Primary Biliary Cirrhosis
Conditions
Keywords
Primary Biliary Cirrhosis, Ursodeoxycholic acid, Abatacept, Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4)
Brief summary
The purpose of this study is to determine if abatacept (Orencia) is effective in patients with primary biliary cirrhosis who do not respond adequately to standard treatment with ursodeoxycholic acid (UDCA, Urso, Ursodiol, Actigall).
Detailed description
This is an open label, active treatment trial to assess the efficacy and safety of abatacept in subject with PBC who have had an incomplete biochemical response to UDCA. In this trial, 20 subjects with PBC who have had an incomplete biochemical response to UDCA will be assigned to treatment with weekly subcutaneous injections of 125 mg of abatacept. The treatment phase of the study will last 24 weeks with an off-treatment follow up at Week 36. Inclusion criteria include: * Confirmed diagnosis of PBC * Alkaline phosphatase \> 1.67 times the upper limit of normal after 6 months of treatment with UDCA
Interventions
BIOLOGICALabatacept
125 mg subcutaneously each week for 24 weeks
Sponsors
Bristol-Myers Squibb
Christopher Bowlus, MD
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Confirmed PBC diagnosis based upon at least 2 of 3 criteria 1. Anti-mitochondrial antibody (AMA) titer \> 1:40 2. Alkaline phosphatase \> 1.5 times the upper limit of normal for at least 6 months 3. Liver biopsy findings consistent with PBC * Incomplete response to UDCA defined by an alkaline phosphatase \> 1.67 X the upper limit of normal after 6 months of UDCA at a minimum dose of 13 mg/kg/d * Taking a stable dose of UDCA for at least 3 months prior to Day 0 * aspartate aminotransferase (AST) and alanine aminotransferase ALT \< 5 times the upper limit of normal
Exclusion criteria
* Presence of concomitant liver diseases including viral hepatitis, primary sclerosing cholangitis, alcoholic liver disease, Wilson's disease, hemochromatosis, or Gilbert's syndrome. * Prior liver transplantation * Decompensated liver disease * Use of immunosuppressants within 6 months of Day 0 * Use of biologic agents within 12 months of Day 0
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Biochemical Response | Week 24 | Number of Participants with a decrease of alkaline phosphatase by \> 40%of the Day 0 level at 24 weeks of treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change in Alanine Transferase (ALT) | Week 24 | The percent change in alanine transferase (ALT) from Day 0 to Week 24. |
| Liver Stiffness Measured by Magnetic Resonance Elastography | Week 24 | Change in liver stiffness measured by magnetic resonance elastography from Day 0 to Week 24. |
| Primary Billiary Cholangitis Quality of Life | Week 24 | Change in quality of life measured by change in primary biliary cholangitis (PBC)-40 from Day 0 to Week 24. is a patient-derived, disease specific quality of life measure developed and validated for use in PBC with subscores for domains of symptoms, itch, fatigue, cognition, social, and emotional. Subdomains are summed with a total score range of 36 to 200. Higher scores indicate worse quality of life. |
| Percent Change in Alkaline Phosphatase | Week 24 | The percent change in alkaline phosphatase from Day 0 to Week 24. |
| Drug Safety | Weeks 2, 4, 12, 24, and 36 | Number of participants with any adverse events, clinically significant changes in vital signs, laboratory test abnormalities, and clinical tolerability of the drug. |
| Absolute Change in Alkaline Phosphatase | Week 24 | The absolute change in alkaline phosphatase from Day 0 to Week 24. |
| Absolute Change in Alanine Transferase (ALT) | Week 24 | The absolute change in alanine transferase (ALT) from Day 0 to Week 24. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Memory T Cell Frequencies | Week 24 | Change in cluster of differentiation 4 (CD4)+ cluster of differentiation 44 (CD44)+ cluster of differentiation 62 ligand (CD62L)- and cluster of differentiation 8+ CD44+ CD62L- frequencies in peripheral blood mononuclear cells from Day 0 to Week 24 |
| Abatacept Levels | Day 0 and Weeks 4, 12, 24, and 36 | Trough serum levels of abatacept |
| Immunoglobulin M (IgM) Levels | Week 24 | Change in IgM level from Day 0 to Week 24 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Abatacept 125 mg Weekly Open label treatment with Abatacept
abatacept: 125 mg subcutaneously each week for 24 weeks | 16 |
| Total | 16 |
Baseline characteristics
| Characteristic | Abatacept 125 mg Weekly |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 2 Participants |
| Age, Categorical Between 18 and 65 years | 14 Participants |
| Age, Continuous | 52 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 13 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 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 | 16 Participants |
| Region of Enrollment United States | 16 participants |
| Sex: Female, Male Female | 15 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 16 |
| other Total, other adverse events | 4 / 16 |
| serious Total, serious adverse events | 0 / 16 |
Outcome results
Primary
Biochemical Response
Number of Participants with a decrease of alkaline phosphatase by \> 40%of the Day 0 level at 24 weeks of treatment.
Time frame: Week 24
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Abatacept 125 mg Weekly | Biochemical Response | 1 Participants |
Secondary
Absolute Change in Alanine Transferase (ALT)
The absolute change in alanine transferase (ALT) from Day 0 to Week 24.
Time frame: Week 24
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Abatacept 125 mg Weekly | Absolute Change in Alanine Transferase (ALT) | 0.5 IU/L |
Secondary
Absolute Change in Alkaline Phosphatase
The absolute change in alkaline phosphatase from Day 0 to Week 24.
Time frame: Week 24
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Abatacept 125 mg Weekly | Absolute Change in Alkaline Phosphatase | -2.8 IU/L |
Secondary
Drug Safety
Number of participants with any adverse events, clinically significant changes in vital signs, laboratory test abnormalities, and clinical tolerability of the drug.
Time frame: Weeks 2, 4, 12, 24, and 36
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Abatacept 125 mg Weekly | Drug Safety | 4 Participants |
Secondary
Liver Stiffness Measured by Magnetic Resonance Elastography
Change in liver stiffness measured by magnetic resonance elastography from Day 0 to Week 24.
Time frame: Week 24
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Abatacept 125 mg Weekly | Liver Stiffness Measured by Magnetic Resonance Elastography | -0.1 kPa |
Secondary
Percent Change in Alanine Transferase (ALT)
The percent change in alanine transferase (ALT) from Day 0 to Week 24.
Time frame: Week 24
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Abatacept 125 mg Weekly | Percent Change in Alanine Transferase (ALT) | 0.01 percent change |
Secondary
Percent Change in Alkaline Phosphatase
The percent change in alkaline phosphatase from Day 0 to Week 24.
Time frame: Week 24
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Abatacept 125 mg Weekly | Percent Change in Alkaline Phosphatase | 0.01 percent change |
Secondary
Primary Billiary Cholangitis Quality of Life
Change in quality of life measured by change in primary biliary cholangitis (PBC)-40 from Day 0 to Week 24. is a patient-derived, disease specific quality of life measure developed and validated for use in PBC with subscores for domains of symptoms, itch, fatigue, cognition, social, and emotional. Subdomains are summed with a total score range of 36 to 200. Higher scores indicate worse quality of life.
Time frame: Week 24
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Abatacept 125 mg Weekly | Primary Billiary Cholangitis Quality of Life | 0 units on a scale |
Other Pre-specified
Abatacept Levels
Trough serum levels of abatacept
Time frame: Day 0 and Weeks 4, 12, 24, and 36
Other Pre-specified
Immunoglobulin M (IgM) Levels
Change in IgM level from Day 0 to Week 24
Time frame: Week 24
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Abatacept 125 mg Weekly | Immunoglobulin M (IgM) Levels | 0.0 mg/dL |
Other Pre-specified
Memory T Cell Frequencies
Change in cluster of differentiation 4 (CD4)+ cluster of differentiation 44 (CD44)+ cluster of differentiation 62 ligand (CD62L)- and cluster of differentiation 8+ CD44+ CD62L- frequencies in peripheral blood mononuclear cells from Day 0 to Week 24
Time frame: Week 24