18 |
Baseline characteristics
| Characteristic | Placebo | VE303 | Total |
|---|---|---|---|
| Age, Continuous | 63 years STANDARD_DEVIATION 7 | 58 years STANDARD_DEVIATION 10 | 60 years STANDARD_DEVIATION 9 |
| Baseline Psychometric HE Score (PHES) | -5.0 units on a scale STANDARD_DEVIATION 3.7 | -6.3 units on a scale STANDARD_DEVIATION 3.4 | -5.8 units on a scale STANDARD_DEVIATION 3.5 |
| Race/Ethnicity, Customized Black or African American | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 4 Participants | 10 Participants | 14 Participants |
| Region of Enrollment United States | 6 Participants | 12 Participants | 18 Participants |
| Sex: Female, Male Female | 2 Participants | 6 Participants | 8 Participants |
| Sex: Female, Male Male | 4 Participants | 6 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 12 |
| other Total, other adverse events | 6 / 6 | 12 / 12 |
| serious Total, serious adverse events | 1 / 6 | 5 / 12 |
Outcome results
Primary
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, where +6 is the best function and -18 is worst function.
Time frame: baseline (pre-vancomycin), Week 6
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| VE303 | Change in Psychometric Hepatic Encephalopathy Score (PHES) as a Measure of Cognitive Function From Pre-vancomycin to Week 6 | -1.0 units on a scale | Standard Deviation 3.7 |
| Placebo | Change in Psychometric Hepatic Encephalopathy Score (PHES) as a Measure of Cognitive Function From Pre-vancomycin to Week 6 | 1.5 units on a scale | Standard Deviation 3.5 |
Primary
Number of Participants Who Experienced Serious Adverse Events up to 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.
Time frame: Week 6
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| VE303 | Number of Participants Who Experienced Serious Adverse Events up to Week 6 | 2 Participants |
| Placebo | Number of Participants Who Experienced Serious Adverse Events up to Week 6 | 0 Participants |
Secondary
Adverse Events up to Week 26
total number of AEs
Time frame: up to week 26
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| VE303 | Adverse Events up to Week 26 | 38 adverse events |
| Placebo | Adverse Events up to Week 26 | 135 adverse events |
Secondary
Change in Microbiome Composition From Pre-vancomycin to Week 26
This will be calculated by alpha diversity between stool collection timepoints and will have metagenomic sequencing on stool to assess this. The Shannon index is a calculation used to measure the diversity of microbial species within a sample, taking into account both the number of different species present (richness) and how evenly distributed their abundances are (evenness). A higher Shannon index indicates a more diverse microbial community, meaning a wider variety of microbes present in roughly equal proportions. The Shannon index was calculated for each sample as part of metagenomic sequencing analysis performed with the tool MetaPhlAn (version 3.0). The minimum Shannon index value is 0 and it could theoretically go to infinity; however, typical values range more in the 1-4 range. Now, this outcome is measuring the CHANGE in Shannon index, therefore negative values are possible, if the diversity of specimens dropped from the pre-vancomycin to the week 26 samples.
Time frame: baseline (pre-vancomycin), week 26
Population: Participants analyzed reflect participants from whom week 26 stool samples could be obtained. Not every participant was able to provide a stool sample at week 26, and therefore this outcome was missing for those patients.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| VE303 | Change in Microbiome Composition From Pre-vancomycin to Week 26 | 0.37 Shannon index | Standard Deviation 0.72 |
| Placebo | Change in Microbiome Composition From Pre-vancomycin to Week 26 | -0.15 Shannon index | Standard Deviation 0.06 |
p-value: 0.13t-test, 2 sided
Secondary
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. Results are presented as change in scores pertaining to physical and mental health.
Time frame: baseline (pre-vancomycin), week 26
Population: Data is missing from two VE303 participants because they did not provide it.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| VE303 | Change in Patient Reported Outcome Measurement Information System (PROMIS) Global Health Reported From Pre-vancomycin to Week 26 | Change in PROMIS Physical Health Scores | 1.8 score on a scale | Standard Deviation 1.8 |
| VE303 | Change in Patient Reported Outcome Measurement Information System (PROMIS) Global Health Reported From Pre-vancomycin to Week 26 | Change in PROMIS Mental Health Scores | 1.2 score on a scale | Standard Deviation 2.1 |
| Placebo | Change in Patient Reported Outcome Measurement Information System (PROMIS) Global Health Reported From Pre-vancomycin to Week 26 | Change in PROMIS Physical Health Scores | 0.4 score on a scale | Standard Deviation 1.9 |
| Placebo | Change in Patient Reported Outcome Measurement Information System (PROMIS) Global Health Reported From Pre-vancomycin to Week 26 | Change in PROMIS Mental Health Scores | 0 score on a scale | Standard Deviation 2.4 |
Secondary
Number of Hospitalizations for Overt Hepatic Encephalopathy (OHE) up to Week 26
Shown as a rate (# of episodes/ number of patients) = # per patient.
Time frame: 26 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| VE303 | Number of Hospitalizations for Overt Hepatic Encephalopathy (OHE) up to Week 26 | .333 episodes/patient |
| Placebo | Number of Hospitalizations for Overt Hepatic Encephalopathy (OHE) up to Week 26 | 1.25 episodes/patient |
Secondary
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.
Time frame: pre-vancomycin up to week 26
Population: Note: Significant data loss due to some participants not participating in this test at 26 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| VE303 | PHES From Pre-vancomycin to Week 26 | -1 score on a scale |
| Placebo | PHES From Pre-vancomycin to Week 26 | 1 score on a scale |
p-value: 0.48Wilcoxon (Mann-Whitney)
Secondary
Time to Overt HE
This is the number of days from Day 1 of Vancomycin to the first OHE event or to the end of study, whichever came first.
Time frame: up to 26 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| VE303 | Time to Overt HE | 180 days |
| Placebo | Time to Overt HE | 147 days |
Other Pre-specified
Change in Serum and Stool Biomarkers From Pre-vancomycin to Week 26
Time frame: baseline (pre-vancomycin), week 26