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

Liver Cirrhosis Clinical Trial

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01951209
• Other study ID #: 01478
• Status: Terminated
• Phase: N/A
• Start date: November 17, 2016
• Est. completion date: June 12, 2017

Study information

• Verified date: March 2021
• Source: Corporal Michael J. Crescenz VA Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 13
• Est. completion date: June 12, 2017
• Est. primary completion date: November 17, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

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

Related Conditions & MeSH terms

• Chronic Hepatitis C
• Fibrosis
• Hepatitis
• Hepatitis A
• Hepatitis C
• Hepatitis C, Chronic
• Hepatitis, Chronic
• Liver Cirrhosis

Intervention

Drug:
• Rifaximin
550mg orally twice daily for 12 weeks
• Placebo
Matched placebo

Locations

Country	Name	City	State
United States	Philadelphia VA Medical Center	Philadelphia	Pennsylvania

Sponsors (2)

Lead Sponsor	Collaborator
David E. Kaplan, MD MSc	Bausch Health Americas, Inc.

Country where clinical trial is conducted

United States, 

References & Publications (1)

Doi H, Iyer TK, Carpenter E, Li H, Chang KM, Vonderheide RH, Kaplan DE. Dysfunctional B-cell activation in cirrhosis resulting from hepatitis C infection associated with disappearance of CD27-positive B-cell population. Hepatology. 2012 Mar;55(3):709-19. doi: 10.1002/hep.24689. Epub 2012 Jan 19. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Change in circulating markers of bacterial translocation	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	Week 0 to Week 12
Primary	Change in CD27+ B-cell frequency		Week 0 (Baseline) to Week 12
Secondary	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