Rifamycin in Minimal Hepatic Encephalopathy

Study Overview
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Brief Summary
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This is a randomized double-blind placebo-controlled trial of MHE in patients with cirrhosis using rifamycin SV-MMX 600mg BID vs placebo for 30 days with PK, safety, microbiota, brain function and brain MRI endpoints.

Detailed Description
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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.

Official Title
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A Double-Blind Randomized Placebo-Controlled Trial of Rifamycin SV MXX in Minimal Hepatic Encephalopathy (RIVET Trial)

Conditions
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Hepatic Encephalopathy, Cirrhosis, Liver

Intervention / Treatment
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* Drug: Rifamycin SV MMX
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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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.

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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rifamycin<br>Rifamycin-SV MMX 600 mg PO two times a day (1200 mg) for 30 days | Drug: Rifamycin SV MMX<br>* Intervention arm<br>* Other names: Aemcolo;|
| Placebo Comparator: Placebo<br>Placebo PO two times a day for 30 days | Other: Placebo<br>* Placebo arm<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cirrhosis Dysbiosis Ratio of stool microbiota | 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 | 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. | 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 | 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 | 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 | 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 | 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) | Investigators will compare this in rifamycin compared to placebo groups | 30 days | 
| Serious adverse events (Hospitalizations, death, prolongation of hospitalizations) | Investigators will compare this in rifamycin compared to placebo groups | 37 days | 
| Adverse events related to rifamycin | Investigators will compare this in rifamycin compared to placebo groups | 30 days | 
| Adverse events related to rifamycin | Investigators will compare this in rifamycin compared to placebo groups | 37 days | 
| Systemic exposure of rifamycin in the blood | 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 | Spot plasma level of rifamycin will be analyzed | 15 days | 
| Systemic exposure of rifamycin in the urine | 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 | Spot urine level of rifamycin will be analyzed | 15 days | 
| Untargeted Metabolomics in serum using LC/MS | Investigators will compare these in rifamycin compared to placebo groups | 30 days | 
| Calprotectin levels in stool | Investigators will compare these in rifamycin compared to placebo groups | 30 days | 
| Untargeted Metabolomics in urine using LC/MS | Investigators will compare these in rifamycin compared to placebo groups | 30 days | 
| Fecal bile acid levels | Using LC/MS. Investigators will compare these in rifamycin compared to placebo groups | 30 days | 
| Microbiota diversity using Shannon index | Stool microbiota diversity. Investigators will compare these in rifamycin compared to placebo groups ranges widely from 0-20 | 30 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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brain MRI, cognitive testing, microbiota, metabolomics, pharmacokinetics