Primary Biliary Cirrhosis
Conditions
Keywords
Primary Biliary Cirrhosis
Brief summary
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
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.
Interventions
DRUGrituximab
rituximab 1000 mg IV day 1 and 15, given over 5 - 6 hours
Sponsors
Genentech, Inc.
University of California, Davis
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 65 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Number of Participants With Adverse Events | 52 weeks |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Serum Immunoglobulin G | 52 Weeks | The difference in serum immunoglobulin G from Baseline to Week 52 |
| Change in Serum Immunoglobulin A | 52 Weeks | The difference in serum immunoglobulin A from Baseline to Week 52 |
| Change in Serum Immunoglobulin M | 52 Weeks | The difference in serum immunoglobulin M from Baseline to Week 52 |
| Change in Serum Alkaline Phosphatase | 52 Weeks | The difference in serum alkaline phosphatase from Baseline to Week 52 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Open Label Study Arm Primary Biliary Cirrhosis
rituximab: rituximab 1000 mg IV day 1 and 15, given over 5 - 6 hours | 6 |
| Total | 6 |
Baseline characteristics
| Characteristic | Open Label Study Arm |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants |
| Anti-mitochondrial Antibody Anti-mitochondrial Antibody Negative | 0 Participants |
| Anti-mitochondrial Antibody Anti-mitochondrial Antibody Positive | 6 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Liver Biopsy Stage Ludwig Stage I | 1 Participants |
| Liver Biopsy Stage Ludwig Stage II | 4 Participants |
| Liver Biopsy Stage Ludwig Stage III | 1 Participants |
| Liver Biopsy Stage Ludwig Stage IV | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 6 Participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 3 / 6 |
| serious Total, serious adverse events | 1 / 6 |
Outcome results
Primary
Number of Participants With Adverse Events
Time frame: 52 weeks
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Open Label Study Arm | Number of Participants With Adverse Events | Serious Adverse Events | 1 Participants |
| Open Label Study Arm | Number of Participants With Adverse Events | Non-Serious Adverse Events | 3 Participants |
| Open Label Study Arm | Number of Participants With Adverse Events | No Events | 2 Participants |
Secondary
Change in Serum Alkaline Phosphatase
The difference in serum alkaline phosphatase from Baseline to Week 52
Time frame: 52 Weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Open Label Study Arm | Change in Serum Alkaline Phosphatase | 55.8 U/L | Standard Deviation 151.5 |
Secondary
Change in Serum Immunoglobulin A
The difference in serum immunoglobulin A from Baseline to Week 52
Time frame: 52 Weeks
Population: 1 subject with missing data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Open Label Study Arm | Change in Serum Immunoglobulin A | 36.8 mg/dL | Standard Deviation 89.7 |
Secondary
Change in Serum Immunoglobulin G
The difference in serum immunoglobulin G from Baseline to Week 52
Time frame: 52 Weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Open Label Study Arm | Change in Serum Immunoglobulin G | 167 mg/dL | Standard Deviation 450 |
Secondary
Change in Serum Immunoglobulin M
The difference in serum immunoglobulin M from Baseline to Week 52
Time frame: 52 Weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Open Label Study Arm | Change in Serum Immunoglobulin M | 121 mg/dL | Standard Deviation 74.5 |