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

Sponsor

David E. Kaplan, MD MSc (U.S. Fed)

Overall Status

Terminated

CT.gov ID

NCT01951209

Collaborator

Bausch Health Americas, Inc. (Industry)

Enrollment

Location

Arms

6.8

Actual Duration (Months)

1.9

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Liver Cirrhosis Chronic Hepatitis C	Drug: Rifaximin Drug: Placebo	N/A

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 Design

Study Type:

Interventional

Actual Enrollment :

13 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Basic Science

Official Title:

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

Actual Study Start Date :

Nov 17, 2016

Actual Primary Completion Date :

Nov 17, 2016

Actual Study Completion Date :

Jun 12, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Rifaximin/Placebo Rifaximin 550mg po bid for 12 weeks followed by crossover to matched placebo po bid x 12 weeks	Drug: Rifaximin 550mg orally twice daily for 12 weeks Other Names: Rifaximin (Xifaxan) Drug: Placebo Matched placebo
Experimental: Placebo/Rifaximin SSD Matched placebo po bid for 12 weeks followed by crossover to Rifaximin 550mg po bid x 12 weeks	Drug: Rifaximin 550mg orally twice daily for 12 weeks Other Names: Rifaximin (Xifaxan) Drug: Placebo Matched placebo

Arm

Intervention/Treatment

Experimental: Rifaximin/Placebo

Rifaximin 550mg po bid for 12 weeks followed by crossover to matched placebo po bid x 12 weeks

Drug: Rifaximin

550mg orally twice daily for 12 weeks

Other Names:

Rifaximin (Xifaxan)

Drug: Placebo

Matched placebo

Experimental: Placebo/Rifaximin SSD

Matched placebo po bid for 12 weeks followed by crossover to Rifaximin 550mg po bid x 12 weeks

Drug: Rifaximin

550mg orally twice daily for 12 weeks

Other Names:

Rifaximin (Xifaxan)

Drug: Placebo

Matched placebo

Outcome Measures

Primary Outcome Measures

Change in CD27+ B-cell frequency [Week 0 (Baseline) to Week 12]

Secondary Outcome Measures

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.

Other Outcome Measures

Change in circulating markers of bacterial translocation [Week 0 to Week 12]
Plasma samples will be studied for sCD14 by ELISA, bacterial DNA by rtPCR of 16S ribosomal RNA using established techniques, and Limulus Amebocyte Lysate Assay

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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