Abatacept For The Treatment Of Primary Biliary Cirrhosis With An Incomplete Biochemical Response To Ursodeoxycholic Acid
Phase: PHASE4
Conditions: Primary Biliary Cirrhosis
Sponsor: Christopher Bowlus, MD

PROTOCOL TITLE: ABATACEPT FOR THE TREATMENT OF PRIMARY 
BILIARY CIRRHOSIS WITH AN INCOMPLETE BIOCHEMICAL RESPONSE TO 
URSODEOXYCHOLIC ACID 
 
 
Page 1 of 26 
Revised: 2September 22, 2015 
1) 
Protocol Title 
a) ABATACEPT FOR THE TREATMENT OF PRIMARY BILIARY 
CIRRHOSIS WITH AN INCOMPLETE BIOCHEMICAL RESPONSE 
TO URSODEOXYCHOLIC ACID 
b) December 30, 2013 
2) 
Author of Protocol 
 
ü UC Davis Researcher 
p Researcher from other institution 
p Private Sponsor 
p Cooperative Group 
p Other: _________________ 
 
3) 
IRB Review History 
n/a. 
4) 
Objectives 
1.1 
Primary Objective 
The primary objective of this study is to evaluate whether abatacept is effective in 
inducing a biochemical response in PBC patients with an incomplete response to UDCA. 
 
1.2 
Secondary Objectives 
 
The secondary objectives of this study are: 
• To assess the safety of abatacept in patients with PBC 
• To assess effect of abatacept on liver stiffness as a measure of liver fibrosis in 
patients with PBC 
• To determine the effects of abatacept on immunologic markers of PBC 
• To assess the impact of abatacept on the quality of life in patients with PBC 
• To characterize pharmacokineticsPKof abatacept 125mg administrated SC 
weekly in patients with PBC  
• To assess immunogenicity of abatacept 125mg administered SC weekly in 
patients with PBC 
 

PROTOCOL TITLE: ABATACEPT FOR THE TREATMENT OF PRIMARY 
BILIARY CIRRHOSIS WITH AN INCOMPLETE BIOCHEMICAL RESPONSE TO 
URSODEOXYCHOLIC ACID 
 
 
Page 2 of 26 
Revised: 2September 22, 2015 
5) 
Background 
Introduction 
Primary biliary cirrhosis (PBC) is a progressive autoimmune disease of biliary epithelial 
cells resulting in biliary cirrhosis. The prevalence of PBC in the US and Europe is 
estimated to be 5-40 per 100,000 persons and accounts for 3-4 % of liver transplants 
performed in the US. The only approved medical therapy of PBC is the hydrophilic bile 
acid ursodeoxycholic acid (UDCA). Multiple studies suggest that UDCA delays 
progression of the disease, particularly those that have a biochemical response which has 
defined by multiple criteria, the simplest being a decrease of the alkaline phosphatase to 
1.67 times the upper limit of normal. However, 20-40% of PBC patients have an 
incomplete response to UDCA and remain at significant risk of disease progression 
leading to death or liver transplantation. 
PBC is characterized by a 90% female predominance, high titers of serum anti-
mitochondrial autoantibodies (AMA) directed against the pyruvate dehydrogenase 
complex E2 subunit and elevated plasma levels of immunoglobulin M (IgM). However, 
evidence from both human and murine models suggests that T-cells, particularly CD8+ T 
cells, are key to the destruction of bile ducts. Genetic evidence of a T-cell defect is also 
supported by our findings and those of others demonstrating significant associations 
between CTLA-4 polymorphisms and PBC. Most notable, are the results we recently 
published in our murine model of PBC in which both AMA and biliary inflammation are 
induced by immunization with the xenobiotic 2-octynoic acid (2-OA). CTLA-4 Ig 
treatment one day before 2-OA immunization, completely inhibited AMA production, 
intra-hepatic T cell infiltrates, and bile duct damage. More critically, treatment with 
CTLA-4 Ig initiated after the 2-OA immunization and development of disease, also 
resulted in reduced intra-hepatic T cell infiltrates and biliary cell damage, although AMA 
levels were not altered. 
 
a) Pathology of Primary Biliary Cirrhosis 
Three important observations must be taken into account for us to understand the 
pathogenic basis of PBC. First, appearance of AMAs before liver disease suggests that 
loss of tolerance to the mitochondrial autoantigen is an early event and could be 
independent of the development of liver disease. Second, although the autoantigen is 
present ubiquitously in all nucleated cells, the immune response is restricted to epithelial 
cells of intrahepatic bile ducts and, to a lesser degree, to cells of salivary and lacrimal 
glands. Finally, recurrence of PBC after liver transplantation supports the idea that the 
bile duct epithelial cell is a generic target and is not unique to the patient with PBC. 
Similar to other complex diseases, the combination of a susceptible genetic background 
and exposure to environmental triggers are needed to initiate and promote the disorder. 

PROTOCOL TITLE: ABATACEPT FOR THE TREATMENT OF PRIMARY 
BILIARY CIRRHOSIS WITH AN INCOMPLETE BIOCHEMICAL RESPONSE TO 
URSODEOXYCHOLIC ACID 
 
 
Page 3 of 26 
Revised: 2September 22, 2015 
Observations that 1–6% of individuals with PBC have at least one family member 
manifesting disease and a 63% concordance rate in monozygotic twins (vs null 
concordance in dizygotic sets), show the substantial genetic effect on disease 
susceptibility, one of the strongest for any autoimmune disorder. Many candidate genes 
have been investigated for a role in susceptibility to PBC, disease progression, or both in 
case-control cross-sectional studies. Findings of a genome-wide association study 
undertaken in a northern American set of patients and controls indicated a significant 
association between PBC and polymorphisms of HLA-DQB1, IL12A, IL12RB2, and to a 
minor extent, STAT4, and these associations have been confirmed in an independent 
cohort of Italian patients and controls with a combined analysis.  
Several environmental factors—mainly infectious and chemical—are also thought to 
contribute to the onset of PBC, largely through molecular mimicry or modification of 
autoantigens. Geographic clustering of cases near toxic waste sites in New York City and 
space-time clustering in northeast England provide epidemiological evidence for a role of 
chemicals, infectious agents, or both. Additional data that lend support to a role for 
infections in disease development include the significantly higher prevalence than usual 
of recurrent urinary-tract infections in patients with PBC and experimental findings of 
sequence similarity between the E2 enzyme of the pyruvate dehydrogenase complex 
recognized by autoantibodies and bacterial proteins. Several bacterial strains—including 
the non-pathogenic gram-negative bacterium Novosphingobium aromaticivorans—have 
the highest known homology to the immunodominant autoepitope of the E2 enzyme. 
Several other infectious agents have been proposed, including Escherichia coli, 
Helicobacter spp, organisms of the genus Mycoplasma, and a human β retrovirus, 
although support for the retrovirus has not been substantiated.  
Other environmental factors proposed to trigger disease onset are foreign chemicals (ie, 
xenobiotics) that can either alter or form a complex with a defined self or non-self 
protein, causing a change in the protein's molecular structure that induces an immune 
response. Lipoic acid is attached to only a few proteins, yet it is a vital component of the 
E2 epitope. The structure of the E2 enzyme exposes lipoic acid at the exterior of the 
protein complex, making this compound accessible to chemical modification. The role of 
xenobiotics in PBC is supported by serum reactivity against specific organic compounds 
with structures similar to lipoic acid; furthermore, two of these compounds (6-
bromohexanoate and 2-octynoic acid) can induce AMAs and liver lesions similar to those 
of PBC in guinea pigs and mouse models.  
AMAs in serum are highly sensitive and specific for PBC: they are detected in nearly 
95% of patients, with specificity close to 100% when tested with recombinant antigens. 
Indirect immunofluorescence remains the test used for screening, but it can be associated 
with a substantial number of false-positive results. Follow-up data from AMA-positive 
individuals without signs of liver disease suggest that autoantibodies arise several years 
before onset of PBC and have a high predictive value. Epitopes recognized by AMAs 

PROTOCOL TITLE: ABATACEPT FOR THE TREATMENT OF PRIMARY 
BILIARY CIRRHOSIS WITH AN INCOMPLETE BIOCHEMICAL RESPONSE TO 
URSODEOXYCHOLIC ACID 
 
 
Page 4 of 26 
Revised: 2September 22, 2015 
include lipoylated domains (via the Asx-Lys-Ala motif) within subunits of the 2-oxoacid 
dehydrogenase family of enzymes of the mitochondrial respiratory chain, in particular, 
E2 subunit and E3 binding-protein components of the pyruvate dehydrogenase complex 
and E2 components of the 2-oxoglutarate dehydrogenase and branched-chain 2-oxo acid 
dehydrogenase complexes.  
 
b) Role of T cells in Primary Biliary Cirrhosis 
In addition to AMAs, autoreactive CD8+ and CD4+ T cells to the E2 component of the 
pyruvate dehydrogenase complex have been identified both in peripheral blood and 
within the liver of patients with PBC, and the immunodominant epitope of these T cells 
maps in close proximity to the epitope recognized by AMAs in serum. Autoreactive 
CD4+ cell clones specific for the E2 enzyme have been isolated in intrahepatic and 
peripheral lymphocytes, not only in AMA-positive individuals but also in patients 
without antibodies, thus corroborating the notion that PBC either positive or negative for 
AMAs is one nosological entity.  
CD4+ CD25high regulatory T cells act to prevent autoreactivity, as shown in several 
autoimmune diseases, including autoimmune hepatitis. Patients with PBC are 
characterized by substantially lower frequencies of CD4+ CD25high regulatory T cells as 
proportions of total T-cell receptor-αβ+/CD4+ cells, and this factor could be important in 
the breakdown of tolerance.  
 
c) Summary of Results of Investigational Program 
Pharmacology of Abatacept 
Abatacept is a recombinant fusion protein consisting of the extracellular domain of 
human CTLA4 and a fragment (hinge- CH2-CH3 domains) of the Fc domain of human 
IgG1 that has been modified to prevent complement fixation and antibody-
dependent cellular cytotoxicity. 
Abatacept is the first drug in a new class of agents termed “selective costimulation 
modulators.” Abatacept binds specifically to the CD80 and CD86 molecules, proteins 
prominently displayed on the surface of antigen-presenting cells (APCs). Activation of 
naive T cells during an immune response requires two stimuli from APCs. The first 
signal is antigen-specific; antigens are presented by APCs, with the signal transmitted to 
the T cell through the T cell’s antigen receptor. The second, or costimulatory, signal is 
not antigen-specific and is delivered following the engagement of a costimulatory ligand 
on the APC with a cognate receptor on the T cell. 
A key costimulatory receptor on T cells is CD28. CD28 is constitutively expressed on 
resting T cells and binds to both CD80 (B7-1) and CD86 (B7-2) on the APC. A 

PROTOCOL TITLE: ABATACEPT FOR THE TREATMENT OF PRIMARY 
BILIARY CIRRHOSIS WITH AN INCOMPLETE BIOCHEMICAL RESPONSE TO 
URSODEOXYCHOLIC ACID 
 
 
Page 5 of 26 
Revised: 2September 22, 2015 
costimulatory signal is required not only for the full activation of naive T cells, but also 
may be required for the survival of memory and autoimmune effector cells. At 24 to 
48 hours following T cell activation, the T cell expresses CTLA4 on its surface, which 
engages the CD80 and CD86 molecules on the APC surface interfering with CD28’s 
ability to bind to its ligands on the APC; CD80 and CD86 preferentially bind to CTLA4 
with a much higher avidity than with CD28. Although the precise mechanisms are as yet 
unclear, CTLA4 expression is associated with a decrease in T cell activation. 
After the T cell activity has been dampened, the CTLA4 recycles into the T cell’s 
cytoplasm. The CTLA4 section of abatacept binds specifically to CD80 and CD86 (B7-1 
and B7-2, respectively) and down-modulates the CD28-mediated costimulation of 
T cells. Thus, abatacept uses a segment of a molecule that is part of the normal immune 
homeostatic mechanism to suppress T cell activity involved in the immunopathogenesis 
of autoimmune diseases. The FC region of abatacept was engineered with several point 
mutations designed to inactivate it. Because of these changes, abatacept does not mediate 
pathways such as antibody-dependent cell cytotoxicity or complement-dependent 
cytotoxicity.  
Study Rationale 
This is an open label, single center, active treatment study of the effects of 
abatacept on PBC patients with an incomplete response to UDCA. These patients 
have been demonstrated to have increased morbidity and mortality with standard-
of-care treatment. An abundance of human and pre-clinical data suggests that T 
cell activation is central to the immune-mediated destruction of biliary epithelial 
cells and that abatacept may be effective in halting this process.  
 
6) 
Inclusion and Exclusion Criteria 
Inclusion Criteria 
1. Signed Written Informed Consent 
a) Before any study procedures are performed, subjects will have the details of the 
study described to them, and they will be given a written informed consent 
document to read. Then, if subjects consent to participate in the study, they will 
indicate that consent by signing and dating the informed consent document in the 
presence of study personnel. 
2. Target Population 
a) Confirmed PBC diagnosis based upon at least 2 of 3 criteria 
i) AMA titer > 1:40 
ii) Alkaline phosphatase > 1.5 times the upper limit of normal for at least 6 
months 
iii) Liver biopsy findings consistent with PBC 

PROTOCOL TITLE: ABATACEPT FOR THE TREATMENT OF PRIMARY 
BILIARY CIRRHOSIS WITH AN INCOMPLETE BIOCHEMICAL RESPONSE TO 
URSODEOXYCHOLIC ACID 
 
 
Page 6 of 26 
Revised: 2September 22, 2015 
b) Incomplete response to UDCA defined by an alkaline phosphatase > 1.67 times 
the upper limit of normal after 6 months of UDCA at a minimum dose of 13 
mg/kg/d. 
c) Taking a stable dose of UDCA for at least 3 months prior to Day 0. 
d) Willing and able to comply with all study requirements. 
e) AST and ALT <  5 X the upper limit of normal 
3. Age and Reproductive Status 
a) Men and women, 18 to 80 years of age. 
b) Reproductive Status: Definition of Women of Child-Bearing Potential 
(WOCBP). WOCBP comprises women who have experienced menarche and who 
have not undergone successful surgical sterilization (hysterectomy, bilateral tubal 
ligation, or bilateral oophorectomy) or who are not post-menopausal (see 
definition below). 
1) Post-menopause is defined as:  
• Women who have had amenorrhea for ³ 12 consecutive months (without 
another cause) and who have a documented serum follicle-stimulating 
hormone (FSH) level > 35 mIU/mL. 
• Women who have irregular menstrual periods and a documented serum FSH 
level > 35 mIU/mL. 
• Women who are taking hormone replacement therapy (HRT). 
The following women are WOCBP: 
• Women using the following methods to prevent pregnancy: Oral 
contraceptives, other hormonal contraceptives (vaginal products, skin patches, 
or implanted or injectable products), or mechanical products such as 
intrauterine devices or barrier methods (diaphragm, condoms, spermicides). 
• Women who are practicing abstinence. 
• Women who have a partner who is sterile (eg, due to vasectomy). 
• WOCBP must be using an acceptable method of contraception to avoid 
pregnancy throughout the study and for up to 10 weeks after the last dose of 
study drug in such a manner that the risk of pregnancy is minimized.  
• WOCBP must have a negative serum or urine pregnancy test result (minimum 
sensitivity 25 IU/L or equivalent units of HCG) within 0 to 48 hours before 
the first dose of study drug.  
• Women must not be breast-feeding. 
• Sexually active fertile men must use effective birth control if their partners are 
WOCBP.  
 

PROTOCOL TITLE: ABATACEPT FOR THE TREATMENT OF PRIMARY 
BILIARY CIRRHOSIS WITH AN INCOMPLETE BIOCHEMICAL RESPONSE TO 
URSODEOXYCHOLIC ACID 
 
 
Page 7 of 26 
Revised: 2September 22, 2015 
Exclusion Criteria 
2) Target Disease Exceptions  
a) Presence of other concomitant liver diseases including viral hepatitis, PSC, 
alcoholic liver disease, Wilson’s disease, hemochromatosis, or Gilbert’s 
syndrome. 
b) Prior liver transplantation 
c) Decompensated liver disease defined by the presence or history of any of the 
following 
i) MELD score > 15 
ii) Hepatic encephalopathy 
iii) Ascites 
iv) Hepatorenal syndrome or serum creatinine > 2 mg/dL 
v) Total Bilirubin > 3.0 mg/dL 
vi) INR > 1.8 unless on anticoagulation such as Coumadin. 
d) Use of immunosuppressants within 6 months of Day 0, including azathioprine, 
prednisone, prednisolone, budesonide, cyclosporine, tacrolimus, methotrexate, or 
mycophenolate mofetil. 
e) Use of biologic agents including anti-cell and anti-cytokine therapies within 12 
months of Day 0. 
f) History of tuberculosis or positive PPD skin test. 
g) Positive hepatitis B surface antigen 
h) Presence of hepatitis C RNA 
i) QT or QTc interval > 500 milliseconds 
 
3) Medical History and Concurrent Diseases 
a) Subjects who are impaired, incapacitated, or incapable of completing study-
related assessments. 
b) Subjects with current symptoms of severe, progressive, or uncontrolled renal, 
hepatic, hematologic, gastrointestinal, pulmonary, cardiac, neurologic, or cerebral 
disease, whether or not related to RA and which, in the opinion of the 
investigator, might place a subject at unacceptable risk for participation in the 
study. 
c) Subjects with a history of cancer in the last 5 years, other than non-melanoma 
skin cell cancers cured by local resection or carcinoma in situ. Existing non-
melanoma skin cell cancers should be removed, the lesion site healed, and 
residual cancer ruled out before administration of the study drug. 
d) Subjects who currently abuse drugs or alcohol. 
e) Subjects with evidence (as assessed by the investigator) of active or latent 
bacterial or viral infections at the time of potential enrollment, including subjects 

PROTOCOL TITLE: ABATACEPT FOR THE TREATMENT OF PRIMARY 
BILIARY CIRRHOSIS WITH AN INCOMPLETE BIOCHEMICAL RESPONSE TO 
URSODEOXYCHOLIC ACID 
 
 
Page 8 of 26 
Revised: 2September 22, 2015 
with evidence of human immunodeficiency virus (HIV) detected during 
screening. 
f) Subjects with herpes zoster or cytomegalovirus (CMV) that resolved less than 2 
months before the informed consent document was signed. 
g) Subjects who have received any live vaccines within 3 months of the anticipated 
first dose of study medication. 
h) Subjects with any serious bacterial infection within the last 3 months, unless 
treated and resolved with antibiotics, or any chronic bacterial infection (eg, 
chronic pyelonephritis, osteomyelitis, or bronchiectasis). 
i) Subjects at risk for tuberculosis (TB). Specifically excluded from this study will 
be subjects with a history of active TB within the last 3 years, even if it was 
treated; a history of active TB greater than 3 years ago, unless there is 
documentation that the prior anti-TB treatment was appropriate in duration and 
type; current clinical, radiographic, or laboratory evidence of active TB; and 
latent TB that was not successfully treated (≥ 4 weeks). 
4) Physical and Laboratory Test Findings 
a) Subjects with any of the following laboratory values 
i) Hemoglobin < 8.5 g/dL 
ii) WBC < 3000/mm3 (< 3 x 109/L) 
iii) Platelets < 75,000/mm3 (< 3 x 109/L) 
iv) Serum creatinine > 2 times the ULN 
v) Serum ALT or AST > 5 times the ULN 
b) Any other laboratory test results that, in the opinion of the investigator, might 
place a subject at unacceptable risk for participation in the study. 
5) Allergies and Adverse Drug Reactions 
c) Any prior adverse reaction to abatacept. 
6) Prohibited Treatments and/or Therapies 
d) Subjects who have at any time received treatment with any investigational drug 
within 28 days (or less than 5 terminal half-lives of elimination) of the Day 1 
dose. 
e) Any concomitant biologic DMARD, such as anakinra. 
7) Other Exclusion Criteria 
f) Prisoners or subjects who are involuntarily incarcerated. 
g) Subjects who are compulsorily detained for treatment of either a psychiatric or 
physical (eg, infectious disease) illness. 
Eligibility criteria for this study have been carefully considered to ensure the 
safety of the study subjects and to ensure that the results of the study can be used. 
It is imperative that subjects fully meet all eligibility criteria. 

PROTOCOL TITLE: ABATACEPT FOR THE TREATMENT OF PRIMARY 
BILIARY CIRRHOSIS WITH AN INCOMPLETE BIOCHEMICAL RESPONSE TO 
URSODEOXYCHOLIC ACID 
 
 
Page 9 of 26 
Revised: 2September 22, 2015 
7) 
Number of Subjects 
a) Study- Wide/Local: 
Up to 20 subjects with PBC will be enrolled in this trial. 
 
8) 
Recruitment Methods 
a) Local: 
Patients will be recruited by direct person to person contact within the 
GI/Hepatology clinic when the potential patients come in for routine 
care. 
If, during their normal visit, it is noted they may qualify for a clinical 
trial, they will be approached by the investigator. 
The principal investigator is also heavily involved in the PBC patient 
support groups of Northern California and will recruit potential subjects 
verbally from these groups as well during normal scheduled 
presentations. 
Patients may also be recruited using recruitment materials such as flyers, 
posters and social media ads. 
 
b) HIPAA: 
We are requesting HIPAA waiver:  
• Study personnel will be accessing patients’ medical records for 
their Standard of Care when it may become evident that a patient 
may qualify for the research. 
• Access to PHI is necessary to confirm eligibility 
• PHI will only be used to assess eligibility and will not be copied or 
stored anywhere. 
• The protected health information will not be inappropriately reused 
or disclosed to any other person or entity. 
• PHI accessed may include, but are not limited to past/current 
diagnoses and lab results. 
9) 
Compensation to the Subjects 
From the ICF: 
If you agree to take part in this research study, we will compensate you $40 per study 
visit you attend for your time and effort. You will not be compensated for study visits 
you do not attend. Payments will be processed on a quarterly basis in the form of a check. 
You may be asked for your social security number for payment purposes. It will not be 
used for any other purpose without your permission. 

PROTOCOL TITLE: ABATACEPT FOR THE TREATMENT OF PRIMARY 
BILIARY CIRRHOSIS WITH AN INCOMPLETE BIOCHEMICAL RESPONSE TO 
URSODEOXYCHOLIC ACID 
 
 
Page 10 of 26 
Revised: 2September 22, 2015 
Patients flying in from out of town will have travel (airfare and hotel) arranged by and 
paid for by the sponsor and be reimbursed for any study related incidentals such as meals 
and parking. Reimbursements will come in the form of a check and be processed 
quarterly. You may be asked for your social security number for payment purposes. It 
will not be used for any other purpose without your permission. 
10) Study Timelines 
Describe: 
• The treatment phase of the study will last 24 weeks with an off-
treatment follow up at Week 36. 
• We anticipate enrollment to be complete after one year. 
• We anticipate primary analysis to be complete after two years. 
11) Study Endpoints 
The primary endpoint assessment will be the biochemical response rate defined by 
normalization of alkaline phosphatase or decrease of alkaline phosphatase by > 40% of 
the Day 0 level at 24 weeks of treatment.  
Secondary endpoints will include: 
• Absolute and percent change in alkaline phosphatase from Day 0 to 24 weeks. 
• Absolute and percent change in alanine transferase (ALT) from Day 0 to 24 
weeks. 
• Change in liver stiffness from Day 0 to week 24 as measured by magnetic 
resonance elastography. 
• Change in quality of life measured by change in PBC-40 from Day 0 to week 24. 
• Change in AMA titer from Day 0 to week 24 
• Change in IgM level from Day 0 to week 24 
• Change in CD4+CD44+CD62L- and CD8+CD44+CD62L- frequencies in PBMC 
from Day 0 to week 24 
• Comparisons of safety assessments pre-treatment, on-treatment, and post-
treatment including adverse events, laboratory observations, and physical exam 
findings. 
• Trough concentrations of abatacept concentrations from Week 0 to Week 24 
• Immunogenicity evaluated over time by measuring anti-abatacept antibodies and 
anti-CTLA-4-T antibodies  

PROTOCOL TITLE: ABATACEPT FOR THE TREATMENT OF PRIMARY 
BILIARY CIRRHOSIS WITH AN INCOMPLETE BIOCHEMICAL RESPONSE TO 
URSODEOXYCHOLIC ACID 
 
 
Page 11 of 26 
Revised: 2September 22, 2015 
12) Procedures Involved 
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.  
All subjects will undergo blood chemistry panel, complete blood count, INR, AMA, 
magnetic resonance elastography (MRE), and PBC-40 survey prior to the first dose of 
study drug. Baseline Mayo Risk Score and MELD score will be calculated from baseline 
lab values. Subjects will complete the 24 week treatment course and undergo repeat MRE 
and laboratory testing. Laboratory testing and assessments for adverse events will be 
conducted at Weeks 2, 4, 12, 24, and 36. Details are given in the Time and Events 
Schedule. 
 
 
 
 
Screening 
Abatacept 125 mg SC 
Off-Treatment FU 
Week        0 
2     4     
        12 
 
    24  
 
  36 
Figure 1. Study Design Schematic 

PROTOCOL TITLE: ABATACEPT FOR THE TREATMENT OF PRIMARY BILIARY CIRRHOSIS WITH AN INCOMPLETE 
BIOCHEMICAL RESPONSE TO URSODEOXYCHOLIC ACID 
 
 
Page 12 of 26 
Revised: 2September 22, 2015 
Time and Events Schedule for Protocol [IM101-457] 
Procedures 
Pre-Treatment 
Visit 
Treatment 
Day 1 
Treatment 
Week 2 
Treatment 
Week 4 
Treatment 
Week 12 
Treatment 
Week 24 
Post-
Treatment 
Week 361 
Eligibility Assessments 
Informed Consent 
X 
 
 
 
 
 
 
Inclusion/Exclusion  
X 
 
 
 
 
 
 
Medical History 
 
 
 
 
 
 
 
Safety Assessments 
 
 
 
 
 
 
 
Physical Exam 
X 
 
 
 
 
X 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
Signs and Symptoms 
 
X 
X 
X 
X 
X 
X 
Adverse Events  
 
X 
X 
X 
X 
X 
X 
ECG 
X 
 
 
 
 
 
 
PPD 
X 
 
 
 
 
 
 
HCV antibody 
X 
 
 
 
 
 
 
HBs antigen 
X 
 
 
 
 
 
 
HIV antibody 
X 
 
 
 
 
 
 
UPT1 
X 
X 
 
X 
X 
X 
 
Efficacy 
Assessments 
 
 
 
 
 
 
 
CMP 
X 
X 
X 
X 
X 
X 
X 
CBC 
X 
X 
X 
X 
X 
X 
X 
INR 
X 
X 
X 
X 
X 
X 
X 
CRP 
X 
 
 
X 
X 
X 
X 
AMA 
X 
X 
X 
X 
X 
X 
X 
IgG, IgM, IgA 
X 
X 
X 
X 
X 
X 
X 
ANA 
X 
X 
X 
X 
X 
X 
X 
Lipid Panel 
X 
 
 
 
X 
X 
X 
MR Elastography 
X 
 
 
 
 
X 
 
PBC-40 
X 
 
 
 
 
X 
 
CD44+CD62L-  
X 
 
 
 
X 
X 
X 
PK/IMG Samples2 
 
X 
 
X 
X 
X 
X 
Clinical Drug Supplies 
Abatacept 125 mg SC 
once weekly 
 
X 
X 
X 
X 
X 
 
1 Also to be performed for any subjects discontinuing the study with documentation for reason for discontinuation.  
2  Weeks 4, 12, and 24 should be drawn pre-dosing. The precise PK sampling times relative to the actual dosing time must be accurately recorded on the 
eCRF. The date and time of sample collection must be recorded so that compliance with the sampling schedule can be confirmed. 
 
 

PROTOCOL TITLE: ABATACEPT FOR THE TREATMENT OF PRIMARY 
BILIARY CIRRHOSIS WITH AN INCOMPLETE BIOCHEMICAL RESPONSE TO 
URSODEOXYCHOLIC ACID 
 
 
Page 13 of 26 
Revised: 2September 22, 2015 
 
From the ICF: 
The clinical study will be done only at UC Davis. The name and address of this study 
center and the investigator for this study center are listed on page 1 of this document. 
Authorized members of the study staff will do all study procedures. 
An initial examination called “Screening” will help decide if you can take part in the 
clinical study. This will include a full physical examination including body weight, 
height, blood pressure, heart rate, breathing rate, and body temperature. You will also 
have an electrocardiogram (ECG) to check the electrical activity of your heart. This 
involves placing several sticky pads on your arms, legs and chest, on your bare skin. 
These pads are attached to a machine that will measure your heart’s electrical activity. 
Also, your medical history and details of your illness will be recorded.  
If you take part in the clinical study, your treatment will begin within 28 days of the first 
examination. The study is expected to last up to 36 weeks, during which time you will 
make 7 planned visits to the study center. Visits will be scheduled approximately once 
every 2 to 4 weeks.  
You will be given enough of the study medication to last between visits. Each week, you 
will be asked to administer a subcutaneous injection (a shot just under the skin) of 125mg 
of Abatacept. The study team will teach you how to administer this shot yourself. 
Blood will be collected. Some blood samples must be taken when you are in a fasting 
state (overnight fast, only water is allowed). Over the course of the study, a total of 
approximately 244 mL (about 8.25 ounces) of blood will be collected. As a comparison, 
450 to 500 mL of blood is taken at a typical blood donation. 
During 2 of the 7 scheduled visits, magnetic resonance elastography (MRE) will be 
performed. This test involves placing a small vibrating pad on your abdomen, over the 
area of your liver. The vibrations into your abdomen will help the study doctor to 
determine the stiffness of your liver.  
Before entering the study, you must tell the investigator about any medications that you 
are taking or have taken during the last 12 months. You will also need to tell the 
investigator about all medications (other than study drug) that you take during the study. 
You may not take any new medications to treat PBC during the study or change the dose 
of any medications you are allowed to take. 
You should inform your general practitioner (family doctor) if you take part in this 
clinical study. Your general practitioner should not change your dosage of study 
medication, except in cases of emergency. The study investigator must be told about any 
medication prescribed by your general practitioner or other physicians during this study. 
Participation in other clinical studies within the last 30 days and during the course of this 
study is not allowed. 
You will be expected to fast (only water is allowed) overnight before some of the blood 
samples are collected. 

PROTOCOL TITLE: ABATACEPT FOR THE TREATMENT OF PRIMARY 
BILIARY CIRRHOSIS WITH AN INCOMPLETE BIOCHEMICAL RESPONSE TO 
URSODEOXYCHOLIC ACID 
 
 
Page 14 of 26 
Revised: 2September 22, 2015 
It is very important that women of childbearing age avoid pregnancy during the 
study. All sexually active women who take part in the study must use a reliable 
form of birth control. A pregnancy test will be performed at Screening and at the 
visits during Day 1, Weeks 2, 4, 12 and 24 of the study. If you become pregnant 
during the study, inform the study center immediately. 
13) Data and Specimen Banking 
n/a. 
14) Data Management and Confidentiality 
STATISTICAL CONSIDERATIONS 
The primary objective of this study is to evaluate whether abatacept is effective in 
inducing a biochemical response in PBC patients with an incomplete response to UDCA. 
The secondary objectives of this study are: 
• To assess the safety of abatacept in patients with PBC 
• To assess effect of abatacept on liver stiffness as a measure of liver fibrosis in 
patients with PBC 
• To determine the effects of abatacept on immunologic markers of PBC 
• To assess the impact of abatacept on the quality of life in patients with PBC 
• To characterize pharmacokineticsPKof abatacept 125mg administrated SC 
weekly in patients with PBC  
• To assess immunogenicity of abatacept 125mg administered SC weekly in 
patients with PBC 
 
Sample Size Determination 
Among patients with PBC who do not have a complete biochemical response to UDCA, 
the probability of achieving serum liver biochemical normalization spontaneously is 
<5%. If abatacept is found to be ineffective among 20 enrolled subjects, the probability of 
observing 3 or fewer treatment responses is >98%. If abatacept is associated with a 
treatment success response rate of 30% or more, then the probability of 4 or more 
individuals responding is 89%. If these endpoints were met, pursuit of a randomized, 
double-blind, placebo-controlled trial would then be justified. 
Populations for Analyses 
The primary analysis set for efficacy and safety analyses will include all subjects who 
received at least one dose of study drug.  

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BILIARY CIRRHOSIS WITH AN INCOMPLETE BIOCHEMICAL RESPONSE TO 
URSODEOXYCHOLIC ACID 
 
 
Page 15 of 26 
Revised: 2September 22, 2015 
Pharmacokinetic Analysis Population: All available plasma concentration data from 
subjects who receive at least 1 dose of study medication and have at least 1 concentration 
result will be reported. However, only subjects without dose interruption will be included 
in the summary statistics. 
Immunogenicity Analysis Population: For immunogenicity samples, included all 
subjects who receive at least 1 dose of abatacept and have at least 1 immunogenicity 
result reported. 
 
Endpoint Definitions 
The primary endpoint assessment will be the biochemical response rate defined by 
normalization of alkaline phosphatase or decrease of alkaline phosphatase by > 40% of 
the Day 0 level at 24 weeks of treatment.  
Secondary endpoints will include: 
• Absolute and percent change in alkaline phosphatase from Day 0 to 24 weeks. 
• Absolute and percent change in alanine transferase (ALT) from Day 0 to 24 
weeks. 
• Change in liver stiffness from Day 0 to week 24 as measured by magnetic 
resonance elastography. 
• Change in quality of life measured by change in PBC-40 from Day 0 to week 24. 
• Change in AMA titer from Day 0 to week 24 
• Change in IgM level from Day 0 to week 24 
• Change in CD4+CD44+CD62L- and CD8+CD44+CD62L- frequencies in PBMC 
from Day 0 to week 24 
• Comparisons of safety assessments pre-treatment, on-treatment, and post-
treatment including adverse events, laboratory observations, and physical exam 
findings. 
• Trough concentrations of abatacept from week 0 to week 24 
• Immunogenicity evaluated over time by measuring serum anti-abatacept 
antibodies and anti-CTLA-4-T antibodies 
 
Analyses 
Endpoints of efficacy will be compared between Day 0 and Week 24 using paired t-test 
(or Wilcoxon signed rank test as indicated) for continuous variables and Chi-square test 

PROTOCOL TITLE: ABATACEPT FOR THE TREATMENT OF PRIMARY 
BILIARY CIRRHOSIS WITH AN INCOMPLETE BIOCHEMICAL RESPONSE TO 
URSODEOXYCHOLIC ACID 
 
 
Page 16 of 26 
Revised: 2September 22, 2015 
(or Fisher’s exact test) for categorical variables. For variables measured at multiple time 
points, Repeated Measures ANOVA will be employed. All analyses will be two-tailed 
and P values less than 0.05 will be considered as statistically significant. 
The primary endpoint assessment will be the biochemical response rate defined by 
normalization of alkaline phosphatase or decrease of alkaline phosphatase by > 40% of 
the Day 0 level at 24 weeks of treatment. We will report the observed biochemical 
response rate and a 95% confidence interval for the expected biochemical response rate. 
We will assess each of the secondary endpoints:  absolute and percent change in alkaline 
phosphatase, absolute and percent change in alanine transferase (ALT), change in liver 
stiffness as measured by magnetic resonance elastography, change in quality of life 
measured by change in PBC-40, change in AMA titer, change in IgM level, and change 
in CD4+CD44+CD62L- and CD8+CD44+CD62L- frequencies in PBMC from Day 0 to 
week 24 by paired t-test or Wilcoxon signed-rank test when appropriate.  Because these 
endpoints will be generated with these studies, to solve the problem of the above multiple 
significance testing, we will use the false discovery rate proposed by Benjamini and 
Hochberg. In addition, PK and immunogenicity of abatacept in patients with PBC will be 
estimated. 
Descriptive statistics will be used to summarize safety data to allow a comparison 
between pre-treatment, on-treatment, and post-treatment. Safety data, including AEs, 
clinical and laboratory observations and physical examination findings, and other safety 
related outcomes will be summarized. Summary tables of treatment-emergent AEs will 
be provided. A treatment emergent AE (TEAE) is any AE that newly appeared, increased 
in frequency, or worsened in severity following initiation of study medication.  AEs will 
be included in the treatment-emergent analysis if the onset date is on or after the first day 
of dosing and up to 56 days post the last dosing day. The incidence of TEAEs will be 
tabulated by system organ class and preferred term for each treatment group, and by 
severity and relationship to treatment. Tables of TEAEs leading to study medication 
discontinuation and SAEs will be provided. Descriptive statistics summarizing laboratory 
data (hematology and chemistry) will be presented for all trial visits. Changes from 
pretreatment to each trial visit will also be summarized. Additional safety assessments 
include vital signs, physical examinations, and ECGs. 
For safety assessments pre-treatment, on-treatment, and post-treatment including adverse 
events, laboratory observations, and physical exam findings, repeated measures analysis 
of variance (ANOVA) will be employed to analyze a continuous outcome variable 
measured at these multiple time points, and a generalized estimating equation will be 
used to analyze a count or binary outcome variable measured at these multiple time 
points in order to take into account a possible unknown correlation among outcomes 
obtained on the same patient. 
 

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BILIARY CIRRHOSIS WITH AN INCOMPLETE BIOCHEMICAL RESPONSE TO 
URSODEOXYCHOLIC ACID 
 
 
Page 17 of 26 
Revised: 2September 22, 2015 
Clinical outcomes will be assessed including death from hepatic and non-hepatic causes, 
liver transplantation or placement on a liver transplant list, MELD score ≥ 15, new 
complications of liver disease including DILI as defined above, esophageal variceal 
bleeding, interventions to manage variceal bleeding, ascites, hepatic encephalopathy, 
renal failure, spontaneous bacterial peritonitis, and hepatocellular carcinoma.  
Summary statistics for abatacept concentrations from Week 0 to Week 24 will be 
tabulated. Lack of immunogenicity is defined as the absence of a positive antibody 
response generated against abatacept administered subcutaneously. The incidence of a 
positive response will be summarized. The data will be analyzed to assess 
immunogenicity and its potential effect on pharmacokinetics and safety. 
Procedures for maintenance of confidentiality: 
• All data and specimens will be stored on password protected 
computers in locked offices and in monitored freezers/refrigerators 
• The data will only be stored for the duration of the study and then 
destroyed. 
• Only authorized research personnel will have access to the data and/or 
specimens. 
• Ultimately the PI is responsible for the transmission of data and 
specimens, but this duty will likely be delegated to a qualified study 
coordinator. 
15) Provisions to Monitor the Data to Ensure the Safety of Subjects 
Data Monitoring Committee 
An independent multidisciplinary Data Monitoring Committee (DMC) 
will review the progress of the study and perform interim data reviews in 
order to protect subject welfare and preserve study integrity. The first 
DMC review will be conducted after the first 5 subjects enrolled complete 
through week 24. The DMC will subsequently meet after every 5 subjects 
complete 24 weeks of treatment and finally after the last subject enrolled 
completes through week 32. In addition, the DMC will receive every 
Serious Adverse Event (SAE) in the trial in real time and monthly listings 
of all Adverse Events (AEs) reported. The DMC members can request an 
ad hoc meeting based on their review of these safety events. Finally, if a 
minimum of 2 subjects in the trial either experience the same treatment-
emergent Grade 3 AE or if any one subject experiences a Grade 4 or 5 AE 
by the MedDRA grading system, this will trigger an ad hoc meeting of the 
DMC to review the safety of continuing the trial. The DMC will provide 
recommendations as needed regarding study design and conduct. The 
DMC has the authority to terminate the trial early if they determine that 
continuing the trial puts the subjects in the trial at undue risk. 

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BILIARY CIRRHOSIS WITH AN INCOMPLETE BIOCHEMICAL RESPONSE TO 
URSODEOXYCHOLIC ACID 
 
 
Page 18 of 26 
Revised: 2September 22, 2015 
16) Withdrawal of Subjects 
Discontinuation of Subjects from Treatment 
Subjects MUST discontinue investigational product (and noninvestigational product at 
the discretion of the investigator) for any of the following reasons: 
• Withdrawal of informed consent (subject’s decision to withdraw for any reason). 
• Any clinical adverse event, laboratory abnormality, or intercurrent illness which, in 
the opinion of the investigator, indicates that continued participation in the study is 
not in the best interest of the subject. 
• Pregnancy 
- Instruct WOCBP to contact the investigator or study staff immediately if they 
suspect they might be pregnant (eg, missed or late menstrual period) at any 
time during study participation. Institutional policy and local regulations 
should determine the frequency of on-study pregnancy tests for WOCBP 
enrolled in the study. 
- The investigator must immediately notify BMS if a study subject becomes 
pregnant. 
• Loss of ability to freely provide consent through imprisonment or involuntary 
incarceration for treatment of either a psychiatric or physical (eg, infectious disease) 
illness. 
All subjects who discontinue should comply with protocol-specified follow-up 
procedures. The only exception to this requirement is when a subject withdraws consent 
for all study procedures or loses the ability to consent freely (ie, is imprisoned or 
involuntarily incarcerated for the treatment of either a psychiatric or physical illness). If a 
subject withdraws before completing the study, the reason for withdrawal must be 
documented appropriately. 
 
17) Risks to Subjects 
From the ICF: 
You may have unwanted effects and symptoms as a result of taking Abatacept.  
Abatacept has been approved by the Federal Drug Administration (FDA) for the 
treatment of Rheumatoid Arthritis (RA). The most common side effects in people with 
RA were: 
Common  
 
Headache  
 
Cough  
 
Upper respiratory tract infection (chest cold)  

PROTOCOL TITLE: ABATACEPT FOR THE TREATMENT OF PRIMARY 
BILIARY CIRRHOSIS WITH AN INCOMPLETE BIOCHEMICAL RESPONSE TO 
URSODEOXYCHOLIC ACID 
 
 
Page 19 of 26 
Revised: 2September 22, 2015 
 
Sore throat  
 
Nausea  
 
Nasopharyngitis (inflammation of nose)  
 
Less Common  
 
Dizziness  
 
Increased blood pressure  
 
Urinary tract infection  
 
Herpes simplex  
 
Runny nose  
 
Abdominal pain  
 
Diarrhea  
 
Indigestion  
 
Fatigue  
 
Rare but Serious  
 
Infusion and allergic reactions  
 
Pneumonia  
 
Cellulites (inflammation of tissue under your skin)  
 
Urinary tract infection  
 
Bronchitis  
 
Diverticulitis (GI irritation)  
 
Acute pyelonephritis (kidney infection)  
 
COPD (chronic obstructive pulmonary disease) episodes (when COPD is 
existing)  
 
Cough  
 
Rhonchi (abnormal breath sound)  
 
Dyspnea (shortness of breath)  
 
Participants with a history of Chronic Obstructed Pulmonary Disease treated with 
abatacept had more COPD episodes, cough, rhonchi (abnormal breath sound), and 
dyspnea (shortness of breath) than those who did not get abatacept.  

PROTOCOL TITLE: ABATACEPT FOR THE TREATMENT OF PRIMARY 
BILIARY CIRRHOSIS WITH AN INCOMPLETE BIOCHEMICAL RESPONSE TO 
URSODEOXYCHOLIC ACID 
 
 
Page 20 of 26 
Revised: 2September 22, 2015 
 
There have also been rare cases of certain kinds of cancer in patients receiving abatacept-
but the role of abatacept in the development of cancer are not known. 
 
There is also an increased risk of serious infection, but is usually seen in those using 
immune suppressing drugs.  
 
You should not receive any live vaccines while on treatment in this study. The vaccines 
may not be as effective while you are receiving Abatacept. 
 
 
 
>10%: 
 
Central nervous system: Headache (≤18%) 
 
Gastrointestinal: Nausea 
 
Respiratory: Nasopharyngitis (12%), upper respiratory tract infection 
 
Miscellaneous: Infection (adults 54%; children 36%), antibody development (2% to 41%)  
 
1% to 10%: 
 
Cardiovascular: Hypertension (7%) 
 
Central nervous system: Dizziness (9%) 
 
Dermatologic: Skin rash (4%) 
 
Gastrointestinal: Dyspepsia (6%), abdominal pain, diarrhea 
 

PROTOCOL TITLE: ABATACEPT FOR THE TREATMENT OF PRIMARY 
BILIARY CIRRHOSIS WITH AN INCOMPLETE BIOCHEMICAL RESPONSE TO 
URSODEOXYCHOLIC ACID 
 
 
Page 21 of 26 
Revised: 2September 22, 2015 
Genitourinary: Urinary tract infection (6%) 
 
Immunologic: Immunogenicity (1% to 2%) 
 
Infection: Herpes simplex infection, influenza 
 
Local: Injection site reaction (3%)  
 
Neuromuscular & skeletal: Back pain (7%), limb pain (3%) 
 
Respiratory: Cough (8%), bronchitis, pneumonia, rhinitis, sinusitis 
 
Miscellaneous: Infusion-related reaction (≤9%), fever 
 
<1% (Limited to important or life-threatening): Acute lymphocytic leukemia, 
anaphylactoid reaction, anaphylaxis, cellulitis, diverticulitis, dyspnea, exacerbation of 
arthritis, exacerbation of chronic obstructive pulmonary disease, hypersensitivity, 
hypotension, joint wear, malignant neoplasm (including malignant melanoma, malignant 
neoplasm of the bile duct, malignant neoplasm of bladder, malignant neoplasm of breast, 
malignant neoplasm of cervix, malignant neoplasm of kidney, malignant neoplasm of 
prostate, malignant neoplasm of skin, malignant neoplasm of thyroid, myelodysplastic 
syndrome, and uterine neoplasm), malignant neoplasm of lung, ovarian cyst, pruritus, 
pyelonephritis, rhonchi, urticaria, varicella, vasculitis (including hypersensitivity angiitis 
[cutaneous vasculitis and leukocytoclastic vasculitis]), wheezing 
There may be other risks that are not yet known. If you experience any unwanted effects, 
make a note of them and report them to the investigator at your next scheduled visit or 
phone call. If you have any serious unwanted effects or if you are not sure if the 
unwanted effect is serious, call the investigator or the study center immediately at 
the telephone number listed on page 1 of this document. 
It is not known whether treatment with Abatacept may cause injury or harm to an unborn 
child if taken during pregnancy. For this reason, pregnant women are not allowed to take 
part in this study. All women of childbearing age must use a reliable form of birth control 
while participating in this study. If you should become pregnant during the study, inform 
the investigator or the study center immediately at the address listed on page 1 of 
this document. Your participation in the study will be stopped, and you may be asked to 
sign a separate consent form so the progress of the pregnancy can be followed until the 
birth of the child. 

PROTOCOL TITLE: ABATACEPT FOR THE TREATMENT OF PRIMARY 
BILIARY CIRRHOSIS WITH AN INCOMPLETE BIOCHEMICAL RESPONSE TO 
URSODEOXYCHOLIC ACID 
 
 
Page 22 of 26 
Revised: 2September 22, 2015 
It is not known if the study medication could cause harm to a breast-feeding infant if 
passed through the breast milk. For this reason, breast-feeding women are not allowed to 
take part in this study. 
It is also not known if the medication can be passed through sperm and cause injury or 
harm to a/during pregnancy. Therefore, it is advised that female partners of male study 
participants do not become pregnant during the treatment phase of this study and use 
effective forms of birth control. 
Subcutaneous Injections: 
Subcutaneous injections may be slightly painful, cause bruising or, rarely, and infection. 
 
Blood Drawing:  
Blood drawing is mildly painful and can cause bruising and, very rarely, fainting, blood 
clots or an infection at the site. 
 
Electrocardiogram (ECG): 
There is no pain or discomfort during an ECG; however, removing the pads may cause 
some irritation to your skin. 
 
Magnetic Resonance Elastography (MRE): 
Magnetic resonance imaging uses a strong magnetic field, which is not harmful in itself, 
but implanted medical devices that contain metal may malfunction or cause problems 
during an MR exam.  If you have any implanted devices please inform the doctors before 
the procedure.  
 
HIV Testing: 
Being tested for HIV may cause anxiety regardless of the test results. A positive test 
indicates that you have been infected with the HIV virus, but no one knows for certain 
when, if ever, you will become sick with AIDS or a related condition. Receiving positive 
results may make you very upset. If other people learn about your positive test results, 
you may have trouble obtaining insurance or employment. If your test is negative, there is 
still the possibility that you could be infected with the HIV virus and test positive at some 
time in the future. Also, it is always possible that the test results could be wrong. 
 
Privacy Risks: 
There may also be risks to your privacy.  The Researchers will store study records and 
other information about you in a secure location and will grant access only to those with a 
need to know.  However, just like with other personal information kept by your health 

PROTOCOL TITLE: ABATACEPT FOR THE TREATMENT OF PRIMARY 
BILIARY CIRRHOSIS WITH AN INCOMPLETE BIOCHEMICAL RESPONSE TO 
URSODEOXYCHOLIC ACID 
 
 
Page 23 of 26 
Revised: 2September 22, 2015 
care providers, your banks, and others, even these safeguards cannot guarantee absolute 
protection of the data.  If private information gets into the wrong hands, it can cause 
harm.  Although rare, there are reported cases of breaches that have resulted in 
discrimination in insurance or employment. 
 
Unknown/Unexpected Risks: 
In addition to the risks listed above, there are risks that are not known or do not happen 
often when subjects take study drugs, including severe or life-threatening allergic 
reactions, interactions between study drugs or interactions with another medication.  You 
will be informed as soon as possible, both verbally and in writing, of any new 
information, findings or changes to the way the research will be done that might 
influence to whether you want to stay in this study. 
 
18) Potential Benefits to Subjects 
From the ICF:  
You may not have any benefits from taking part in this clinical study. It is possible that 
treatment with Abatacept may improve your PBC. 
Although you may not receive any personal benefit, taking part in this study may benefit 
others by providing new information about the treatment of PBC. 
 
19) Vulnerable Populations 
n/a. 
20) Multi-Site Research 
n/a 
21) Community-Based Participatory Research 
n/a. 
22) Sharing of Results with Subjects 
Results will not be shared with patients; however information regarding 
the progress of the trial will be available on clinicaltrials.gov. 
23) Setting 
UC Davis Medical Center, Main Hospital, 2315 Stockton Blvd., 
Sacramento, CA 95817 
And 

PROTOCOL TITLE: ABATACEPT FOR THE TREATMENT OF PRIMARY 
BILIARY CIRRHOSIS WITH AN INCOMPLETE BIOCHEMICAL RESPONSE TO 
URSODEOXYCHOLIC ACID 
 
 
Page 24 of 26 
Revised: 2September 22, 2015 
UC Davis Medical Center Ticon 1, 2000 Stockton Blvd, Suite 100, 
Sacramento, CA 95817 
o Patients will be recruited from the GI/Hepatology clinic. 
All research procedures will be performed at the above mentioned 
addresses. 
24) Resources Available 
All staff has also been delegated research specific responsibilities by the 
PI who is compliant and up to date with all required training. 
Role 
Research Duties 
Principal Investigator 
Determination of eligibility, consent, f/u evaluations, supervision of all study 
personnel and procedures.  
Co-Investigator/  
Sub-Investigator 
Perform PI functions if PI absent 
Consent, determination of eligibility, f/u evaluations 
Study Coordinator 
Consent, CRFs, patient visits, study protocol compliance, documentation, 
IRB communication 
 
 
 
• We should have no problem reaching the goal of 20 patients. 
• Each coordinator is tasked with 2-4 studies depending on study 
complexity and availability. This ensures that coordinators are 
able to devote adequate and ample time to each study. 
• We are a clinical trial research clinic only consisting of patients 
rooms, a laboratory and office space. 
• The main hospital is across the street should urgent medical 
attention be needed. 
• All research staff are CITI trained and have been delegated 
authority to conduct the research by the PI according to their job 
descriptions. 
• All research staff are delegated by the PI to perform any clinical 
trial and are trained extensively on the protocol by self and the 
sponsor. 
25) Prior Approvals 
n/a 
26) Provisions to Protect the Privacy Interests of Subjects 
Potential subjects will be approached by the PI to gauge interest in 
participating. If the subject declines, no other attempts will be made.  

PROTOCOL TITLE: ABATACEPT FOR THE TREATMENT OF PRIMARY 
BILIARY CIRRHOSIS WITH AN INCOMPLETE BIOCHEMICAL RESPONSE TO 
URSODEOXYCHOLIC ACID 
 
 
Page 25 of 26 
Revised: 2September 22, 2015 
In order to help the subjects feel at ease, all conversations will be discreet 
and will occur in private patient areas.  
Only the PI and research staff is permitted to access information about the 
subject in regards to the study. 
27) Compensation for Research-Related Injury 
If patients are injured as a result of being in this study, the University of 
California will provide necessary medical treatment. Depending on the 
circumstances, the costs of the treatment may be covered by University or 
the study sponsor or may be billed to your insurance company just like 
other medical costs. The University and the study sponsor do not normally 
provide any other form of compensation for injury. 
 
28) Economic Burden to Subjects 
Subjects are not responsible for any costs. 
29) Consent Process 
• Consent will take place at UC Davis Medical Center, Ticon 1, 2000 
Stockton Blvd.,Suite 100,  Sacramento, CA 95817. 
• Subjects will have all questions answered before signing the consent 
form. 
• Patients will be re-consented if changes to the protocol affect their 
study involvement or the risks change. 
• The PI will be following “SOP: Informed Consent Process for 
Research (HRP-090).” 
HIPAA Authorization for Research 
HIPAA Authorization form will be presented to patients or their legally 
authorized representative. 
30) Process to Document Consent in Writing 
The PI will be following “SOP: Written Documentation of Consent (HRP-
091).” 
31) Drugs or Devices 
• Identify of the holder of the IND/IDE/Abbreviated ID: Bristol Myers 
Squibb 
• The UC Davis Investigational Pharmacy will be handling all 
investigational drug(s) for the trial in accordance with their SOPs for 
storing, handling and dispensing. 
• Patients will be given cooler bags to accommodate the study drug on 
their way from the clinic to their homes. 

PROTOCOL TITLE: ABATACEPT FOR THE TREATMENT OF PRIMARY 
BILIARY CIRRHOSIS WITH AN INCOMPLETE BIOCHEMICAL RESPONSE TO 
URSODEOXYCHOLIC ACID 
 
 
Page 26 of 26 
Revised: 2September 22, 2015 
• Explain and/or provide reference material for procedures that will 
follow and comply with FDA sponsor requirements for the following: 
 
Applicable to: 
FDA Regulation 
IND 
studies 
IDE 
studies 
Abbreviated 
IDE studies 
21 CFR 11 
• Electronic Records and Signatures 
X 
X 
 
21 CFR 54 
• Financial Disclosure by Clinical 
Investigators 
X 
X 
 
21 CFR 210 
• Current Good Manufacturing Practice in 
Manufacturing, Processing, Packing, or 
Holding of Drugs 
X 
 
 
21 CFR 211 
• Current Good Manufacturing Practice for 
Finished Pharmaceuticals 
X 
 
 
21 CFR 312 
• Investigational New Drug Application 
X 
 
 
21 CFR 812 
• Investigational Device Exemptions 
 
X 
X 
21 CFR 820 
• Quality System Regulation 
 
X 
 
21 CFR 11- All study related activities take place at UC Davis medical 
center using UC Davis computers that comply with this regulation 
21 CFR 54- The PI does not have a financial conflict of interest. 
21 CFR 210- Please refer to the sponsor’s Investigator’s 
Brochure/package insert 
21 CFR 211- Information not available to us. IRB may contact the 
sponsor if needed. 
21 CFR 312- Sponsor has applied for and received an IND for the 
experimental drug. 
21 CFR 812 – n/a 
21 CFR 820 – n/a