Initial Study of Rituximab to Treat Primary Biliary Cirrhosis

Study Overview
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Brief Summary
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The purpose of this study is to determine the safety of the anti-CD20 antibody rituximab in treating patients with Primary Biliary Cirrhosis (PBC). Rituximab is a laboratory-made antibody currently used to treat some kinds of lymphoma. Rituximab may also help people with PBC, a disease of the immune system. However, the safety of rituximab in PBC patients must first be established.

Detailed Description
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This is a pilot, open-label, study on 10 female patients with AMA-positive PBC to determine the effects of two infusions of rituximab on response of memory B cells to bacterial motifs, on biochemical function, and histological features. We will enroll 10 consecutive AMA-positive patients with the diagnosis of PBC based on internationally accepted criteria and histological staging determined at liver biopsy and being currently treated with UDCA. Importantly, patients with advanced histological stages, decompensated liver disease, or waiting for OLT will not be included in the study (see exclusion criteria). Patients eligible and willing to enter the study will be evaluated at baseline by isolation and study of frequency and absolute numbers of B cells and their function, biochemical and AMA tests. Histology and quality of life will be also evaluated in all patients. The methodology to be used for B cell study is already well-established in our laboratory as can be seen in the attached paper (Kikuchi et al. 2005b). Patients will be administered 1,000 mg rituximab intravenously by slow infusion on Day 1 and Day 15 (+/- 1 day). Rituximab's pharmacokinetics indicate that complete B cell depletion is obtained 2-3 days after administration and that such effect may be lost after 9 months (Vieira et al. 2004). In addition to our B cell work, serum samples will undergo AMA testing, including titers, using recombinant mitochondrial antigens (Miyakawa et al. 2001). Patients will also undergo serum chemistry panel, which includes liver function tests. Patients will continue on a steady dose of UDCA therapy throughout the study.

Official Title
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Effects of Rituximab (Rituxan) on B Cell and AMA Response in Patients With Primary Biliary Cirrhosis

Conditions
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Primary Biliary Cirrhosis

Intervention / Treatment
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* Drug: rituximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Liver biopsy showing histological PBC stages I, II, or III Presence of all criteria for the diagnosis of PBC serum AMA at titer >1:40 alkaline phosphatase >2X normal value for >6 months compatible liver histology Incomplete response to UDCA after 6 months of treatment. Negative pregnancy test (female patients in fertile age) Adequate renal function (serum creatinine < 1.2) Exclusion Criteria: End-stage/decompensated liver disease ascites jaundice with serum bilirubin > 2mg/dl history of digestive bleeding secondary to portal hypertension or endoscopic evidence of varices at stage F2 history of hepatic encephalopathy INR>1.2 Other coexisting causes of liver disease Use of other immunosuppressive medications 4 weeks prior to enrollment Diuretics use

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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Female

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: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>rituximab 1000 mg IV on days 1 and 15, given over 5 - 6 hours | Drug: rituximab<br>* rituximab 1000 mg IV day 1 and 15, given over 5 - 6 hours<br>* Other names: Rituxan (R);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events |  | 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Serum Immunoglobulin G | The difference in serum immunoglobulin G from Baseline to Week 52 | 52 Weeks | 
| Change in Serum Immunoglobulin A | The difference in serum immunoglobulin A from Baseline to Week 52 | 52 Weeks | 
| Change in Serum Immunoglobulin M | The difference in serum immunoglobulin M from Baseline to Week 52 | 52 Weeks | 
| Change in Serum Alkaline Phosphatase | The difference in serum alkaline phosphatase from Baseline to Week 52 | 52 Weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Primary Biliary Cirrhosis