- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04082780
Rifamycin in Minimal Hepatic Encephalopathy (RIVET)
A Double-Blind Randomized Placebo-Controlled Trial of Rifamycin SV MXX in Minimal Hepatic Encephalopathy (RIVET Trial)
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Hepatic encephalopathy (HE) is a highly prevalent neuro-cognitive complication of cirrhosis characterized by cognitive dysfunction, and high rate of subsequent mortality and recurrence. HE also places a tremendous burden with a relentless increase in inpatient stay duration with charges topping $7244.7 million in 20092. There were almost 23,000 hospitalizations for HE in 2009 and far more patients with HE who are being managed as an outpatient in the US. In the NACSELD (North American Consortium for the Study of End-Stage Liver Disease) experience, HE in inpatients is an independent risk factor for mortality and the leading cause of readmissions in patients with cirrhosis.
HE has two major phases, covert or minimal HE (MHE), which is only recognized by specialized tests and overt HE (OHE), which is clinically obvious. OHE forms the tip of the iceberg, while MHE affects as many as 60% of tested patients with cirrhosis.
MHE is associated with changes in specific cognitive domains that result in altered health-related quality of life and daily function. This can promote the development of OHE, impair driving and employment, increase falls and is independently associated with a risk of hospitalizations and mortality.
There is an alteration of gut microbial composition and function (bile acid changes, endotoxemia and gut metabolic products) in cirrhosis, which worsens with disease progression with MHE and OHE. Current treatments for OHE are mostly focused on the gut, including lactulose and rifaximin. However, despite extracting a major toll on disease progression, there is no current guideline to treat MHE. Prior studies using lactulose and rifaximin have been performed in this setting with improvement in brain function, brain MRI changes and microbial function. However, these are still not standard of care.
Rifamycin SV MMX® 200 mg is a gut-specific antibiotic with a long track record of safety that has been FDA approved for the treatment of traveler's diarrhea. Unlike rifaximin, rifamycin-SV MMX mostly affects the colon, where the bacterial load is much larger than in the other parts of the GI tract. The impact of rifamycin on MHE has not been studied to date. This is a randomized double-blind placebo-controlled trial of MHE in patients with cirrhosis.
Study Type
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Contact
- Name: Jasmohan Bajaj, MD
- Phone Number: 8046755802
- Email: jasmohan.bajaj@vcuhealth.org
Study Contact Backup
- Name: Edith Gavis
- Phone Number: 8046755584
- Email: edith.gavis@va.gov
Study Locations
-
-
Virginia
-
Richmond, Virginia, United States, 23249
- Hunter Holmes McGuire VA Medical Center
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
Inclusion Criteria:
- Age 18-75 years
Cirrhosis defined by any one of the following
- Cirrhosis on liver biopsy or transient elastography
- Nodular liver on imaging
- Endoscopic or radiological evidence of varices in a patient with chronic liver disease
- Platelet count <150,000/mm3 and AST/ALT ratio >1 in a patient with chronic liver disease
- Women of childbearing age will need to be on accepted birth control for 10 days prior to entering study and 30 days after the end of the last dose of the study drug.
- Cognitive impairment on PHES aggregate score [more than or greater than] -4SD or EncephalApp Stroop - based on norms published in Allampati et al located at the website www.encephalapp.com17 (This is the accepted diagnosis of minimal HE.)
- Willing and able to participate, provide samples and complete follow-up
- Stable Liver function tests between 2-12 weeks prior to enrollment (can include the screening laboratory values details in exclusion criteria)
Exclusion Criteria:
- Unclear diagnosis of cirrhosis (does not meet the criteria outlined above)
- Child score >8
- Increasing trend of ALT and AST in the 2-12 weeks prior to study inclusion (Baseline values established by at least two samples obtained at least 2 weeks and no more than 8-12 weeks apart) to account for disease related changes in liver enzymes and bilirubin while on study that may otherwise be inappropriately attributed to study drug. >20% increase in baseline serum AST, ALT, ALP and total bilirubin (TBL) will be considered an exclusion criterion.
- Unable to consent, follow for the study duration
- Normal performance on PHES
- Mini-mental status exam<2518
- Recent alcohol abuse (within 3 months)
- Recent illicit drug abuse (within 3 months) except marijuana
- Current use of psychoactive drugs apart from long-standing opioids or stable anti-depressant use.
- Prior overt HE episodes defined as West-Haven Criteria grade 2 or higher in the past that required hospitalization or initiation of lactulose or rifaximin therapy
- Currently on lactulose or rifaximin
- Current or recent invasive bacterial or fungal infections (<1 month)
- Allergic reactions to rifamycin, rifampin or rifaximin
- MELD >20
- TIPS placement
- Serum sodium<125
- On SBP prophylaxis
- Post-transplant cirrhosis
- Infections within 4 weeks
- End-stage organ failures: CHF with EF<25%, End-stage renal disease on dialysis, COPD on home oxygen
- Pregnancy (positive urine pregnancy test at screening)
- In the opinion of the PI, those who are unlikely to survive or remain without liver transplant for 6 weeks, or cannot adhere to the trial activities.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Quadruple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Rifamycin
Rifamycin-SV MMX 600 mg PO two times a day (1200 mg) for 30 days
|
Intervention arm
Other Names:
|
Placebo Comparator: Placebo
Placebo PO two times a day for 30 days
|
Placebo arm
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Cirrhosis Dysbiosis Ratio of stool microbiota
Time Frame: 30 days
|
Comparing this ratio in rifamycin compared to placebo groups (Lachnospiraceae + Ruminococcaceae + Clostridium Cluster XIV + Veillonellaceae / Enterobacteriaceae + Bacteroidaceae)
|
30 days
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Psychometric hepatic encephalopathy score (PHES) composite score ranges from -15 to +5
Time Frame: 30 days
|
Battery of 5 cognitive tests that yield a numeric composite score.
Investigators will compare this score in rifamycin compared to placebo groups.
Higher total score = better performance.
Norms are at www.encephalapp.com,
which are adjusted for age, gender and education status.
|
30 days
|
EncephalApp Stroop OffTime+OnTime is the total time taken to complete 5 runs in Off and 5 runs in On state.
Time Frame: 30 days
|
Cognitive test.
Investigators will compare this score in rifamycin compared to placebo groups.
High score = worse performance.
Norms are at www.encephalapp.com,
which are adjusted for age, gender and education status.
|
30 days
|
Sickness Impact Profile total score is the total score determined after all 12 domains are scored
Time Frame: 30 days
|
Validated questionnaire for health-related quality of life.
Investigators will compare this score in rifamycin compared to placebo groups.
There is no defined range but a higher score indicates worse QOL.
|
30 days
|
Sickness Impact Profile psychosocial score is the score of the psychosocial part of the SIP
Time Frame: 30 days
|
Validated questionnaire for health-related quality of life.
Investigators will compare this score in rifamycin compared to placebo groups.
There is no defined range but a higher score indicates worse QOL.
|
30 days
|
Sickness Impact Profile physical score is the score of the physical part of the SIP
Time Frame: 30 days
|
Validated questionnaire for health-related quality of life.
Investigators will compare this score in rifamycin compared to placebo groups.There is no defined range but a higher score indicates worse QOL.
|
30 days
|
Pittsburgh sleep quality index
Time Frame: 30 days
|
Validated questionnaire for sleep quality.
Investigators will compare this in rifamycin compared to placebo groups
|
30 days
|
Serious adverse events (Hospitalizations, death, prolongation of hospitalizations)
Time Frame: 30 days
|
Investigators will compare this in rifamycin compared to placebo groups
|
30 days
|
Serious adverse events (Hospitalizations, death, prolongation of hospitalizations)
Time Frame: 37 days
|
Investigators will compare this in rifamycin compared to placebo groups
|
37 days
|
Adverse events related to rifamycin
Time Frame: 30 days
|
Investigators will compare this in rifamycin compared to placebo groups
|
30 days
|
Adverse events related to rifamycin
Time Frame: 37 days
|
Investigators will compare this in rifamycin compared to placebo groups
|
37 days
|
Systemic exposure of rifamycin in the blood
Time Frame: Baseline
|
AUC of rifamycin levels in the 6 hourly blood collection time-points post rifamycin ingestion will be studied on day 1
|
Baseline
|
Systemic exposure of rifamycin in the blood
Time Frame: 15 days
|
Spot plasma level of rifamycin will be analyzed
|
15 days
|
Systemic exposure of rifamycin in the urine
Time Frame: Baseline
|
AUC of rifamycin levels in the 6 hours urine collection post rifamycin ingestion will be studied on day 1
|
Baseline
|
Systemic exposure of rifamycin in the urine
Time Frame: 15 days
|
Spot urine level of rifamycin will be analyzed
|
15 days
|
Calprotectin levels in stool
Time Frame: 30 days
|
Investigators will compare these in rifamycin compared to placebo groups
|
30 days
|
Fecal bile acid levels
Time Frame: 30 days
|
Using LC/MS.
Investigators will compare these in rifamycin compared to placebo groups
|
30 days
|
Microbiota diversity using Shannon index
Time Frame: 30 days
|
Stool microbiota diversity.
Investigators will compare these in rifamycin compared to placebo groups ranges widely from 0-20
|
30 days
|
Untargeted Metabolomics in serum using LC/MS
Time Frame: 30 days
|
Investigators will compare these in rifamycin compared to placebo groups
|
30 days
|
Untargeted Metabolomics in urine using LC/MS
Time Frame: 30 days
|
Investigators will compare these in rifamycin compared to placebo groups
|
30 days
|
Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Handgrip strength
Time Frame: 30 days
|
Jamar hand dynanometer; Investigators will compare these in rifamycin compared to placebo groups
|
30 days
|
Body Muscle composition
Time Frame: 30 days
|
InBody assessment; Investigators will compare these in rifamycin compared to placebo groups
|
30 days
|
Brain MR Spectroscopy in Anterior cingulate cortex, posterior gray matter, and right parietal white matter in a subset
Time Frame: 30 days
|
Investigators will compare these in rifamycin compared to placebo groups and measure choline, GSH, glutamate/glutamine and myoinositol
|
30 days
|
Collaborators and Investigators
Investigators
- Principal Investigator: JASMOHAN BAJAJ, Hunter Holmes McGuire Medical Center
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
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
- Anti-Infective Agents
- Antirheumatic Agents
- Anti-Bacterial Agents
- Rifamycins
- Rifamycin SV
Other Study ID Numbers
- BAJAJ0025
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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