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

Primary Purpose

Liver Cirrhosis, Chronic Hepatitis C

Status
Terminated
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
Rifaximin
Placebo
Sponsored by
David E. Kaplan, MD MSc
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Liver Cirrhosis focused on measuring Human, Hepatitis C, Cirrhosis, B-cell, Rifaximin

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept 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

Sites / Locations

  • Philadelphia VA Medical Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Rifaximin/Placebo

Placebo/Rifaximin SSD

Arm Description

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

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

Outcomes

Primary Outcome Measures

Change in CD27+ B-cell frequency

Secondary Outcome Measures

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.

Full Information

First Posted
September 20, 2013
Last Updated
March 8, 2021
Sponsor
David E. Kaplan, MD MSc
Collaborators
Bausch Health Americas, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT01951209
Brief Title
Pilot Study Of The Effect Of Rifaximin On B-Cell Dysregulation In Cirrhosis
Official Title
Prospective Pilot Study of the Effect of Rifaximin on B-Cell Dysregulation in Cirrhosis Due to Chronic Hepatitis C Infection
Study Type
Interventional

2. Study Status

Record Verification Date
March 2021
Overall Recruitment Status
Terminated
Why Stopped
Inadequate enrollment prior to expiration date of unreplaceable blinded investigational product
Study Start Date
November 17, 2016 (Actual)
Primary Completion Date
November 17, 2016 (Actual)
Study Completion Date
June 12, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
David E. Kaplan, MD MSc
Collaborators
Bausch Health Americas, Inc.

4. Oversight

Data Monitoring Committee
No

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Liver Cirrhosis, Chronic Hepatitis C
Keywords
Human, Hepatitis C, Cirrhosis, B-cell, Rifaximin

7. Study Design

Primary Purpose
Basic Science
Study Phase
Not Applicable
Interventional Study Model
Crossover Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
13 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Rifaximin/Placebo
Arm Type
Experimental
Arm Description
Rifaximin 550mg po bid for 12 weeks followed by crossover to matched placebo po bid x 12 weeks
Arm Title
Placebo/Rifaximin SSD
Arm Type
Experimental
Arm Description
Matched placebo po bid for 12 weeks followed by crossover to Rifaximin 550mg po bid x 12 weeks
Intervention Type
Drug
Intervention Name(s)
Rifaximin
Other Intervention Name(s)
Rifaximin (Xifaxan)
Intervention Description
550mg orally twice daily for 12 weeks
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Matched placebo
Primary Outcome Measure Information:
Title
Change in CD27+ B-cell frequency
Time Frame
Week 0 (Baseline) to Week 12
Secondary Outcome Measure Information:
Title
Change in basal B-cell activation
Description
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.
Time Frame
Week 0 to Week 12
Other Pre-specified Outcome Measures:
Title
Change in circulating markers of bacterial translocation
Description
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
Time Frame
Week 0 to Week 12

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
David E Kaplan, MD, MSc
Organizational Affiliation
Corporal Michael J. Crescenz VA Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Philadelphia VA Medical Center
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
Deidentified primary data will be made available for verification
Citations:
PubMed Identifier
21932384
Citation
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.
Results Reference
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Pilot Study Of The Effect Of Rifaximin On B-Cell Dysregulation In Cirrhosis

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