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

Not Applicable

Terminated

• Conditions: Liver Cirrhosis; Chronic Hepatitis C
• Interventions: Drug: Rifaximin; Drug: Placebo

• Registration Number: NCT01951209
• Lead Sponsor: David E. Kaplan, MD MSc

Brief Summary

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

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.

Study Timeline

• Study First Submitted: 2013-09-20
• Study First Submitted QC: 2013-09-23
• Study First Posted: 2013-09-26
• Study Start: 2016-11-17
• Primary Completion: 2016-11-17
• Study Completion: 2017-06-12
• Status Verified: 2021-03
• Last Update Submitted: 2021-03-08
• Last Update Posted: 2021-03-11

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 13

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Rifaximin/Placebo	Placebo	Rifaximin 550mg po bid for 12 weeks followed by crossover to matched placebo po bid x 12 weeks
Placebo/Rifaximin SSD	Placebo	Matched placebo po bid for 12 weeks followed by crossover to Rifaximin 550mg po bid x 12 weeks
Rifaximin/Placebo	Rifaximin	Rifaximin 550mg po bid for 12 weeks followed by crossover to matched placebo po bid x 12 weeks
Placebo/Rifaximin SSD	Rifaximin	Matched placebo po bid for 12 weeks followed by crossover to Rifaximin 550mg po bid x 12 weeks

Primary Outcome Measures

Name	Time	Method
Change in CD27+ B-cell frequency	Week 0 (Baseline) to Week 12

Secondary Outcome Measures

Name	Time	Method
Change in basal B-cell activation	Week 0 to Week 12	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.

Trial Locations

Locations (1)

Philadelphia VA Medical Center; 🇺🇸 Philadelphia, Pennsylvania, United States