Pilot Study Of The Effect Of Rifaximin On B-Cell Dysregulation In Cirrhosis

Study Overview
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Brief Summary
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Hepatitis C is the leading cause of chronic liver disease and cirrhosis in United States veterans. Cirrhosis is associated with impaired antibody responses and increased risk of bacterial infections. We have recently identified that cirrhosis is associated with abnormalities of memory B-cells, cells that make antibodies and help protect against bacterial infections. We have identified that chemicals associated with gut bacteria might play a role in causing these B-cell abnormalities. It is well known that gut bacteria have increased access to the blood in individuals with cirrhosis, a process called bacterial translocation. We hypothesize that reducing bacteria counts in the gut by using poorly-absorbed antibiotics (also known as selective gut decontamination) will partially reverse losses of memory B-cells in cirrhosis by reducing bacterial translocation.

Detailed Description
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We intend to enroll 18 patients with cirrhosis who do not have hepatic encephalopathy to prospectively evaluate the impact of rifaximin on B-cell phenotype and function. We plan to employ a randomized, double-masked, prospective crossover design to minimize bias. Subjects will be randomized to receive either rifaximin SSD 80mg or a matched placebo once daily for 12 weeks then crossed over to opposite therapy for 12 weeks. Serum and lymphocytes will be collected at baseline and every 4 weeks for in vitro assessment markers of gut microbial translocation and B-cell assays. Stool will be collected at baseline and every 12 weeks for future evaluation of changes of the gut microbiome.

Official Title
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Prospective Pilot Study of the Effect of Rifaximin on B-Cell Dysregulation in Cirrhosis Due to Chronic Hepatitis C Infection

Conditions
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Liver Cirrhosis, Chronic Hepatitis C

Intervention / Treatment
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* Drug: Rifaximin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Current or prior chronic Hepatitis C infection as documented by detectable HCV RNA in prior 5 years Child-Turcotte-Pugh stage A5-B8. Cirrhosis diagnosis may be based on either histological criteria (an previous liver biopsy showing F4/4 or F5-6/6 fibrosis) or clinical criteria (nodular liver on abdominal imaging, splenomegaly, thrombocytopenia, spider telangiectasias, palmar erythema, ascites, varices). Platelet count < 175,000/ul Subject capable of giving informed consent Exclusion Criteria: Active alcohol use > 20g/d Current or planned (within following 6 months) antiviral therapy for hepatitis C HIV co-infection Diagnosis of overt hepatic encephalopathy Current lactulose use Exposure to rifaximin, rifampin or rifabutin within 12 months History of C. difficile colitis History of adverse drug reaction or sensitivity to rifaximin, rifampin or rifabutin or any inactive components of rifaximin Pregnancy Anemia with hemoglobin < 10g/dl or hematocrit < 30% Chronic kidney disease with creatinine > 2.1mg/dl Total bilirubin > 3.0g/dl Active non-hepatic medical conditions such as congestive heart failure, chronic lung disease requiring oxygen, coronary artery disease with unstable angina Requirement for chronic immunosuppressive therapy such as corticosteroids, cyclophosphamide, azathioprine, TNF-alpha antagonists Chronic autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis Post-liver transplantation status or anticipated liver transplantation within 6 months. Systemic antimicrobial exposure within 30 days of planned Visit 1

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rifaximin/Placebo<br>Rifaximin 550mg po bid for 12 weeks followed by crossover to matched placebo po bid x 12 weeks | Drug: Rifaximin<br>* 550mg orally twice daily for 12 weeks<br>* Other names: Rifaximin (Xifaxan);Drug: Placebo<br>* Matched placebo<br>|
| Experimental: Placebo/Rifaximin SSD<br>Matched placebo po bid for 12 weeks followed by crossover to Rifaximin 550mg po bid x 12 weeks | Drug: Rifaximin<br>* 550mg orally twice daily for 12 weeks<br>* Other names: Rifaximin (Xifaxan);Drug: Placebo<br>* Matched placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in CD27+ B-cell frequency |  | Week 0 (Baseline) to Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in basal B-cell activation | 5 x 104/well B-cells negatively selected from normal donor PBMC will be cultured in 50% RPMI 1640/50% cirrhotic patient serum for 48 hours. After 48 hours, B-cells will be assessed for activation markers such as HLA-DR geometric mean fluorescence intensity. | Week 0 to Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Human, Hepatitis C, Cirrhosis, B-cell, Rifaximin