Clinical trial NCT02429934
Conditions: Systemic Lupus Erythematosus Arthritis
Keywords: Systemic Lupus Erythematosus (SLE) Abatacept (Orencia) Arthritis
Sponsor: University of California, Los Angeles
Start date: 2015-10-01; Completion date: 2019-09-01
Enrollment: 28 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This research trial is for patients who have been diagnosed with systemic lupus erythematosus (SLE) with swollen, tender joints (which is called inflammatory polyarthritis) because of the SLE.

The purpose of this clinical research study is to evaluate the safety and effectiveness of treatment with abatacept (Abatacept) 125mg injected subcutaneously (under the skin) weekly for 16 weeks versus placebo injections(a substance with no active ingredients and therefore may have no treatment benefit) in subjects with SLE and inflammatory polyarthritis. The effectiveness will be assessed primarily by the number of swollen, tender joints (called a joint count) at each of study visits.

Study Medication Abatacept is approved in the U.S. for treating rheumatoid arthritis by prescription and has not been approved by the U.S. Food and Drug Administration for treating SLE yet.

In this study, subjects will receive treatment with either abatacept or placebo once a week for 16 weeks (a total of 16 injections).

Detailed description:

Arms: arm 1: 32 SLE patients to be treated with subcutaneous abatacept 125mg sq once a week for 16 weeks. arm 2: 32 SLE patients to be treated with subcutaneous placebo once a week for 16 weeks. Injection will be vehicle injected subcutaneously once a week for 16 weeks
Interventions: intervention 1: abatacept also known as Orencia also known as CTLA4-Ig intervention 2: Placebo
Intervention descriptions: intervention 1: 125mg injected subcutaneously weekly for 16 weeks intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
 
Protocol Amendment 1, November 30, 2015 
1 
 
 
 
 
Efficacy of Abatacept in Inflammatory Polyarthritis of Systemic Lupus Erythematosus 
(SLE) 
 
 
 
Bevra H. Hahn, MD 
Professor of Medicine 
UCLA David Geffen School of Medicine 
1000 Veteran Avenue, Room 32-59, Los Angeles, CA 90095-1670 
Phone Number: (310) 825-7991 
Fax Number: (310) 206-8606 
bhahn@mednet.ucla.edu 
 
 
 
[Protocol Version/Date: Amendment 2, June 11, 2018] 
 
 
 
 
 


 
Protocol Amendment 1, November 30, 2015 
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TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................... 2 
PROTOCOL SYNOPSIS.................................................................................................... 1 
1 
INTRODUCTION ......................................................................................... 6 
1.1 
Research Hypothesis ...................................................................................... 6 
1.2 
Product Development Rationale .................................................................... 6 
1.2.1 
Overview of Systemic Lupus Erythematosus .................................................. 6 
1.2.2 
Polyarthritis in Lupus Patients ...................................................................... 6 
1.2.3 
Role of T cells in Systemic Lupus Erythematosus .......................................... 7 
1.3 
Summary of Results of Investigational Program in Rheumatoid Arthritis .... 8 
1.3.1 
Core Efficacy Studies of Abatacept in Rheumatoid Arthritis ......................... 9 
1.3.2 
Pharmacokinetics of Subcutaneous Formulation .......................................... 9 
1.3.3 
Safety of Abatacept in Core Rheumatoid Arthritis Studies .......................... 12 
1.3.4 
Safety of SC Formulation ............................................................................. 13 
1.4 
Overall Risk/Benefit Assessment ................................................................. 16 
1.5 
Study Rationale ............................................................................................ 17 
2 
STUDY OBJECTIVES ................................................................................ 17 
2.1 
Primary Objective ........................................................................................ 17 
2.2 
Secondary Objectives .......................................................................................  
3 
ETHICAL CONSIDERATIONS ................................................................. 18 
3.1 
Good Clinical Practice ................................................................................. 18 
3.2 
Institutional Review Board/Independent Ethics Committee ........................ 18 
3.3 
Informed Consent ......................................................................................... 19 
3.4  
Stopping Rules 
4 
INVESTIGATIONAL PLAN ...................................................................... 19 
4.1 
Study Design and Duration .......................................................................... 19 
4.2 
Study Population .......................................................................................... 22 
4.2.1 
Inclusion Criteria ......................................................................................... 22 
4.3 
Concomitant Treatments .............................................................................. 27 
4.3.1 
Prohibited and/or Restricted Treatments ..................................................... 27 
4.3.2 
Other Restrictions and Precautions ............................................................. 27 
4.4 
Discontinuation of Subjects from Treatment ............................................... 27 
5 
TREATMENTS ........................................................................................... 28 


 
Protocol Amendment 1, November 30, 2015 
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5.1 
Study Treatment: Abatacept ......................................................................... 28 
5.1.1 
Identification ................................................................................................ 28 
5.1.2 
Storage, Handling, and Dispensing ............................................................. 28 
5.1.3 
Additional Information for the Handling, Dispensing, and Storage of 
Abatacept ..................................................................................................... 29 
5.2 
Method of Assigning Subjects to a Treatment ............................................. 29 
5.3 
Selection and Timing of Dose for Each Subject .......................................... 29 
5.3.1 
Dose Modifications for Adverse Events ....................................................... 29 
5.4 
Blinding/Unblinding .................................................................................... 30 
5.5 
Concomitant Treatments .............................................................................. 30 
5.5.1 
Prohibited and/or Restricted Treatments ..................................................... 30 
5.5.2 
Other Restrictions and Precautions ............................................................. 30 
5.5.2.1 
Immunizations .............................................................................................. 30 
5.6 
Management of Possible Acute Hypersensitivity Reactions to Abatacept .. 31 
5.7 
Treatment Compliance ................................................................................. 32 
6 
STUDY ASSESSMENTS AND PROCEDURES ....................................... 32 
6.1 
Time and Events Schedule ........................................................................... 32 
6.1.1 
Study Completion or Early Discontinuation Visit ........................................ 35 
6.1.2 
Study Drug Discontinuation ......................................................................... 35 
6.2 
Study Materials ............................................................................................ 40 
6.3 
Safety Assessments ...................................................................................... 40 
6.3.1 
Physical Examinations ................................................................................. 40 
6.3.2 
Manual Breast Examination and Breast Cancer Screening ........................ 40 
6.3.3 
Tuberculin Skin Testing ............................................................................... 40 
6.4 
Efficacy Assessments ................................................................................... 41 
6.4.1 
Primary Efficacy Assessment ....................................................................... 43 
6.4.2 
Secondary Efficacy Assessments .................................................................. 43 
7 
ADVERSE EVENT REPORTING .............................................................. 44 
7.1 
Adverse Events ............................................................................................ 44 
7.1.1 
Serious Adverse Events ................................................................................ 44 
7.1.2 
Nonserious Adverse Events .......................................................................... 45 
7.2 
Assignment of Adverse Event Intensity and Relationship to Abatacept...... 45 
7.3 
Collection and Reporting ............................................................................. 46 


 
Protocol Amendment 1, November 30, 2015 
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7.3.1 
Serious Adverse Events ................................................................................ 46 
7.3.2 
Handling of Expedited Safety Reports ......................................................... 47 
7.3.3 
Nonserious Adverse Events .......................................................................... 48 
7.4 
Laboratory Test Abnormalities .................................................................... 48 
7.5 
Overdose ...................................................................................................... 48 
7.6 
Pregnancy ..................................................................................................... 48 
7.6.1 
Requirements for Pregnancy Testing ........................................................... 49 
7.6.2 
Reporting of Pregnancy ............................................................................... 49 
7.7 
Other Safety Considerations ........................................................................ 49 
8 
STATISTICAL CONSIDERATIONS ......................................................... 50 
8.1 
Sample Size Determination .......................................................................... 50 
8.2 
Populations for Analyses ............................................................................. 50 
8.3 
Endpoint Definitions .................................................................................... 50 
8.4 
Analyses ........................................................Error! Bookmark not defined. 
8.4.1 
Demographics and Baseline Characteristics ............................................... 51 
8.4.2 
Safety Analyses ............................................................................................. 51 
8.4.3 
Efficacy Analyses ......................................................................................... 51 
8.4.4 
Other Analyses ............................................................................................. 52 
9 
ADMINISTRATIVE SECTION .................................................................. 52 
9.1 
Compliance with the Protocol ...................................................................... 52 
9.2 
Records Retention ........................................................................................ 52 
9.3 
Destruction of Investigational Product......................................................... 52 
10 
GLOSSARY OF TERMS ............................................................................ 54 
11 
LIST OF ABBREVIATIONS ...................................................................... 55 
12 
REFERENCES ............................................................................................ 58 
 
 


 
Protocol Amendment 1, November 30, 2015 
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PROTOCOL SYNOPSIS 
 
Protocol Title: 
 
Site Numbers & 
Names: 
001: UCLA Rheumatology  002: UCSD Rheumatology 
Research 
Hypothesis: 
Primary:  Abatacept will improve lupus inflammatory 
polyarthritis in patients by 16 weeks of treatment. 
Study Rationale 
Inflammatory polyarthritis is common in people with SLE, with 
swollen, tender joints occurring in up to 88% of patients 1.  
Inflammatory arthritis often improves on aggressive therapies, 
including glucocorticoids, mycophenolate, and 
cyclophosphamide 2, sometimes with azathioprine, and 
occasionally with methotrexate or leflunomide.  The use of 
abatacept by the subcutaneous route is a highly attractive 
alternative for treatment of lupus arthritis for the following 
reasons.  
1) Abatacept is effective in rheumatoid arthritis, which lupus 
arthritis resembles 3,  
2) The synovitis of SLE depends on activated innate and 
adaptive immunity, with antigen-presenting cells (APC) 
activating effector T cells, which activate B cells. Together, these 
cells secrete pro-inflammatory cytokines including IFN type 1, 
IFNgamma and IL-17 4. Interruption of CD80/86-CD28 
interactions by abatacept should block APC/T cell signals that 
drive inflammation, without blocking regulatory cell generation 
that is anti-inflammatory. 
 3) A prospective controlled trial of abatacept in SLE showed a 
lower flare rate in patients with polyarthritis who received 
abatacept compared to patients with polyarthritis who received 
placebo 5. 
4)   A recently published retrospective study of 6 patients with 
rhupus (satisfying ACR criteria for both rheumatoid arthritis and 
systemic lupus erythematosus) showed that all responded to 
abatacept with decrease in Clinical Disease Activity Index (a 
validated measure of disease activity in rheumatoid arthritis) and 
minimal adverse events6. 
 


 
Protocol Amendment 1, November 30, 2015 
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Study Objectives: 
 
 
 
 
 
 
 
 
Primary:  Improvement of lupus inflammatory polyarthritis 
measured by ≥20% improvement in tender and swollen 28 joint 
counts at 16 weeks. 
Secondary: 
1. Mean and median joint counts in treated vs placebo patients 
at 16 weeks, compared to baseline scores. 
2.  Proportion of patients who achieve improvement in 
SLEDAI 2K at 16 weeks of >3 points. 
3. Mean and median changes in CDAI comparing abatacept to 
controls at 16 weeks. 
4. Changes in a) synovitis, b) tenosynovitis and c) erosions 
measured by high-energy ultrasound with Doppler flow at 
zero and 16 weeks. 
5. Proportion of patients with BILAG A in any system other 
than musculoskeletal at week 16. 
6. Proportion of patients with no significant increase in 
physician global assessment (defined as <0.8 on a 1-10 
scale) at 16 weeks. 
7. Steroid sparing effect of abatacept, measured as ability to 
taper prednisone to ≤10mg/day by week 16.  
8. Effects on fatigue at 16 weeks as measured by the FACIT 
fatigue score instrument 
9. Effects on quality of life at 16 weeks as measured by the SF 
36 
10. Safety, measured in standard methods as AE and SAE, 
including likelihood that the AE/SAE was related to the 
study biologic. 
11. Time to response, measured as time to  ≥20% decrease in 
joint counts (sum of tender and swollen joints) at zero, 4, 8, 
12, and 16 weeks. 
12. Change in peripheral blood T cell compartments indicating 
decline in pro-inflammatory profiles, i.e., we expect 
decrease in CD4+ effector T cells that make IFNgamma 
(TH1) and IL-17 (TH17) and increase in ratio of Treg to 
Teff, as well as decreased function of Thelper and increased 
functions of Tregs. CD4+CD25+ Foxp3+ and CD8+Foxp3+ 
will be the definition of regulatory T cells.  These will be 
measured at zero and 16 weeks. 
13. Change in anti-DNA and total IgG levels, as well as rise in 
serum complement levels as disease improves and fewer B 
cells are activated: measure these at zero, 8 and 16 weeks. 
14. Effects of abatacept on serum levels of BLyS (BAFF) at 
baseline, 8 and 16 weeks. As numbers of activated B cells 
and plasmablasts fall, we expect an increase in BLyS levels 
.  
 


 
Protocol Amendment 1, November 30, 2015 
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Study Design: 
 
Randomized trial of 32 SLE patients treated with subcutaneous 
abatacept 125mg sq once a week vs. 32 placebo treated subjects 
over a 16 week period. Patients will be seen every 4 weeks from 
baseline.  One half of patients will be recruited at UCLA and one-
half at UCSD. We expect 30 patients in each group to complete 
the 16 week study. 
Study Schema 
Drugs / Doses /  
Length of 
Treatment) 
 
Abatacept 125 mg or placebo will be administered 
subcutaneously once a week for 16 weeks.  There will be a 
telephone follow up 2 months after the last injection to capture 
post-treatment adverse events. 
Accrual Goal: 
(Total number of 
subjects) 
64 (32 at UCLA and 32 at UCSD)  
Accrual Rate: 
(Number of 
subjects expected 
per month) 
2-3 subjects per month at each site 
FPFV:  April 1, 
2015  
LPFV: March 31, 
2018 
Follow Up: 16 
weeks per patient 
plus 8 weeks of 
observation for 
adverse events 
 
 
Correlative Studies: 
These will be 
performed at the 
UCLA site only 
 
1) Biomarkers:  a) T cell numbers and phenotypic and functional 
characteristic in PBMC measured at week 0 and 16. These will 
include for T cells  CD4+, CD3+, CD25+, CD8+, Foxp3+ and 
cytoplasmic stains for IFNgamma, IL2, IL-17, IL21 and IL-10.  
b) B cell numbers and subsets, including naïve, activated and 
plasmablasts. 
c) Ability of autologous CD4+CD25hi T cells to suppress 
proliferation of  CD4+CD25- T cells. 
d) Cytokines in serum: IFNgamma, IL-6, IL-10,  IL-17, IL23 and 
BLyS 
2) Ultrasound with power Doppler of  joints assessing synovitis, 
tenosynovitis (18 joints) and erosions at week 0 and 16. 


 
Protocol Amendment 1, November 30, 2015 
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Inclusion Criteria 
 
 
 
 
 
 
 
 
 
 
1. Meet at least 4 of the 11 American College of 
Rheumatology (ACR) 1997 criteria for classification of SLE 
(see Appendix 1).OR meet the recent classification 
recommended by SLICC (Appendix 2) 6 
2. ≥3 swollen and tender joints on 2 examinations at least 2 
weeks apart and no more than 8 weeks apart. 
3. SLEDAI2K score ≥4 indicating active disease. 
4. Documented positive ANA (≥1:80) and/or anti-dsDNA 
during course of SLE. 
5. Men and women, at least 18 years of age.  Women of 
childbearing potential must use adequate method(s) of 
contraception to avoid pregnancy throughout the study and 
for up to 2 months after last study drug dose.  They must 
have a negative serum or urine pregnancy test prior to the 
start of study medication. 
6.   Background therapies allowed: antimalarials (dose constant 
for ≥ one month before study entry and during 16 weeks of 
trial), methotrexate (same criteria as for antimalarials), 
azathioprine (same criteria), mycophenolate (same criteria), 
leflunomide (same criteria).  
During the screening period and for up to 6 weeks after 
randomization, a daily prednisone (or equivalent) regimen 
of up to 20 mg daily  may be initiated to treat the moderate 
to severe disease activity present at screening.  The initial 
steroid regimen is not required if investigators or patients 
believe that the risks would outweigh the potential 
benefits.  Patients who do not take any glucocorticoids 
during the study will be included in the treatment groups 
and analysis. 
 
*Steroids should be tapered to a target dose of no more than 
10 mg/day of prednisone (or equivalent) by the end of Week 
8 (Day 56). The steroid regimen should be tapered as 
quickly as safely possible.  Prednisone dose requirements 
higher than 10 mg daily at the 8 week visit will cause the 
patient to be ruled a non-responder for the abatacept 
treatment arm. 
 


 
Protocol Amendment 1, November 30, 2015 
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Exclusion Criteria: 
 
 
1. Subjects with active infection requiring oral or IV 
antibiotics within one month of first dose of study 
medication. 
2. Subjects with BILAG A in any system outside the 
musculoskeletal system. 
3. Subjects with positive quantiferon Gold test in the absence 
of treatment for tuberculosis. 
4. Subjects with positive tests for active infection with 
hepatitis B or C during the past 6 months. Any confirmed 
positive test for HIV at any time prior to entry into this 
study. 
5. Subjects with active glomerulonephritis (>3 g protein/24h 
and/or active urine sediment). 
6. Subjects with active CNS disease. 
7. Subjects with any other serious disease that would require 
immunosuppressive or parenteral anti-microbial therapy 
outside the study protocol. 
8. Inability to self-administer subcutaneous injections, to 
comply with instructions, or to keep appointments for study 
visits. 
9. Treatment with rituximab within the past 6 months (B cells 
must be detectable in peripheral blood at onset of treatment 
with study biologic), belimumab within the past 3 months, 
cyclophosphamide within the past 3 months. 
10. Treatment with any other immunomodulatory biologic or 
cyclophosphamide during treatment with abatacept is not 
allowed. 
11.  Patients requiring >20 mg of prednisone daily. 
12. Women who are pregnant or breast feeding. 
13. Women of child bearing potential unwilling or unable to use 
an acceptable method to avoid pregnancy for the entire 
study period and for up to 2 months after last study drug. 
14. Subjects with a history of cancer within the last five years 
(other than non-melanoma skin cell cancers cured by local 
resection). 
15. Any laboratory test results that, in the opinion of the 
Investigator, might place the subject at unacceptable risk for 
participation in this study. 
 
Criteria for 
Evaluation: 
(Efficacy, safety, 
stopping rules, etc.) 
See text 
Statistics: 
See text 


 
Protocol Amendment 1, November 30, 2015 
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1 
INTRODUCTION 
1.1 
Research Hypothesis 
Abatacept via subcutaneous injection will induce clinical response in inflammatory polyarthritis in 
patients with systemic lupus erythematosus.  
1.2 
Product Development Rationale 
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 7-10. A 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 11, 12. 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 13. 
1.2.1 
Overview of Systemic Lupus Erythematosus  
Systemic Lupus Erythematosus (SLE) is an autoimmune disease with unknown etiology.  It is of 
great clinical variation as it can affect virtually all body systems including musculoskeletal, 
mucocutaneous, cardiovascular, neurological, respiratory, renal, ophthalmic, hematological and 
gastrointestinal systems.  
1.2.2 
Polyarthritis in Lupus Patients 
Inflammatory polyarthritis is common in systemic lupus patients, with swollen, tender joints 
occurring in up to 88% 1.   Although SLE arthritis is generally less destructive than rheumatoid 


 
Protocol Amendment 1, November 30, 2015 
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arthritis, joint deformities similar to rheumatoid arthritis can occur in 25-35% of SLE patients.  
Erosions detectable on standard x-rays occur in approximately 4%.  However, in multiple studies16-
19, high-resolution ultrasound and/or power Doppler of the wrists, MCPs and PIPs in SLE patients 
with hand arthritis showed synovitis in 70-95% depending on joint studied (synovitis was most 
abundant in wrists), erosions in approximately 50% (particularly in MCPs) and tenosynovitis in 
65%. 
Lupus arthritis can cause pain, stiffness, swelling, tenderness, and warmth of joints in a waxing and 
waning pattern.  Several joints may be involved at the same time and all major and minor joints 
may be affected.   
There is no definitive treatment or cure for lupus polyarthritis.  Standard of care for patients with 
lupus such as corticosteroids, NSAIDs, anti-malarials, and immunosuppressive drugs and biologics 
treat lupus polyarthritis as well as other SLE symptoms.  These treatments, however, especially 
immunosuppressive medications, have many side effects, including infectious complications. 
The PI recently reviewed 10 patients with lupus arthritis she examined serially. On a 66-joint 
tender/swollen joint count, the average score was 21. In two patients who had just completed 12-
week-long open clinical trials and who reported improvement, counts dropped from 22-31 to 
zero-4. Thus, arthritis is an important component of SLE and can easily be quantitated by 
experienced investigators to assess benefits of interventions. We are proposing here to use a 
standard 28 joint count, which includes the joints most frequently involved in SLE (hand 1-5 
PIPs, 1-5 MCPs, wrists, elbows, knees). Reliability of these joint counts (28 joints) has been well 
documented in patients with rheumatoid arthritis, the 28 joint count is standard in clinical 
investigations in RA, and the ultrasound examination for synovitis proposed here will examine 
the hand (PIP2-5, MCP 2-5) and wrist joints. Change in joint counts can be evaluated as a 
dichotomous variable (as we are proposing for the primary outcome measure), or as a continuous 
measure to increase sensitivity. In addition, as a secondary outcome we are proposing use of the 
Clinical Disease Activity Measure (CDAI)7,20 which is also a continuous variable. We have not 
used CDAI in studies of lupus arthritis, but a recent publication6 reports that the CDAI responded 
favorably to abatacept therapy in 6 of 6 patients with rhupus – an overlap syndrome between 
rheumatoid arthritis and systemic lupus. In RA, CDAI (a sum of swollen joints, tender joints, 
physician global assessment and patient global assessment) correlates well with DAS28, ACR 
response rates 20/50/70, HAQ scores and radiographic changes over time7. It has the advantage of 
not requiring laboratory assessments and thus can be done at the patient visit. 
1.2.3 
Role of T cells in Systemic Lupus Erythematosus 
The arthritis of SLE, like RA, is an inflammatory synovitis.  Histology, cell infiltrates and gene 
expression in synovial specimens from patients with SLE, RA and osteoarthritis were compared in 
a recent study4.  SLE arthritis was characterized by proliferation of synovial lining cells (less than 
in RA), diffuse mononuclear cells infiltrating into the synovium, and perivascular mononuclear cell 
infiltrates.  Infiltrating cells include CD3+ T cells, CD8+ T cells, CD20+ B cells, CD68+ 
macrophages and CD138+ plasma cells.  Nearly half of the genes dysregulated in RA synovial 
tissue related to T and B cell functions; nearly half in SLE were interferon-regulated genes and 
STAT1 (in the IFN pathway).  Since clinical disease in SLE is initiated by autoantibodies and 
immune complexes which deposit in target tissues, activate complement, and initiate inflammation, 
the role of B cells is central in the disease. Increases in circulating mature B cell subsets, such as 


 
Protocol Amendment 1, November 30, 2015 
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memory B cells, activated B, plasmablasts and short-lived plasma cells are characteristic21. Since 
most pathogenic autoantibodies and immune complexes contain IgG, and T cell help is required 
for Ig switch from IgM to IgG, T cell help is critical for sustaining many autoreactive B cells and 
promoting their differentiation to autoantibody-secreting plasma cells 22.  Helper CD4+ T cells can 
secrete IFNgamma or IL-17. Therefore, interfering with T cell activation and thus T cell help by 
administering abatacept should reduce B cell stimulation and therefore reduce quantities of 
autoantibodies and possibly of total IgG.  In this study, we propose to determine biological 
consequences of treatment with abatacept, which might include 1) decrease in numbers of activated 
CD4+CD25- T cells and in those cells that stain for IFNgamma or IL-17; 2) increased numbers 
(measured as CD4+CD25+Foxp3+ and CD8+Foxp3+ peripheral blood cells) and/or function of 
Tregs (measured as ability of CD4+CD25hi T cells to suppress proliferation of autologous  
CD4+CD25- T cells); 3 ) decreased plasma levels of IFNgamma, IL17 and IL23,  with increased 
levels of IL10 and TFGbeta. 4) decreased numbers of activated B cells and plasmablasts; 5) 
decreased quantities of total IgG, and IgG anti-DNA; 6) increased plasma levels of BLyS in 
response to lower numbers of activated/mature B cells and plasmablasts.  Any of these features 
would indicate a biologic effect of abatacept, whether or not those effects correlate with clinical 
outcomes. 
Recent data, published in abstract form, from other institutions performing clinical trials of 
abatacept in SLE suggest that responders can be differentiated from non-responders by 1) 
transcriptome differences in mononuclear cells at baseline, and 2) interferon signatures at baseline, 
based on changes in expression of genes induced by interferons (Bandyopadhyay S et al, De-
convolution of whole blood transcriptomic data from a phase IIb, randomized, double-blind, 
placebo-controlled trial of abatacept in systemic lupus erythematosus. 2015 ACR/ARHP Annual 
Meeting, abstract number 2067.) 
Most importantly, the treatment should suppress disease activity. In the published phase III 
trial of abatacept in SLE (without active nephritis), overall disease activity suppression 
occurred in both placebo and abatacept groups, but the group with polyarthritis had a 
significantly fewer flares with abatacept than with placebo 5. 
1.3 
Summary of Results of Investigational Program in Rheumatoid Arthritis 
The initial efficacy and safety of abatacept (previously known as CTLA4-Ig and BMS-188667) 
was established in clinical studies of RA, psoriasis, and multiple sclerosis. The subsequent 
registrational program was in juvenile idiopathic arthritis (JIA), with data being collected from the 
ongoing long-term extension portion. Current active registrational programs for abatacept include 
studies in systemic lupus erythematosus (SLE) including lupus nephritis, and psoriatic arthritis. 
A full development program conducted in adult RA led to regulatory approval in the United States 
for this indication in December 2005, in Canada in June 2006, and in Europe in May 2007. In the 
US, abatacept now has two indications: (1) treatment of moderate to severe active RA in adults, 
and (2) treatment of moderate to severe juvenile idiopathic arthritis (JIA) in patients who have 
failed prior therapy with disease-modifying anti-rheumatic drugs (DMARDs). 


 
Protocol Amendment 1, November 30, 2015 
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1.3.1 
Core Efficacy Studies of Abatacept in Rheumatoid Arthritis 
The RA clinical program consisted of five core studies: IM101-100, IM101-101, IM101-102, 
IM101-029, and IM101-031 (N=2944) 23-27. Each study had a double-blind placebo-controlled 
period of 6 months or 1 year. In Study IM101-100, subjects received abatacept 2 mg/kg, 10 mg/kg, 
or placebo. In the other studies, subjects received abatacept 10 mg/kg or a fixed dose that 
approximated 10 mg/kg or placebo. 
Subjects who completed the double-blind period were offered entry into an uncontrolled, open-
label period, in which all subjects received abatacept (in a fixed dose that approximated 10 mg/kg). 
A total of 2624 subjects in the core RA studies received the approved abatacept dose (10 mg/kg or 
a fixed dose that approximated 10 mg/kg) in the combined double-blind and open-label periods, 
representing 4603 person-years of exposure28. 
The efficacy of abatacept at a weight-tiered dose approximating 10 mg/kg was demonstrated in 
placebo-controlled studies in adult subjects with active RA and an inadequate response to 
methotrexate (IM101-100, IM101-102, and IM101-043), and in one study in adult subjects with 
active RA and an inadequate response to at least one TNF-blocking agent (etanercept and/or 
infliximab; IM101-029) 23-27,29-33  Other studies have provided additional supportive evidence of 
efficacy. Abatacept (10 mg/kg or a fixed dose approximating 10 mg/kg) was significantly more 
effective than placebo in reducing the signs and symptoms of RA, including induction of major 
clinical response, improving physical function, slowing the progression of structural damage, and 
improving the quality of life in subjects with moderately to severely active RA. 
In Studies IM101-102 and IM101-029, improvement in signs and symptoms assessed by the 
American College of Rheumatology (ACR) 20 response rate versus placebo was observed after 
administration of the first dose, as measured at Day 15, and it was maintained through the double-
blind study phase and for up to 3 years (in IM101-029 and IM101-102) and up to 5 years (in 
IM101-100)30,31. In the open-label extensions of IM101-100, IM101-102, and IM101-029, durable 
and sustained ACR20, ACR50, and ACR70 responses have been observed through 48, 24, and 18 
months, respectively, of abatacept treatment 30,32,33. 
1.3.2 
Pharmacokinetics of Subcutaneous Formulation 
Subcutaneous (SC) formulation in adult population 
Single SC doses of abatacept (50 to 150 mg) demonstrated approximately dose proportional PK in 
healthy adult subjects34. Following administration of single doses of 50 to 150 mg of abatacept, the 
mean Cmax increased from 3.5 to 10.7 μg/mL and the geometric mean AUC(INF) increased from 
1490 to 4270 μghour/mL. The median time to occurrence of Cmax (Tmax) following SC 
administration ranged between 48 and 168 hours. Mean T1/2 values in healthy subjects ranged from 
11.2 to 14.7 days. T1/2 values from this study were comparable with the T1/2 values obtained with 
abatacept administered IV to subjects with RA (13 to 14 days) 30. The fact that T1/2 values 
following SC dosing were comparable to T1/2 values obtained after IV dosing suggests that the 
elimination characteristics of abatacept were not altered following SC administration. 
A double-blind, randomized, placebo-controlled, parallel-group, multiple-dose study (IM101063) 
assessed the steady-state trough serum concentrations of abatacept following SC administration in 


 
Protocol Amendment 1, November 30, 2015 
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subjects with RA35. Subjects were randomized to receive either abatacept or placebo in 1 of 5 
parallel groups based on body weight obtained at the screening visit (Table 1.3.2). The SC dose 
regimens were selected to target trough levels between 10-30 ug/ml, which was associated with 
efficacy with the IV formulation. 
Table 1.3.2A 
IM101063 Treatment Groups Based on Body Weight 
Treatmen
t Group 
Subject weight 
(kg) 
IV dose on  
Day 1 (mg) 
SC dose weekly for 
12 weeks (mg) 
SC injection volume 
(mL) 
1 
< 60 
500 
75 
0.6 
2 
< 60 
500 
125 
1 
3 
60 - 100 
750 
125 
1 
4 
> 100 
1000 
125 
1 
5 
> 100 
1000 
200 
0.6 + 1.0 
Source: IM101063 CSR 
On Day 1, subjects received a single IV infusion (loading dose) of abatacept or placebo, based on 
their weight range. Approximately 1 hour after the completion of the IV infusion, subjects received 
their assigned SC dose of abatacept or placebo. Abatacept or placebo was administered weekly by 
the SC route, at the same dose as the SC dose on Day 1, for a total of 12 SC injections. Blood 
samples for PK analysis were collected on Day 1 prior to and at the end of the IV infusion. In 
addition, blood samples were collected prior to each weekly SC dose of abatacept. 
Steady-state trough serum concentrations were achieved after ~ 4 to 5 weeks following the 
combined regimen of a single IV loading dose and weekly SC injections. With the exception of 
Treatment group 4 (abatacept 125 mg SC weekly dose for subjects weighing > 100 kg), the mean 
steady-state trough concentrations across all other treatment groups appeared to be comparable.  
However, to truly represent the steady-state serum levels from SC administration without the 
contribution of the IV loading dose, Cmin values on Days 71-85 were selected, since contribution 
from IV was expected to be negligible. Comparison of mean steady-state trough concentrations on 
Day 71, 78 and 85 indicated that abatacept did not appear to accumulate following weekly dosing 
(Table 1.3.2B). 
Table 1.3.2B: 
Summary Statistics for Abatacept Steady-State Cmin Values on 
Days 71, 78, and 85 - IM101063 
Treatment Group 
Study 
Day 
n 
Cmin (g/mL) 
Geometric Mean 
(CV%) 
Cmin (g/mL) 
Median (Min, Max) 
1 (500 mg IV / 75 mg SC) 
71 
7 
22.64 (20.13) 
20.92 (17.06, 29.84) 
 
78 
7 
21.66 (19.99) 
22.40 (16.01, 28.93) 
 
85 
7 
23.62 (31.63) 
21.91 (18.24, 39.60) 


 
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Table 1.3.2B: 
Summary Statistics for Abatacept Steady-State Cmin Values on 
Days 71, 78, and 85 - IM101063 
Treatment Group 
Study 
Day 
n 
Cmin (g/mL) 
Geometric Mean 
(CV%) 
Cmin (g/mL) 
Median (Min, Max) 
2 (500 mg IV / 125 mg 
SC) 
71 
4 
28.03 (42.13) 
32.57 (13.73, 43.30) 
 
78 
3 
34.17 (29.49) 
33.10 (25.97, 46.40) 
 
85 
3 
36.73 (31.64) 
37.50 (26.26, 50.30) 
3 (750 mg IV / 125 mg 
SC) 
71 
26 
24.05 (40.65) 
26.53 (7.97, 54.11) 
 
78 
23 
24.41 (52.35) 
27.54 (5.40, 68.90) 
 
85 
25 
24.93 (38.42) 
26.01 (9.57, 53.80) 
4 (1000 mg IV / 125 mg 
SC) 
71 
3 
16.22 (24.39) 
15.15 (13.37, 21.07) 
 
78 
5 
11.57 (32.25)  
13.20 (6.89, 16.33) 
 
85 
5 
13.01 (41.35) 
13.30 (6.66, 22.73) 
5 (1000 mg IV / 200 mg 
SC) 
71 
5 
26.52 (56.53) 
26.20 (8.68, 55.20) 
 
78 
5 
29.21 (52.96) 
40.40 (8.04, 57.10) 
 
85 
5 
27.53 (58.87) 
29.01 (8.74, 62.00) 
Source:  IM101063 CSR, Supplemental Table S.8.2.2 
n=number of observations 
 
Steady-state pharmacokinetic parameters of abatacept after weekly SC administration were 
determined between the SC dosing interval from Day 71 to 78. Cmax and AUC(TAU) appear to be 
comparable in Treatment Groups 1, 3 and 5 (Table 1.3.2C). 


 
Protocol Amendment 1, November 30, 2015 
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Table 1.3.2C 
Summary Statistics for Abatacept Steady-State Pharmacokinetic 
Parameters - IM101063 
Treatment Group 
Pharmacokinetic Parameter 
Cmax (µg/mL)  
Geometric Mean (CV%) 
AUC(TAU) (µg*h/mL) 
Geometric Mean (CV%) 
1 (500mg IV / 75mg SC) 
n = 7  
26.3 (29.5) 
n = 7 
4066 (22.2) 
2 (500mg IV / 125mg 
SC) 
n = 4 
34.9 (46.6) 
n = 3 
6699 (20.7) 
3 (750mg IV / 125mg 
SC) 
n = 26 
31.9 (42.8) 
n = 24 
4607 (38.6) 
4 (1000mg IV / 125mg 
SC) 
n = 5 
14.7 (44.3) 
n = 4 
2555 (30.1) 
5 (1000mg IV / 200mg 
SC) 
n = 5 
41.7 (41.2) 
n = 5 
5849 (40.5) 
Source: IM101063 CSR, Supplemental Table S.8.2.3 
n = number of subjects, TAU = 7 days 
Cmax and AUC(TAU) were calculated between a SC dosing interval from Day 71 to Day 78 
profile. 
 
SC formulation in pediatric population 
Data are not available for clinical pharmacokinetic parameters of SC abatacept in children. 
1.3.3 
Safety of Abatacept in Core Rheumatoid Arthritis Studies 
The clinical safety data for abatacept (IV formulation) in subjects with RA is derived from:  
 
the open-label, long term (LT) periods of the 5 core RA studies, plus LT data from 
3 supportive studies (IM101043, IM101064, and IM101015) and ST and LT data from 
IM101023 36 
 
the double-blind period of the JIA study (IM101033)  
 
the post marketing experience with abatacept and  
 
the data collected for post-marketing commitments to regulatory authorities. 
 
The safety data from the open label LT periods of the clinical studies were analyzed in 2 ways; one 
to assess the LT safety profile of abatacept (Integrated Population) and another to assess the safety 
profile of abatacept across 3 prior therapy populations (Prior Therapy Population). Collectively, 
the Integrated Population safety experience covers the LT periods of the RA clinical studies from 
the methotrexate inadequate-responders (MTX-IR) and tumor necrosis factor inadequate 
responders TNF-IR studies, which includes up to 8 years of continued exposure (11,658 person-
years [p-y] experience with 1030 subjects with at least 5 years of exposure); new data from an 
earlier population of MTX-naïve subjects followed for 2 years including assessments at 1 and 2 


 
Protocol Amendment 1, November 30, 2015 
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years; as well as data from pharmacovigilance monitoring under the conditions of market usage 
(~32,187 p-y experience). For the Prior Therapy Population, there were 4,632 subjects (12,375 p-
y) treated with abatacept in combination with MTX,  
 
1,280 MTX-IR subjects, representing 4,465 p-y of exposure, who were treated for up to total 
of 8 years; and 
 
1419 TNF-IR subjects, representing 1,986 p-y of exposure, who were treated for up to total 
of 5.5 years;  
 
The remaining 483 MTX-naive subjects represented 717 p-y of exposure and were treated with 
abatacept for up to 2 years 36.  
1.3.4 
Safety of SC Formulation 
SC formulation in adult population 
IM101013 
In Study IM10101334, a double-blind, randomized (within dose), placebo-controlled, 
parallel-group, single-dose study in healthy subjects weighing  100 kg, single SC doses of 
abatacept were well-tolerated by healthy adult subjects. There were no deaths, no discontinuations, 
and no SAEs reported. All AEs were mild to moderate in intensity. In general, there was no 
difference between the frequency and types of AEs reported by the abatacept (all abatacept groups 
combined, n = 40) and placebo (all placebo groups combined, n = 8) groups. The most common 
type of AEs reported by abatacept and placebo subjects were injection site reactions including 
erythema, swelling, and tenderness. Infections were commonly reported by both the abatacept and 
placebo groups and were not more common in abatacept-treated subjects than in placebo-treated 
subjects. One (1) abatacept-treated subject had laboratory abnormalities (increases in alanine 
aminotransferase and gamma-glutamyl transferase levels) that were considered by the investigator 
to be clinically significant and were reported as AEs. 
Overall, 11 of the 40 subjects (27.5%) developed antibodies to the CTLA4 region of the abatacept 
molecule, with endpoint titers in healthy subjects followed for 71 days ranging from Day 33 to Day 
872. Only 1 of the 11 subjects developed antibodies that had abatacept neutralization activity. The 
earliest onset of seroconversion was at Day 43 (seen in 1 subject), after approximately 3 to 4 half-
lives of abatacept and accounting for over 94% of the drug being eliminated from the vascular 
system.. The presence of an immune response resulted in increased clearance of abatacept from the 
vascular system. This resulted in a shorter T1/2 (range = 3.2 to 7.5 days) compared with the T1/2 for 
subjects who did not exhibit an immune response to abatacept (range = 11.2 to 14.7 days). The 
incidence rate of seroconversion in subjects receiving a single SC dose of abatacept (27.5%) was 
higher compared with subjects who discontinued IV abatacept treatment (7.4%) in the Phase 2/3 
development program of IV abatacept for RA. The development of immunogenicity did not appear 
to be associated with adverse safety outcomes; the safety profile of abatacept in subjects with and 
without an immune response was comparable. 
IM101063 


 
Protocol Amendment 1, November 30, 2015 
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Study IM101063, a double-blind, randomized, placebo-controlled, parallel-group, multiple-dose 
study in subjects with active RA who are on background DMARDs (MTX or MTX plus no more 
than 1 additional oral DMARD) was designed to evaluate the safety and immunogenicity of several 
doses of SC abatacept. No deaths were recorded during the short-term 12-week phase of the study. 
Safety evaluations from the 51 abatacept-treated subjects and 17 placebo-treated subjects showed 
that abatacept administered by SC injections weekly was safe and well tolerated. The most common 
infections observed in both abatacept-treated and placebo-treated subjects were upper respiratory 
and 
urinary 
tract 
infections. 
There 
were 
7 
SAEs 
(diastolic 
dysfunction/chest 
discomfort/dyspnea/COPD/sleep apnea in 1 subject; wound infection in 1 subject; and drug 
overdose in 1 subject) reported during the short-term phase of the study. All the SAEs were reported 
to be unrelated or unlikely related to study drug by the investigator. In addition, injection site 
reactions from the weekly SC injections were uncommon and predominantly mild in intensity. 
Overall, the safety profile for SC abatacept was observed to be consistent with that for IV 
abatacept35,36.  
IM101173 
IM101173 37,  a multi-center open-label study in adults with active RA requiring a new therapeutic 
intervention, was designed to evaluate SC abatacept in a monotherapy setting and to assess if the 
use of background MTX influences the development of immunogenicity. An initial IV abatacept 
loading dose was not given in this study in order to maximize the potential for immunogenicity 
following SC administration of abatacept. In addition, this study was designed to assess whether 
the development of immunogenicity following SC abatacept impacted the PK, safety, or 
effectiveness of the drug. Safety and exploratory efficacy data for subjects treated for 4 months 
with SC abatacept in Study IM101173 were available. 
A total of 100 subjects with RA and requiring a new therapeutic intervention were stratified based 
on their current MTX use to 4 months of open-label treatment with SC abatacept monotherapy (N 
= 49) or to SC abatacept in combination with MTX (N = 51). Subjects in both cohorts received 
weekly SC injections of abatacept 125 mg (dosing irrespective of body weight). 
The safety profile for SC abatacept in adults with RA in this study appeared favorable overall. 
Treatment with SC abatacept 125 mg/week, with or without background MTX, and in the absence 
of an IV loading dose, was well tolerated by subjects with RA in this study. During the 4-month 
short-term treatment period, there were no deaths, SAEs assessed as at least possibly related to 
study treatment were reported in only 2 subjects, and AEs resulted in treatment discontinuation for 
4 (4%) subjects. Local injection site reactions, a common finding for SC-injected drugs, were 
infrequent (7%); all were mild and did not result in treatment discontinuation. Similarly, systemic 
injection site reactions occurring within 24 hours following SC injection of abatacept were also 
infrequent (8%) and mostly mild in intensity. One subject experienced angioedema following the 
initial SC injection of abatacept, which was moderate in intensity, serious and led to treatment 
discontinuation. The angioedema resolved the same day. The rate of systemic injection reactions 
with SC abatacept was consistent with the rates of peri-infusional AEs reported for IV abatacept 
38,39. 
Consistent with the experience with IV abatacept, infections and infestations were the most 
commonly reported AEs in subjects receiving SC abatacept (32% in short-term period). Fewer than 


 
Protocol Amendment 1, November 30, 2015 
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3% of treated subjects had an infection AE(s) that was serious or required discontinuation of 
abatacept treatment.  
In IM101173, one previously un-labelled SAE was reported: severe grade 4 Pneumocystis jiroveci 
pneumonia 37. The subject had been on study for 3 months, receiving 125 mg of abatacept SC once 
a week and developed bilateral pneumonia with severe respiratory failure. The subject was 
hospitalized to receive treatment for the infection and severe respiratory failure; the subject 
recovered and was discharged 1 month later. 
STUDY IN SYSTEMIC LUPUS ERYTHEMATOSUS 
In NCT 001 10678, A phase IIb study in SLE was conducted and published 5. 118 patients were 
treated with 10mg/kg abatacept i.v. in the standard RA dose, and 57 with placebo. 65% completed 
12 months of study. The primary outcome, rate of flare beginning after prednisone taper, over a 
total of 12 months, measured by adjudicated BILAG A and B, did not show significant differences 
between the groups. However, patients with lupus polyarthritis at entry had significantly fewer 
flares compared to placebo in both BILAG A flare (36.5% in placebo vs 12.5% in abatacept) and 
physician-identified flares. The incidence of serious adverse events was higher in abatacept 
(19.8%) vs placebo (6.8%) without any particular type of SAE identified. 
In a recent study in patients with lupus nephritis40, 198 individuals were treated with abatacept i.v.. 
for 12 months (one group with a loading dose of 30 mg/kg once a month x3 followed by 10 mg/kg 
monthly; a second with 10 mg/kg monthly i.v. for the entire 12 month period). At 12 months, there 
were no statistically significant differences in response rates (defined as complete renal response 
or partial- plus- complete renal responses) between the group that received placebo infusions plus 
standard care compared to either of the groups that received abatacept plus standard care. The 
occurrence of severe adverse events did not differ significantly between the groups: SAEs occurred 
in 28-33.3% of the abatacept groups and 31% of the placebo group.  There were 7 deaths in the 
abatacept groups (one of which was a gunshot wound) for a rate of 2.5%, with 7 deaths in the 
placebo group for a rate of 7%. Treatment related SAEs occurred in 19-20% of the abatacept groups 
and 15% of the placebo groups. 
To summarize, there are published data on abatacept, administered i.v., to 316 patients with SLE 
for 12 months5,40. In the patients most comparable to the subjects to be studied here (no active 
nephritis or CNS disease), SAEs occurred in approximately 20%. We expect the SAE rate to be 
lower in the study proposed here because the treatment duration is 16 weeks rather than 52 weeks. 
Another difference is that the treatments will be administered subcutaneously instead of 
intravenously. Perhaps more relevant to this proposal is study IM101173 described above, in which 
patients with rheumatoid arthritis on methotrexate received 125 mg of abatacept weekly for 16 
weeks; SAEs in that study occurred in 2%. One individual had pneumocystis pneumonia requiring 
hospitalization. 
SC formulation in pediatric population 
Data are not available for the safety of SC abatacept in the pediatric population. 


 
Protocol Amendment 1, November 30, 2015 
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1.4 
Overall Risk/Benefit Assessment 
Lupus is an autoimmune disorder that involves inflammatory polyarthritis that can lead to 
deformity, significant physical disability, and poor quality of life.  
In the past decade, the success of abatacept and other biologic immune/inflammation modifiers 
such as TNF inhibitors in suppressing rheumatoid arthritis have led to testing of some of these 
products in patients with SLE. To date, TNFalpha inhibitors have been disappointing in that a high 
infection rate has cause early stopping of some trials41.   Although the efficacy, tolerability, and 
safety profile of abatacept was demonstrated in the RA clinical development program, the two trials 
to date using abatacept in SLE did not identify an overall benefit. However, the subset of patients 
with active lupus polyarthritis at entry had significant benefit, shown as a significant reduction in 
flares of SLE. Abatacept, a biologic DMARD with a unique mechanism of action, has demonstrated 
a good efficacy/safety profile in RA. Abatacept has been on the market in the US since 
January 2006 and in Europe since May 2007. 
Abatacept, a selective costimulation modulator, is a soluble fusion protein that consists of the 
extracellular domain of human cytotoxic T-lymphocyte (T-cell)-associated antigen 4 (CTLA-4) 
linked to the modified Fc (hinge, CH2, and CH3 domains) portion of human immunoglobulin G1 
(IgG1). An intravenous (IV) formulation of abatacept is approved in several countries including 
the United States and in the European Union (EU) for the treatment of moderate to severe 
rheumatoid arthritis (RA) in adults. The subcutaneous preparation is currently approved in the 
United States for rheumatoid arthritis in adults. Based on the clinical trial experience in adults, the 
risks that may be associated with the use of abatacept include infections, some of which may be 
serious or fatal, infusion related reactions, and an increase in respiratory adverse events and 
infections in patients with chronic pulmonary obstructive disease (COPD). Other potential risks 
may include the development of malignancies or autoimmune disorders, but an increased risk of 
these types of events has not been observed. As with the use of any protein therapeutic, antibodies 
against abatacept (immunogenicity) may develop. The rate of immunogenicity has generally been 
low and there has not been an apparent effect on safety, efficacy, or pharmacokinetics (PK). 
Abatacept intravenous is also currently approved for the treatment of moderately to severely active 
polyarticular juvenile idiopathic arthritis (JIA) in pediatric patients 6 years of age or older in several 
countries including the USA for patients aged 6 - 17 years old. Abatacept was generally safe and 
well tolerated in subjects with JIA.  
For the period from the fourth quarter of 2005 to the third quarter of 2009 inclusive, the total 
number of patients exposed to abatacept is estimated to be equivalent to 60,225 patient-years of 
exposure. The overall pattern of safety reporting raises no new safety concerns. A subcutaneous 
(SC) formulation of abatacept is being studied for the treatment of a number of immune mediated 
disorders; results from 3 completed clinical studies in RA are included in this document. 
Within the clinical studies, there were no reports of progressive multifocal leukoencephalopathy 
(PML). In the post-marketing experience, there was 1 healthcare professional report of recurrent 
PML that involved a 44-year-old female with previous history of PML while receiving 
methotrexate (10 years ago). The patient received 6 doses of abatacept prior to hospitalization due 
to status epilepticus. A brain magnetic resonance image scan was atypical for PML; a cerebral 
spinal fluid analysis was negative for the JC virus. At the time of the report, the patient was 


 
Protocol Amendment 1, November 30, 2015 
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recovering from hemiparesis and expressive dysphasia. The overall pattern of safety reporting 
raises no new safety concerns.  
The ongoing efficacy of abatacept is robust and persistent, based on ongoing clinical study data 
and confirmed by clinical practice in the marketplace. The long term safety profile of abatacept, in 
the context of maintained efficacy, is reassuring and confirms the positive benefit/risk of abatacept 
in the treatment of rheumatoid arthritis.  
In treatment of lupus nephritis patients with Abatacept over 12 months, it has been reported that 
abatacept had a similar safety profile compared to mycophenolate mofetil and steroids35.   
Abatacept may have been more effective than placebo in that study, depending on the stringency 
of criteria used to define renal response36. In the phase IIb trial published, serious adverse events 
were more common with abatacept (19.8%) than with placebo (6.8%) but no particular type of 
adverse event emerged as more common with abatacept, such as infection5,35,40. Therefore, 
abatacept has been shown to have acceptable safety. 
1.5 
Study Rationale 
SLE is a systemic autoimmune disease with life-threatening manifestations.  Currently, there are 
limited approved treatments for SLE and none (except high dose glucocorticoids) have been shown 
to prolong survival or permanently reverse the course of the disease.  SLE remains a disease with 
unmet medical need, especially for patients with active and life-threatening manifestations, and for 
the many with adverse effects from chronic glucocorticoid use. 
Lupus arthritis is a common manifestation of lupus.  It can cause a debilitating and disabling 
condition in lupus patients resulting in poor quality of life.  Currently, the therapies in treating lupus 
arthritis such as glucocorticoids, NSAIDs, hydroxychloroquine, belimumab or MMF are far from 
optimum, inducing complete remission in fewer than 50% of affected patients.   
Thus, there is an unmet need in patients with lupus arthritis for more effective and safe therapy.  
Rationale for abatacept to work in treating lupus arthritis is based on abatacept’s mechanism of 
action, evidence of its safety in lupus nephritis patients and experience in Rheumatoid arthritis.      
 
2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
Improvement of lupus inflammatory polyarthritis measured by proportion of patients who achieve  
>=20% improvement in tender and swollen 28 joint counts at 16 weeks. 
Secondary Objectives: 
1.   Mean and median joint scores in treated vs placebo patients at 16 weeks, compared to baseline 
scores. 
2.    Proportion of patients who achieve improvement in SLEDAI 2K at 16 weeks of >3 points, 
comparing abatacept to placebo. 
3.    Proportions of patient who do not worsen by PGA score (≤0.8 change from initial PGA score 
on 3 point line). 
4.    Mean and median changes in CDAI comparing abatacept to controls at 8, 12 and 16 weeks. 


 
Protocol Amendment 1, November 30, 2015 
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5.    Changes in a) synovitis, b) tenosynovitis and c) erosions measured by high-energy ultrasound 
with Doppler flow at zero, and 16 weeks, compared to placebo. 
6.    Steroid sparing effect of abatacept, measured as ability to taper prednisone to <10mg/day by 
week 16 comparing abatacept-treated subjects to placebo-treated subjects.  
7.Change in fatigue from baseline to 16 weeks as measured by the FACIT fatigue score instrument 
8.Change in quality of life comparing baseline to 16 weeks as measured by the SF 36. 
9.Safety, measured in standard methods as AE and SAE, including likelihood that the AE/SAE was 
related to the study biologic. 
10.Time to response, measured as joint counts (sum of tender and swollen joints) at zero, 4, 8, 12, 
and 16 weeks. 
11.Change in peripheral blood T cell compartments indicating decline in pro-inflammatory 
profiles, i.e., we expect decrease in CD4+ effector T cells that make IFNgamma (TH1) and IL-17 
(TH17) and increase in ratio of Treg to Teff, as well as decreased function of Thelper and increased 
functions of Tregs. CD4+CD25+ Foxp3+ and CD8+Foxp3+ will be the definition of regulatory T 
cells.  These will be measured at baseline and 16 weeks 
12.Change in anti-DNA and total IgG levels, as well as rise in serum complement levels as disease 
improves and fewer B cells are activated: measure these at zero, 8 and 16 weeks. 
13.Effects of abatacept on serum levels of BLyS (BAFF). As numbers of activated B cells and 
plasmablasts fall, we expect an increase in BLyS levels. Measure at baseline and 16 weeks. 
14. Changes in transcriptome in whole blood and/or purified mononuclear cells in peripheral blood, 
and changes in interferon-induced gene expressions at baseline that may predict response or non-
response at 16 weeks. Measure at baseline and last study visit. 
 
3 
 3.  ETHICAL CONSIDERATIONS 
2.3  Good Clinical Practice 
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by the 
International Conference on Harmonisation (ICH) and in accordance with the ethical principles 
underlying European Union Directive 2001/20/EC and the United States Code of Federal 
Regulations, Title 21, Part 50 (21CFR50). 
The study will be conducted in compliance with the protocol. The protocol, any amendments, and 
the subject informed consent will receive Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) approval/favorable opinion before initiation of the study. 
All potential serious breaches must be reported to Bristol-Myers Squibb (BMS) immediately. A 
serious breach is a breach of the conditions and principles of GCP in connection with the study or 
the protocol, which is likely to affect, to a significant degree, the safety or physical or mental 
integrity of the subjects of the study or the scientific value of the study. 
Study personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks. This study will not use the services of study personnel 
where sanctions have been invoked or where there has been scientific misconduct or fraud (eg, loss 
of medical licensure; debarment). Systems with procedures that ensure the quality of every aspect 
of the study will be implemented. 
3.1 
Institutional Review Board/Independent Ethics Committee 


 
Protocol Amendment 1, November 30, 2015 
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Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, subject recruitment materials/process (eg, 
advertisements), and any other written information to be provided to subjects. The investigator 
should also provide the IRB/IEC with a copy of the Investigator Brochure or product labeling, 
information to be provided to subjects, and any updates. The investigator should provide the 
IRB/IEC with reports, updates, and other information (eg, expedited safety reports, amendments, 
and administrative letters) according to regulatory requirements or institution procedures. 
3.2 
Informed Consent 
Investigators must ensure that subjects (or, in those situations where consent cannot be given by 
subjects, the legally acceptable representative) are clearly and fully informed about the purpose, 
potential risks, and other critical issues regarding clinical studies in which they volunteer to 
participate. Freely given written informed consent must be obtained from every subject (or, in those 
situations where consent cannot be given by subjects, the legally acceptable representative) before 
clinical study participation, including informed consent for any screening procedures conducted to 
establish subject eligibility for the study. An additional informed consent form will be signed by 
subjects willing to supply DNA and RNA for research to predict response to abatacept. 
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society. 
3.4 Stopping Rules 
The study will be put on hold if 1) there are two deaths thought to be possibly, probably or definitely 
related to the treatment, or 2) there are 3 patients with SAEs thought to be probably or definitely 
related to the treatment. If either of these occurs, the study will be suspended until the DSMB 
determines whether it is safe for patients to continue on the therapy. This determination will be 
made within two weeks of the events described so that patients will hold their doses of abatacept 
or placebo for no longer than two weeks if the reviewers determine it is safe to continue. A data 
safety monitoring board (one to-be-named Rheumatology faculty member plus one to-be-named 
statistician) will review the SAEs quarterly and issue a report to the IRB and to the investigators 
regarding AEs and SAEs, reported according to patient assignments to groups A or B (the double-
blind code will not be broken); these reports will also be supplied to the sponsor 
 
4 
INVESTIGATIONAL PLAN 
4.1 
Study Design and Duration 
This is a randomized placebo-controlled double-blind study for the 16 weeks, in patients with SLE 
whose active lupus manifestation is primarily arthritis.  The study consists of a baseline visit, a 16-
week treatment period (with visits every 4 weeks), and a telephone follow up 8 weeks after the last 
dose of study drug.  Patients are expected to participate in the study for up to approximately 26 
weeks (including screening visit). 
Informed consent will be obtained at the Screening Visit, prior to patients undergoing any study 
procedures.  Eligibility criteria will be assessed and medical history will be reviewed prior to 


 
Protocol Amendment 1, November 30, 2015 
20 
 
patient’s participation in this study.  Starting at the baseline visit, patients will receive 125 mg sc 
of abatacept or placebo every week for 16 weeks.    Patients may continue on their stable 
background standard of care medications (according to the protocol) throughout the study.  In the 
first dose visit, patients will be monitored for systemic symptoms for at least 1 hour after abatacept 
has been administered.   
Subjects who discontinue the trial early, i.e. prior to Week 16 should come to a follow-up study 
completion visit within 1 week of treatment termination. 
Unscheduled visits for safety or for any other reason may be conducted at any time during the 
study. 
During the study period, at 4 week intervals, swollen and tender joint counts (28 joints), the British 
Isles Lupus Assessment Group (BILAG) score, SLE Disease Activity Index (SLEDAI 2K), 
Physician Global Assessment Score and Patient Global Assessment will be assessed in addition to 
routine safety laboratory and physical tests.  Disease related immunology tests/biomarkers will be 
taken at baseline and 16 weeks.   
Bilateral Posterior-Anterior (PA) Hand X-rays (including wrists) will be performed at baseline for 
all subjects.  Ultrasound examination of the PIP (2-5), MCP (2-5), and wrist joints designated below 
will be performed at baseline and at 16 weeks. At baseline and 16 weeks, synovitis (18 joints), 
tenosynovitis and erosions will be assessed.  
Please see Time and Events Schedule in Section 6. 
SLE patients with 3 or more swollen and tender joints and moderate or severe lupus activity 
(SLEDAI 2K score 4 or greater) will be eligible for this study.  In addition, patients must have 
current or historical documented positive Antinuclear Antibody (ANA) and/or anti-double stranded 
deoxynucleotide antibody (anti-dsDNA). 
The established SLE therapy (as allowed by the study) at study entry will be continued as 
background therapy.  Background therapy should be kept stable throughout the study, although 
increase in prednisone to not more than 30 mg a day, which much be tapered to ≤ 10 mg daily by 
8 weeks, will be permitted. Tapering of prednisone dose at any time will be permitted. Dosage 
increases in antimalarial, or any other non-glucocorticoid immunosuppressives, or introduction of 
any of these or a biologic agent as a new therapy (not allowed by the protocol) will be regarded as 
a treatment failure.  Subjects requiring prednisone or equivalent doses >10 mg a day at/after the 8 
week visit will be regarded as treatment failures.  
The US will be performed by a rheumatologist with expertise in musculoskeletal ultrasound and 
images will be digitally saved. US will be performed at UCLA only, for the 32 patients enrolled 
there. Each UCLA patient will have ultrasounds performed on the same machine by the same 
ultrasonographer at baseline and 16 weeks.   


 
Protocol Amendment 1, November 30, 2015 
21 
 
18-Joint US Scoring System (bilat wrists, bilat MCPs 2-5, bilat PIPs 2-5)  
JOINT 
VIEW 
Power 
Doppler 
Synovitis 
B-mode 
Synovial 
Hypertrophy 
Tendons 
Erosions 
Wrists 
 
Dorsal Longitudinal 
Midline 
(Radio carpal, intercarpal) 
X 
X 
 
 
MCPs (2-5) 
 
Dorsal Orthogonal 
X 
X 
 
X (MCP 
1,2,and 
5) 
Volar Longitudinal 
X 
X 
X 
 
Dorsal Paratendon 
X 
X 
X 
 
PIPs/IP (2-5) 
Volar Longitudinal 
X 
X 
X 
 
 
US assessments will be performed using the 18-joint US score. To date, no single US scoring 
system has been determined as the prevailing method. However, several US scoring systems have 
demonstrated that power Doppler synovitis and B-mode synovial hypertrophy scores are sensitive 
to change.   For this proposal, selection of the specific 18  joints was based on maximizing 
precision, reliability, and feasibility for ultrasonography.  Most US scoring systems weigh heavily 
on the hands and wrists.  Some studies demonstrate the presence of normal amounts of fluid at the 
1st metarsophalangeal (MTP) joints primarily as well as with 2-5 MTPs. In addition, these joints 
frequently demonstrate the presence of deformities such as hammer toes. Thus, these joints were 
excluded42,43. Grey-scale synovial hypertrophy and power doppler will be assessed for bilateral 
wrists (dorsal), MCPs 2-5 (dorsal and volar), and PIPs/IPs 2-5 (volar). In addition, MCP 2, and 5 
will be assessed for erosions. All the above areas will be examined with B-Mode and power 
Doppler mode sonography (Table above). Standard OMERACT definitions will be used for 
effusion and synovial hypertrophy.  
Assessment of the extensor and flexor tendons (grey-scale and power doppler) of the MCPs 
bilaterally will be obtained as well for further exploratory analyses. 
 


 
Protocol Amendment 1, November 30, 2015 
22 
 
4.2 
Study Population 
For entry into the study, the following criteria MUST be met. Any exceptions must be approved by 
the Principal Investigator and/or IRB/IEC before enrollment.  
4.2.1 
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. 
Target Population 
b) SLE as defined by meeting at least 4 of the 11 classification criteria of the American 
College of Rheumatology for the classification of Systemic Lupus Erythematosus.  The 
4 criteria need not be present at the time of study entry. 
OR 
Patients meet the new SLICC criteria for SLE8. Patients must fulfill at least 4 criteria, including 
at least one clinical and one immunologic. Clinical criteria are acute cutaneous lupus, chronic 
cutaneous lupus, oral or nasal ulcers,  nonscarring alopecia, synovitis (2 or more joints with 
swelling, or tenderness in 2 or more plus at least 30 min of morning stiffness), serositis, renal 
disease, neurologic, hemolytic anemia, leucopenia or lymphopenia, thrombocytopenia.  
Immunologic criteria are ANA above laboratory reference range, anti-dsDNA, anti-Sm, 
antiphospholipid, low complement and direct Coomb’s test. 
c) Active arthritis, as defined by: 
 
1) At least 3 or more swollen and tender joints 
 
2) Moderate or severe lupus activity - SLEDAI 2K score 4 or greater 
d) Patients must have documented positive Antinuclear Antibody (ANA) and/or anti-double 
stranded deoxynuclear antibody (anti-dsDNA). Presence/absence of anti-CCP and 
rheumatoid factor will be measured but results will not exclude patients from the trial. 
e) No active nephritis, active central nervous system disease, or other life-threatening 
manifestations of SLE 
Age and Sex 
f) Men and women,  18 years of age 
g) Women of childbearing potential (WOCBP) must use highly effective methods of birth 
control [for up to 4 weeks after the last dose of abatacept] to minimize the risk of 


 
Protocol Amendment 1, November 30, 2015 
23 
 
pregnancy. WOCBP must follow instructions for birth control for the entire duration of 
the study including a minimum of 28 days after dosing has been completed.   
o Acceptable methods of highly effective birth control include: 
o  Condom with spermicide 
o Hormonal contraceptives 
o  Diaphragm and spermicide 
o Cervical cap and spermicide 
o Intrauterine device 
Women must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L 
or equivalent units of HCG) within 48 hours prior to the start of investigational product.  
 
c) Women must not be breastfeeding 
Sexually active fertile men must use highly effective birth control if their partners are 
WOCBP.  Men that are sexually active with WOCBP must follow instructions for birth 
control for the entire duration of the study and a minimum of 28 days after dosing has been 
completed.  
d) Women who are not of childbearing potential (ie, who are postmenopausal or surgically 
sterile; see Section 3.3.3 for the definition of WOCBP) and men may be included in the 
study. 
e) Exclusion Criteria 
Individuals to be excluded if:  
a) WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy 
for the entire study period and for at least 4  weeks after the last dose of study drug.  
b) Women who are pregnant or breastfeeding. 
c) Women with a positive pregnancy test on enrollment or before administration of 
abatacept. 
d) Sexually active fertile men not using effective birth control if their partners are WOCBP. 
Medical History and Concurrent Diseases 
e) Subjects who are impaired, incapacitated, or incapable of completing study-related 
assessments. 
f) Subjects with current symptoms of severe, progressive, or uncontrolled renal, hepatic, 
hematologic, gastrointestinal, pulmonary, cardiac, neurologic, or cerebral disease, 


 
Protocol Amendment 1, November 30, 2015 
24 
 
whether or not related to SLE and which, in the opinion of the investigator, might place 
a subject at unacceptable risk for participation in the study. 
g) Female subjects who have had a breast cancer screening that is suspicious for malignancy 
and in whom the possibility of malignancy cannot be reasonably excluded by additional 
clinical, laboratory, or other diagnostic evaluations. 
h) 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. 
i) Subjects who currently abuse drugs or alcohol. 
j) Subjects with evidence (as assessed by the investigator) of active or latent bacterial or 
viral infections at the time of potential enrollment, including subjects with evidence of 
human immunodeficiency virus (HIV), hepatitis B or hepatitis C detected at any time 
prior to screening for this study 
k) Subjects with herpes zoster or cytomegalovirus (CMV) that resolved less than 2 months 
before the informed consent document was signed. 
l) Subjects who have received any live vaccines within 3 months of the anticipated first 
dose of study medication. 
m) 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). 
n) 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). 
o) Subjects with concomitant illness that in the opinion of the investigator, is likely to 
require additional high dose oral glucocorticosteroid therapy (i.e. >30 mg prednisone or 
equivalent per day) during the study (e.g. severe asthma) 
Physical and Laboratory Test Findings 
p) Subjects must not be positive for hepatitis B surface antigen. 
q) Subjects who are positive for hepatitis C antibody if the presence of hepatitis C virus was 
also shown with polymerase chain reaction or recombinant immunoblot assay. 


 
Protocol Amendment 1, November 30, 2015 
25 
 
r) Subjects with any of the following laboratory values 
i) Hemoglobin < 8.5 g/dL 
ii) WBC < 2000/mm3 (< 3 x 109/L) 
iii) Platelets < 100,000/mm3 (< 3 x 109/L) 
iv) Serum creatinine > 2 times the ULN 
v) Serum ALT or AST > 2 times the ULN 
s) Any other laboratory test results that, in the opinion of the investigator, might place a 
subject at unacceptable risk for participation in the study. 
Prohibited Treatments and/or Therapies 
t) 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. 
u) Any concomitant biologic DMARD, such as anakinra. 
v) Treatment with rituximab within the past 6 months (B cells must be detectable in 
peripheral blood at onset of treatment with study biologic); belimumab within the past 3 
months, cyclophosphamide within the past 3 months prior to study baseline visit. 
w) Previous treatment with abatacept 
Prednisone or equivalent at doses higher than 20 mg daily. 
 Other Exclusion Criteria 
x) Prisoners or subjects who are involuntarily incarcerated. 
y) 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. 
4.2.2 
Women of Childbearing Potential 
Women of childbearing potential (WOCBP) include any female who has experienced menarche 
and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, 
or bilateral oophorectomy), and who is not postmenopausal. Post menopause is defined as:  
 
Amenorrhea ≥ 12 consecutive months without another cause, and a documented serum 
follicle stimulating hormone (FSH) level > 35 mIU/mL or  
 
Women with irregular menstrual periods and a documented serum follicle stimulating 
hormone (FSH) level > 35 mIU/mL or 


 
Protocol Amendment 1, November 30, 2015 
26 
 
NOTE: FSH level testing is not required for women  62 years old with amenorrhea of  1 year 
Women who are using oral or other hormonal contraceptives, such as vaginal products, skin 
patches, or implanted or injectable products, or mechanical products, such as an intrauterine device 
or barrier methods (diaphragm, condoms, spermicides), to prevent pregnancy or who are practicing 
abstinence or who have a sterile (eg, vasectomy) partner should be considered to be of childbearing 
potential. 
4.2.3 Discontinuation of Subjects from Treatment 
If a study subject is found to have worsening disease activity during the duration of the 
study, the choice of using a rescue medication (e.g.increase prednisone dose but not to >20 mg 
daily) will be considered. However, if significant worsening of disease activity is found at 8 
weeks in comparison to baseline disease activity, the investigator will consider the 
discontinuation of the subject from the study after discussing in detail with the patient alternative 
SLE treatment strategies.   Throughout the duration of the study, background allowed standard of 
care therapies (prednisone, MMF, leflunomide, hydroxychloroquine) will be continued at the 
baseline dosage. 
Subjects MUST discontinue study treatment and withdraw from the study for any of the 
following reasons: 
 
Withdrawal of informed consent (subject’s decision to withdraw for any reason) 
 
Any clinical adverse event (AE), 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. The mechanism for reporting pregnancy is described in Section 
7.6. 
 
Termination of the study by BMS 
 
Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness 
 


 
Protocol Amendment 1, November 30, 2015 
27 
 
4.3 
Concomitant Treatments 
4.3.1 Prohibited and/or Restricted Treatments 
Initiation of therapy with any of the following medications or treatments during the study is not 
allowed: 
 
Methotrexate 
 
Azathioprine 
 
Cyclophosphamide 
 
Leflunomide 
 
Rituximab 
 
Belimumab 
 
Cyclosporine 
 
Tacrolimus 
 
Gammaglobulin 
 
Experimental therapies for treatment of SLE 
 
Plasmapheresis 
 
Prednisone or equivalent at doses >20 mg daily.  
The prescribing label of all concomitant medications used as subject’s background therapy should 
be evaluated by the investigator for continued administration during subject’s participation in this 
study (e.g. known toxicities, drug-drug interactions). 
Change in SLE standard of care (SOC) therapy after 12 weeks will not be permitted to allow 
assessment of efficacy of abatacept. 
4.3.2 Other Restrictions and Precautions 
Due to risk of infection, vaccination of subjects with any live vaccine is absolutely contraindicated 
for 3 months before and during the course of the study.  In view of the long half-life of abatacept, 
study subjects should not receive a live virus vaccine for a minimum of 3 months following the last 
dose of abatacept. 
4.4 
Discontinuation of Subjects from Treatment 
Subjects MUST discontinue study treatment and withdraw from the study for any of the following 
reasons: 
 
Withdrawal of informed consent (subject’s decision to withdraw for any reason) 
 
Any clinical adverse event (AE), 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 


 
Protocol Amendment 1, November 30, 2015 
28 
 
 
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. 
The mechanism for reporting pregnancy is described in Section 7.6. 
 
Termination of the study by BMS 
 
Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness 
5 
TREATMENTS 
5.1 
Study Treatment: Abatacept 
An investigational product, also known as investigational medicinal product in some regions, is 
defined as follows: A pharmaceutical form of an active substance or placebo being tested or used 
as a reference in a clinical study, including products already with a marketing authorization but 
used or assembled (formulated or packaged) in a way different from the authorized form, or used 
for an unauthorized indication, or when used to gain further information about the authorized form. 
In this protocol, the investigational product is abatacept. 
Other medications used in the study as support or escape medication for preventative, diagnostic, 
or therapeutic reasons as components of a given standard of care are considered noninvestigational 
products.  
5.1.1 
Identification 
Abatacept Injection, 125 mg/Syringe (125 mg/mL), is a sterile solution for SC administration, 
which contains approximately 126 mg abatacept, 171 mg sucrose, 8 mg Poloxamer 188, 0.28 mg 
monobasic sodium phosphate, monohydrate, and 0.84 mg dibasic sodium phosphate, anhydrous, in 
Water for Injection. It is packaged in 1 mL long glass syringe barrel staked with a 29 gauge stainless 
steel needle and stoppered with a 7.1 mm rubber stopper. The composition of this solution has a 
ratio of monobasic sodium phosphate, monohydrate, and dibasic sodium phosphate, anhydrous, 
used to achieve the target pH of 7.2. 
5.1.2 
Storage, Handling, and Dispensing 
The investigator is responsible for ensuring that it is dispensed only to study subjects and only 
from official study sites by authorized personnel, as dictated by local regulations. 
All investigational product supplies that will be used in the study must be maintained securely 
under the direct responsibility of the investigator or delegated by the investigator to the hospital 
pharmacist, or other personnel licensed to store and dispense drugs. All drugs shall be dispensed in 
accordance with the investigator’s responsibility to ensure that an accurate record of drugs issued 
and returned is maintained. 


 
Protocol Amendment 1, November 30, 2015 
29 
 
The investigator is responsible for ensuring that the investigational product is stored under the 
appropriate environmental conditions (temperature, light, and humidity), as determined by the 
sponsor and defined by the Investigator Brochure or SmPC/ reference label. If concerns regarding 
the quality or appearance of the investigational product arise, do not dispense the investigational 
product and contact the sponsor immediately. Care should be taken when handling the injectable 
drug products that are used in this protocol. Proper aseptic techniques must be used when preparing 
and administering sterile parenteral products such as abatacept. Parenteral drug products should be 
inspected visually for particulate matter prior to administration. Refer to the Investigator Brochure 
for additional information regarding handling, preparation, and storage of abatacept.  
5.1.3 
Additional Information for the Handling, Dispensing, and Storage of Abatacept 
ABATACEPT INJECTION FOR SUBCUTANEOUS (SC) 
ADMINISTRATION:ABATACEPT INJECTION, 125 MG/ML, AND 
PLACEBO FOR SC ADMINISTRATION ARE READY TO USE 
SOLUTIONS PROVIDED IN PRE-FILLED SILICONIZED 
SYRINGES. NO ADDITIONAL DRUG PREPARATION IS 
REQUIRED PRIOR TO ADMINISTERING TO PATIENTS. A 
SUFFICIENT AMOUNT OF ABATACEPT OR PLACEBO 
SOLUTION IS INCORPORATED INTO EACH SYRINGE SO THAT 
EACH SYRINGE CAN DELIVER LABELED AMOUNT UPON 
ADMINISTRATION. 
5.1.4 RECOMMENDED STORAGE AND USE CONDITIONS 
ABATACEPT INJECTION FOR SC ADMINISTRATION: ABATACEPT SC 
FORMULATIONS (PREFILLED SYRINGES) AND CORRESPONDING 
PLACEBO SHOULD BE STORED UNDER REFRIGERATION 
(APPROXIMATELY 2C TO 8C). DO NOT USE BEYOND THE LABELED 
EXPIRATION DATE ON THE PRODUCT. PROTECT FROM LIGHT BY 
STORING IN THE ORIGINAL PACKAGE UNTIL TIME OF USE. DO NOT 
ALLOW THE PREFILLED SYRINGE TO FREEZE. 
5.2 
Method of Assigning Subjects to a Treatment 
5.3 
Selection and Timing of Dose for Each Subject 
Subjects will receive SC dose of Abatacept (125mg) or placebo at baseline for 16 weeks. Study 
drug will be provided for subjects to take at home.  Qualified study personnel will teach subjects 
the proper administration of the study drug at baseline visit and teach subjects proper storage of the 
syringes to be taken home (see section 5.1.4 above.   
5.3.1 
Dose Modifications for Adverse Events 
If there is evidence of toxicity, as determined by laboratory tests or by clinical assessment that 
could place the subject at increased risk in the judgment of the investigator, administration of 
abatacept should be interrupted and the investigator should notify BMS. Subjects may be 
considered eligible to continue with abatacept treatment only if full resolution of the adverse event 
is documented. If the adverse event completely resolves and the next dose of abatacept cannot be 


 
Protocol Amendment 1, November 30, 2015 
30 
 
administered within 14 days of the target date, then that scheduled dose should be skipped. The 
next dose of abatacept should then be administered on the next targeted day for administration. 
5.4 
Blinding/Unblinding 
No data will be unblinded until the conclusion of the study, unless a serious adverse event cannot 
be treated effectively without the information, or unless 2 or more deaths that may be related to the 
therapy occur.  
5.5 Concomitant Treatments 
5.5.1 Prohibited and/or Restricted Treatments 
The following medications are prohibited throughout the 24 week study period: 
 
Any biologic DMARD (such as but not limited to: anakinra, infliximab, etanercept, 
adalimumab, rituximab, belimumab or any other investigational biologic). 
 
Live vaccines. 
 
Use of any investigational drug other than study medication. 
 
Corticosteroid use higher than the equivalent of prednisone 10 mg/day is not permitted after 
week 8. 
The following rescue medications may be used: 
 
Nonsteroidal antiinflammatory drugs (NSAIDS) or  Aspirin 
 
Acetaminophen 
 
Combination products, including acetaminophen and narcotic analgesics (eg, acetaminophen 
with codeine phosphate or propoxyphene napsylate or oxycodone hydrochloride or 
hydrocodone bitartrate). 
 
Tramadol 
 
Morphine. 
 
Prednisone at doses not to exceed 20 mg a day in the first 4 weeks of the study, but not more 
than 10 mg daily after 8 weeks 
5.5.2 Other Restrictions and Precautions 
Immunizations 
There is limited information available regarding the effectiveness of immunizations in non-human 
primates and humans that have been treated with abatacept. Limited data are available on the effect 
of therapeutic vaccinations in subjects receiving abatacept. 
Due to the risk of infection, vaccination of subjects with any live vaccine is absolutely 
contraindicated during the treatment phase of the study (that is, at any time after entry into the 
induction period), as is the administration of LIVE oral polio vaccine to household contacts. The 


 
Protocol Amendment 1, November 30, 2015 
31 
 
Centers for Disease Control and Prevention Advisory Committee on Immunization Practices 
(CDC-ACIP) recommends that subjects should not be administered a live virus vaccination for at 
least 3 months after discontinuing high-dose corticosteroid therapy (defined as more than 20 mg of 
prednisone per day for more than 2 weeks). In view of the long half-life of abatacept, study subjects 
should not be administered a live virus vaccine for a minimum of 3 months following the last dose 
of abatacept. 
5.6 Management of Possible Acute Hypersensitivity Reactions to Abatacept 
Hypersensitivity or acute allergic reactions may occur as a result of the protein nature of abatacept.  
The following information is provided to assist in the recognition of hypersensitivity reactions and 
in the management of those reactions should they occur during or after the administration of study 
drug. Care should be taken to treat any acute toxicities expeditiously, should they occur. 
Signs and management of potential acute hypersensitivity reactions: 
Sign 
Management 
Symptomatic 
Hypotension 
Discontinue the abatacept injection if it has not been 
completed. Pplace the subject in the Trendelenburg position 
and administer IV fluid. Administer epinephrine, 
glucocorticoids, antihistamines, and pressor agents as 
indicated. Since injections will be self-administered after the 
initial dose, the subject will have emergency contact 
information for all the physician investigators participating in 
this trial. We will also ensure that patients have immediate 
emergency access to a local physician (if they live more than 
20 miles away from the UCLA Medical Center) and 
Emergency Room. 
Dyspnea 
Discontinue the abatacept injection. Observe the subject for 
worsening of the event and for the appearance of additional 
signs and symptoms of anaphylaxis.  Administer 
antihistamines, epinephrine, and glucocorticoids as indicated. 
Since injections will be self-administered after the initial dose, 
the subject will have emergency contact information for all 
physicians participating in this trial. We will also ensure that 
patients have immediate emergency access to a local 
physician (if they live more than 20 miles away from the 
UCLA Medical Center) and Emergency Room 
Acute Pain in Chest, 
Back or Extremities 
These are potential signs of anaphylaxis. Follow the same 
treatment regimen as is used to treat dyspnea. 
Chills, Fever, Urticaria, 
or Generalized 
Erythema 
These may be signs of an allergic reaction to protein products. 
Treat by administration of acetaminophen and antihistamines. 
Because abatacept has immunomodulatory activity, subjects may be at increased risk of infectious 
complications. Significant infectious complications should be treated appropriately. Study 
medication should be withheld, and restarted only when the infection is clinically resolved. 


 
Protocol Amendment 1, November 30, 2015 
32 
 
5.7 Treatment  Compliance 
During the study, subjects will complete a weekly dosing diary and return the diary to the study 
personnel to check for compliance.   
During the study, all investigational drug (used and unused) and the corresponding accountability 
forms must be reconciled on an on-going basis.   
6 
STUDY ASSESSMENTS AND PROCEDURES 
6.1 
Time and Events Schedule 
The Time and Events Schedule (Section 6, Table 1) summarizes the frequency and timing of 
various measurements. 
Screening Visit 
The following assessment and procedures will be performed at screening visit 
 
Obtain written informed consent 
 
Inclusion/exclusion criteria review 
 
Medical history 
 
Physical examination 
 
Vital signs (temperature, pulse, systolic and diastolic blood pressure), height and weight 
 
Clinical laboratory tests (chemistry, hematology, and urinalysis) 
 
Serology A (hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab) 
 
Serology B (anti-dsDNA, , ANA) 
 
HIV testing 
 
Beta human chorionic gonadotropic (beta-HCG) on all women of childbearing potential. 
 
Concomitant medication review 
 
SLEDAI-2K 
 
28- Tender/Swollen Joint Count 
 
Quantiferon gold assay for tuberculosis 
Baseline Visit (Visit 1) 
The following procedures/assessments will be performed at Baseline Visit (Visit 1) 
 
Patient Global Assessment 
 
SF 36 and fatigue scale questionnaire 


 
Protocol Amendment 1, November 30, 2015 
33 
 
 
Concomitant medications 
 
Adverse events 
 
Physical Examination 
 
Vital signs (temperature, pulse, systolic, and diastolic blood pressure) and weight 
 
28 Tender and Swollen Joint Count 
 
Urine pregnancy test (beta-hCG) for all women of child-bearing potential.  In case of 
positive result, the subject will not be eligible to participate in the study and will be 
considered as a Screening failure. 
 
Review all laboratory assessments for subject safety/clinical significance 
 
Review all inclusion exclusion criteria including compliance with allowed 
concomitant medications prior to Baseline and assess subject’s final eligibility. 
 
Bilateral Posterior-Anterior (PA) hand x-rays (including wrists) should be performed 
for eligible subjects (unless already performed within 4 weeks prior to Baseline) 
 
Joint Ultrasound (18 joints: 2-5PIPs, 2-5 MCPs and wrists, bilaterally) 
 
SLEDAI 2K 
 
BILAG 2004 
 
Physician Global Assessment 
 
Safety Laboratory Testing (hematology and biochemistry) 
 
Urinalysis 
 
Immunology assessments (C3, C4, IgG) 
 
Lupus Biomarkers; IFN gamma, IL10, TGFbeta, IL17, IL23 and BLyS levels. 
 
T and B cell studies 
 
First dose administration of Study drug.  The subject should stay at the study site for 
1 hour following the administration of the first dose. 
 
Subjects will be given all the necessary supplies and detailed instructions for 
administration of study drug.  In addition, subjects will be instructed to contact the 
study center if any questions or problem arise. 
 
Instruct subjects to complete study drug dosing diary for accountability and 
compliance. 


 
Protocol Amendment 1, November 30, 2015 
34 
 
Visits 2, 3, and 4 (Weeks 4, 8 and 12 from Baseline Visit) (+/-5 days) 
 
Patient Global Assessment 
 
SF 36 and fatigue scale questionnaire 
 
Concomitant medication 
 
Adverse events 
 
Vital signs (temperature, pulse, systolic and diastolic blood pressure, weight) 
 
Physical Examination 
 
28 Tender and Swollen Joint Count (shoulders, wrists, 1-5 PIP, 1-5 MCP and knees, 
all bilaterally) 
 
SLEDAI 2K 
 
BILAG 2004 
 
Physician’s global assessment. Verify whether the predefined withdrawal criteria or 
safety stopping rules have been met 
 
Safety laboratory tests (hematology, biochemistry, urinalysis) 
 
Urine pregnancy test for women with child-bearing potential 
 
Immunology assessments (anti-dsDNA, C3, C4, IgG) at weeks 0,8 and 16 
 
Dispense study drug and review compliance and accountability.  Instruct subjects to 
complete the dosing diary.  
Visit 5 (Week _16 from Baseline Visit) (+/-5 days) 
 
Patient Global Assessment 
 
SF 36 and fatigue scale questionnaire 
 
Concomitant medication 
 
Adverse events 
 
Vital signs (temperature, pulse, systolic and diastolic blood pressure, weight) 
 
Physical Examination 
 
28 Tender and Swollen Joint Count 
 
SLEDAI 2k 
 
BILAG 2004 


 
Protocol Amendment 1, November 30, 2015 
35 
 
 
Physician’s global assessment 
 
Verify whether the predefined withdrawal criteria or safety stopping rules have been 
met 
 
Safety laboratory tests (hematology, biochemistry, urinalysis) 
 
Urine pregnancy test for women with child-bearing potential 
 
Immunology assessments (anti-dsDNA, C3, C4, IgG at weeks 0,8 and 16 
 
Lupus biomarkers (cytokines, T and B cell surface markers) at Week 0 z and 16 (visit 
5) 
 
Ultrasound at Week zero and 16 (visit 5) 
 
Review compliance and accountability.  Instruct subjects to complete the dosing 
diary.  
 
 
Study follow up phone call, 8 weeks after last study dose (Week 24) 
The study coordinator will conduct a follow up phone call 8 weeks after subject’s last study visit 
(week 24) to ask about any Adverse Events.  At minimum two attempts should be made to 
contact the subjects if subject is not available upon first contact. 
 
Early Withdrawal/Termination Visit 
Early Withdrawal/Termination Visit will follow procedure as outlined for Visit 7 (week 24). 
 
 
6.1.1 
Study Completion or Early Discontinuation Visit 
At the time of study early withdrawal, the reason for early withdrawal and any new or continuing 
adverse events should be documented. 
6.1.2 
Study Drug Discontinuation 
If study drug administration is discontinued, the reason for discontinuation will be recorded. 
 


 
 
Protocol Amendment 1, November 30, 2015 
36 
 
Procedure 
Screening 
Baseline 
Visit 2-3-4 
Visit 5 
Study follow 
up phone call 
at Week 24 
Early 
Withdrawal/Termination 
Visit 
Eligibility Assessments 
 
 
 
 
 
 
Phone call 
 
 
 
 
Xi 
 
Informed Consent 
X 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
Xa 
 
 
 
 
Verify withdrawal criteria 
and safety stopping rules  
 
 
X 
X 
 
X 
Medical History 
X 
 
 
 
 
 
Safety Assessments 
 
 
X 
X 
X 
X 
Physical Examination 
X 
X 
X 
X 
 
X 
Vital Signs 
Height, weight 
X 
 
x 
X 
 
X 
Assessment of Signs and 
Symptoms 
 
Xe 
x 
Xe 
 
Xe 
Concomitant Medication 
review 
X 
X 
X 
X 
X 
X 
Adverse Events Assessment 
 
X 
X 
X 
X 
X 
Review all Laboratory 
Assessments for safety 
 
X 
x 
x 
 
 
Urine Pregnancy Test 
 
Xb 
Xb 
Xb 
 
Xb 
 
 
 
 
 
 
 


 
 
Protocol Amendment 1, November 30, 2015 
37 
 
Procedure 
Screening 
Baseline 
Visit 2-3-4 
Visit 5 
Study follow 
up phone call 
at Week 24 
Early 
Withdrawal/Termination 
Visit 
Laboratory Assessments 
CBC & Platelets 
X 
X 
X 
X 
 
X 
Chemistry Panel 
X 
X 
X 
X 
 
X 
PPD or quantiferon gold 
X 
 
 
 
 
 
 
Urinalysis 
X 
X 
X 
X 
 
X 
Hepatitis B surface antigen, 
hepatitis C virus antibody 
X 
 
 
 
 
 
Lupus Biomarkers 
(cytokines)) 
 
X 
 
Xf 
 
Xf 
Anti-dsDNA, C3, C4, IgG 
 
X 
X 
X 
 
X 
ANA,anti-CCP, rheumatoid 
factor 
X 
 
 
 
 
 
HIV testing 
X 
 
 
 
 
 
ß-HCG serum test 
Xb 
 
 
 
 
 
 
Biomarker Sample 
Collection 
 
Efficacy Assessments 
 
X 
 
X 
 
 


 
 
Protocol Amendment 1, November 30, 2015 
38 
 
Procedure 
Screening 
Baseline 
Visit 2-3-4 
Visit 5 
Study follow 
up phone call 
at Week 24 
Early 
Withdrawal/Termination 
Visit 
Physician Global 
Assessment 
 
X 
X 
X 
 
X 
Patient Global Assessment 
 
X 
X 
X 
 
X 
Joint x-ray 
 
Xc 
 
 
 
 
Joint ultrasound 
 
Xd 
 
Xd 
 
Xd 
SLEDAI-2K 
X 
X 
X 
X 
 
 
BILAG 2004 
X 
X 
X 
X 
 
 
28 Tender/Swollen Joint 
Count 
X 
X 
X 
X 
 
X 
Clinical Drug Supplies 
 
 
 
 
 
 
Dispense Study Treatment 
 
X 
Xh 
 
 
 
a. Review all inclusion/exclusion criteria including compliance with allowed concomitant medications and assess subject’s final eligibility. 
b. Required for women of childbearing potential (Serum pregnancy test must be performed at screening. Urine pregnancy test must be performed 
at all subsequent visits  
c. Bilateral Posterior-Anterior (PA) hand x-rays (including wrists) should be performed for eligible subjects (unless already performed within 4 
weeks prior to Baseline visit). 
d. Joint ultrasound done at Baseline and Week 16 (visit 5) 
e. Study subjects should stay at the study site for 1 hour following the administration of the first dose for assessment of signs and symptoms of 
adverse reactions 
f. Done at Baseline and 16 weeks (Visit 5) only. 


 
 
Protocol Amendment 1, November 30, 2015 
39 
 
h. Dispense study drug and review compliance and accountability. Instruct subjects to complete the dosing diary  
i. A follow up phone call at Week 24 (8 weeks after subject’s last study visit) should be conducted to ask about any Adverse Events and 
Concomitant Medication. At minimum, two attempts should be made to contact the subject if the subject is not available upon first contact. 
 


 
Protocol Amendment 1, November 30, 2015 
40 
 
6.2 
Study Materials 
Bristol-Myers Squibb (BMS) will provide abatacept and placebo at no cost for this study. 
6.3 
Safety Assessments 
All subjects who receive a dose of study drug will be evaluated for safety. Safety outcomes include 
adverse events, clinically significant changes in vital signs, laboratory test abnormalities, and 
clinical tolerability of the drug. The investigator will determine the severity of each adverse event 
as mild, moderate, severe, or very severe. Laboratory findings that the investigator feels are 
clinically relevant should be recorded as adverse events. In addition, the investigator will determine 
the relationship of the adverse event to the administration of the study drug. Any occurrence of a 
SAE from time of consent forward, up to and including follow-up visits will be reported. A data 
safety monitoring board (one to-be-named Rheumatology faculty member plus one to-be-named 
statistician) will review the SAEs quarterly and issue a report to the IRB and to the investigators 
regarding AEs and SAEs, reported according to patient assignments to groups A or B (the double-
blind code will not be broken); these reports will also be supplied to the sponsor.  See Section 7.3.1 
for the SAE reporting procedures. 
6.3.1 
Physical Examinations 
During the treatment period, the physical examination is to be performed before administration of 
abatacept. While the interim physical examination may not be as comprehensive as the complete 
physical examination, important body systems should be included as deemed clinically indicated 
by the investigator. These body systems may include lymph nodes, liver, spleen, and breast. An 
interim physical examination may note any changes in the subject’s condition since the last 
assessment and does not preclude examination of any of the body systems as clinically indicated. 
6.3.2 
Manual Breast Examination and Breast Cancer Screening 
A manual breast palpation must be performed on all female subjects prior to randomization . A 
manual breast palpation performed within 1 month of study entry will be accepted as meeting the 
pre-randomization requirement. Documentation of the prior palpation must be on file at the 
investigator’s site for the screening procedures to be considered complete. 
In addition, those female subjects who meet local age and risk factor appropriate screening criteria 
are required to have a mammography or other imaging modality for breast cancer screening in 
accordance with local medical guidelines. The breast cancer screening guidelines utilized by the 
investigational site should be made available to the local IRB/Ethics Committee and explained in 
the subject’s informed consent. Documentation of the most recent breast cancer screening study 
must be on file at the investigator’s site to be considered valid. 
Subjects having a manual breast palpation or a breast cancer screening that is suspicious for 
malignancy will have drug administration withheld until the possibility of malignancy can be 
reasonably excluded following additional clinical, laboratory or other diagnostic evaluations. 
6.3.3 
Tuberculin Skin Testing 
A tuberculin skin test (PPD test: purified protein derivative tuberculosis skin test) should be 
performed and interpreted according to the applicable local Health Authority and/or Medical 


 
Protocol Amendment 1, November 30, 2015 
41 
 
Society guidelines (those that provide recommendations for tuberculin skin testing for subjects who 
are to receive biologics, who are immunosuppressed, who have a prior history of BCG 
vaccinations44,45, or who have a prior positive test). Tuberculin skin testing is not contraindicated 
for persons who have been vaccinated with BCG. 
QuantiFERON® testing is an acceptable alternative when tuberculin skin testing is not appropriate. 
A tuberculin skin test is not required if one was performed within 6 months of screening and 
documentation of testing is on file. If tuberculin skin testing is performed at screening, then the 
72-hour reading must be completed before administration of abatacept. 
6.4 
Efficacy Assessments 
The number of tender and swollen joints will be used to assess Lupus Arthritis activity. 
Joint tenderness is defined as the presence of tenderness and/or pain in a joint at rest with pressure 
or on passive movement of the joint/joint manipulation.  Joint swelling is soft tissue swelling that 
is detectable along the joint margins. 
Both joint tenderness and swelling are dichotomic measures (swollen versus non swollen and tender 
versus non tender). 
28 joints will be examined for tenderness and 28 joints (same as those examined for tenderness) at 
all study visits. 
Subjects at least 3 tender and swollen joints at Screening will be eligible for the study. 
SLE Disease Activity Index 2K (SLEDAI 2K) 
The SLE disease activity index (SLEDAI 2K) is a validated tool developed as a global assessment 
of disease activity in SLE patients.  The SLEDAI 2K assesses 24 descriptors (sixteen clinical 
manifestations and eight laboratory measures) in 9 organ systems.  Descriptors are given different 
weights, based on clinical importance, with dichotomic score (present/not present within the 
previous 30 days).  A descriptor must be attributed to active SLE or otherwise should not be scored.  
The SLEDAI 2K is intended to evaluate current lupus activity and not chronic damage. 
The SLEDAI 2K will be assessed at screening, baseline, and all study visits as well as study follow-
up visits at Week 28. 
BILAG 2004 
The BILAG Index is a validated comprehensive index for measuring clinical disease activity in 
SLE .BILAG assessment consists of 97 variables based on patient’s history, examination findings, 
and laboratory/imaging results.  The questions are grouped under nine systems; Constitutional, 
Mucocutaneous, 
Neuropsychiatric, 
Musculoskeletal, 
Cardorespiratory, 
Gastrointestinal, 
Ophthalmic, Renal and Hematological. 
The index capture only SLE related disease activity in the previous 4 weeks prior to each 
assessment.  Each of the clinical variables may be recorded as: 
0. Absent. 


 
Protocol Amendment 1, November 30, 2015 
42 
 
1. Improved.  Sufficient for considering reduction in therapy and improvement present on 
assessment and for at least 2 weeks or completely resolved within the entire last week. 
2. Same.  No improvement and no deterioration within the last 4 weeks compared to the 
previous 4 weeks or improvement dose not meet improvement criteria. 
3. Worse.  Deteriorated during the last 4 weeks compared to the previous 4 weeks. 
4. New or recurrent episode during the last 4 weeks (compared to the previous 4 weeks), 
which is not improving. 
Based upon the scoring of each of these variables, a pre-defined algorithm, specific for each 
system, provides a disease activity score ranging from A to E for each system: 
Grade “A” = severe disease activity requiring treatment with high dose steroids (>20mg/day 
oral prednisolone or equivalent or IV pulse >500 mg MP), systemic immunomodulators or high 
dose anticoagulation 
Grade “B” = moderate disease activity requiring treatment with low dose oral steroids (<20 
mg/day prednisolone or equivalent), IM or IA steroids (equivalent to MP<500 mg), topical 
steroids or immunomodulators, antimalarials or symptomatic therapy (e.g. NSAIDS). 
Grade “C” = mild disease. 
Grade “D” = indicate previously affected but currently inactive 
Grade “E” = this system has never been involved 
The BILAG index will be assessed every visit (except for screening) 
Physician Global Assessment 
Physician Global Assessment is a Visual Analogue Scale.  It measures the disease activity 
based on the physician subjective assessment from none active to worse disease activity.  PGA 
will be performed at every visit (except for screening) 
Patient Global Assessment 
Patient Global Assessment is a Visual Analogue Scale.  It measures the subject perception of 
his/hers overall health condition, from very well to very poor.  PGA will be performed at every 
visit (except for Screening).  It is important that the Patient Global Assessment be collected 
before other planned visit activities/evaluations to minimize potential influence on patient’s 
perspective. 
SLE Disease Biomarkers 
Blood samples for the analysis of disease biomarkers that may correlate with potential clinical 
effect will be collected from all subjects at Baseline and Visit 5 (16 weeks).  The serum and 
PBMC’s from lupus arthritis patients’ blood will be analyzed for Panel of SLE relevant 
cytokines, cell surface markers, T cell helper and suppressor functions and B cell numbers and 
subsets. Peripheral blood DNA will be obtained for analysis of interferon-induced gene 
expression and RNA for analysis of differences in transcriptome that may associate with 


 
Protocol Amendment 1, November 30, 2015 
43 
 
response compared to no response over the 16 week study period.  SLE biomarkers may change 
upon new research and publication in literature. 
Ultrasound 
The US will be performed by a rheumatologist with expertise in musculoskeletal ultrasound 
and images will be digitally saved.  US assessments of 18 joints for synovitis and 6 joints for 
erosions will be obtained. 
6.4.1 
Primary Efficacy Assessment 
1. Proportion of patients who achieve >= 20% Improvement in tender and swollen joint 
counts at 16 weeks 
 
6.4.2 
Secondary Efficacy Assessments 
1. Changes in synovitis, tenosynovitis and erosions measured by high-energy ultrasound 
with Dopper flow at Baseline and 16 weeks. 
2. STEROID SPARING EFFECT OF ABATACEPT, MEASURED AS 
COMPARISON OF DAILY DOSE AT BASELINE AND 16 WEEKS AND AS 
CUMULATIVE GLUCOCORTICOID DOSE OVER THE 16 WEEKS 
PERIOD. 
3. PROPORTION OF SUBJECTS WITH NO BILAG A IN ANY SYSTEM 
OTHER THAN MUSCULOSKELETAL AT 16 WEEKS. 
4. Proportion of subjects with no deterioration in physician global assessment at 16 
weeks.  
5. Comparison of  fatigue at baseline and 16 weeks as measured by the FACIT 
6. Comparison of  quality of life at baseline and 16 weeks as measured by the SF 36 
7. Safety, measured in standard methods as AE and SAE, inducing likelihood that the 
AE/SAE was related to the study biologic. 
8. Time to ≥20% response, measured as joint counts (sum of tender and swollen joints) 
at baseline, 4, 8, 12 and 16 weeks. 
9. Change in peripheral blood T cell compartments indicating decline in pro-
inflammatory profiles, i.e. we expect decrease in CD4+ effector T cells that make 
IFNgamma (TH1) and IL-17 (TH17) and increase in ratio of Treg to Teff, as well as 
increased functions of the Tregs and decreased function of the helper T cells. 
CD4+CD25+ Foxp3 and CD8+Foxp3+ will be the definition of regulatory T cells.  
These will be measured at baseline and 16 weeks. 
10. Change in anti-DNA and complement levels measured at zero, 8 and 16 weeks. 


 
Protocol Amendment 1, November 30, 2015 
44 
 
 
11.  Change in BLyS levels from baseline to 16 weeks. We expect BLyS levels may rise as 
abatacept interferes with T cell action and thus with T cell help to B cells, with less 
B cell activation and less progression of B cells to short-lived plasma cells, and 
therefore a potential drop in B cell numbers and rise in BLyS levels. If this does not 
occur, then the effects of abatacept on B cells would be considered less dramatic 
than the effects of B cell depletion by rituximab.  
12. Effects of treatment on extra-articular systems involved with SLE, such as skin, mucous 
membranes, serosal surfaces, systemic symptoms at baseline, 4, 8, 12 and 16 weeks. 
7 
ADVERSE EVENT REPORTING 
7.1 
Adverse Events 
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
pre-existing medical condition in a patient or clinical investigation subject administered an 
investigational (medicinal) product and that does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use of 
investigational product, whether or not considered related to the investigational product. 
7.1.1 
Serious Adverse Events 
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose:  
 
results in death 
 
is life-threatening (defined as an event in which the subject was at risk of death at the time 
of the event; it does not refer to an event which hypothetically might have caused death if it 
were more severe) 
 
requires inpatient hospitalization or causes prolongation of existing hospitalization (see note 
below for exceptions) 
 
results in persistent or significant disability/incapacity 
 
is a congenital anomaly/birth defect 
 
is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical 
and scientific judgment, may jeopardize the subject or may require intervention [eg, 
medical, surgical] to prevent one of the other serious outcomes listed in the definition 
above.) Examples of such events include, but are not limited to, intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions 
that do not result in hospitalization.)  Potential drug induced liver injury (DILI) is also 
considered an important medical event.  (See Section 6.6 for the definition of potential 
DILI.) 
Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the study drug 
is an SAE. 


 
Protocol Amendment 1, November 30, 2015 
45 
 
All pregnancies, regardless of outcome, must be reported to BMS, including pregnancies that 
occur in the female partner of a male study subject. All pregnancies must be followed to 
outcome. See Section 7.6 for instructions on reporting pregnancies. 
Although pregnancy, overdose, cancer, and potential drug induced liver injury (DILI) are not 
always serious by regulatory definition, these events must be handled as SAEs and should also be 
reported to BMS in an expedited manner, as described in Section 7.2. 
NOTE: The following hospitalizations are not considered SAEs in BMS clinical studies: 
 
a visit to the emergency room or other hospital department lasting less than 24 hours that 
does not result in admission (unless considered an “important medical event” or a 
life-threatening event) or administration of intravenous antibiotics 
 
elective surgery planned before signing consent 
 
admissions as per protocol for a planned medical/surgical procedure 
 
routine health assessment requiring admission or procedures for baseline/trending of health 
status (eg, routine colonoscopy) 
 
medical/surgical admission for purpose other than remedying ill health state that was planned 
before study entry. Appropriate documentation is required in these cases. 
 
admission encountered for another life circumstance that carries no bearing on health status 
and requires no medical/surgical intervention (eg, lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative). 
7.1.2 
Nonserious Adverse Events 
Nonserious adverse events are all adverse events that are not classified as SAEs. 
7.2 
Assignment of Adverse Event Intensity and Relationship to Abatacept 
All adverse events, including those that are serious, will be graded by the investigator as follows: 
 
Mild (Grade 1): awareness of event but easily tolerated 
 
Moderate (Grade 2): discomfort enough to cause some interference with usual activity 
 
Severe (Grade 3): inability to carry out usual activity 
 
Very Severe (Grade 4): debilitating; significantly incapacitates subject despite symptomatic 
therapy. 
The following categories and definitions of causal relationship to investigational product as 
determined by a physician should be used: 
 
Related: There is a reasonable causal relationship to investigational product administration 
and the adverse event. 
 
Not Related: There is not a reasonable causal relationship to investigational product 
administration and the adverse event. 
The expression “reasonable causal relationship” is meant to convey in general that there are facts 
(eg, evidence such as de-challenge/re-challenge) or other arguments to suggest a positive causal 
relationship. 


 
Protocol Amendment 1, November 30, 2015 
46 
 
7.3 
Collection and Reporting 
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. To prevent reporting bias, subjects should not be questioned 
regarding the specific occurrence of one or more adverse events. 
If known, the diagnosis of the underlying illness or disorder should be recorded, rather than its 
individual symptoms. The following information should be captured for all AEs: onset, duration, 
intensity, seriousness, relationship to investigational product, action taken, and treatment required. 
If treatment for the event was administered, it should be recorded in the medical record. The 
investigator must supply BMS and the IRB/IEC with any additional information requested, notably 
for reported deaths of subjects. 
Completion of supplemental CRFs may be requested for AEs and/or laboratory abnormalities that 
are reported/identified during the course of the study. 
A data safety monitoring board (one to-be-named Rheumatology faculty member plus one to-be-
named statistician) will review the SAEs quarterly and issue a report to the IRB and to the 
investigators regarding AEs and SAEs, reported according to patient assignments to groups A or B 
(the double-blind code will not be broken); these reports will also be supplied to the sponsor 
7.3.1 
Serious Adverse Events 
Following the subject’s written consent to participate in the study, all SAEs must be collected, 
including those thought to be associated with protocol-specified procedures. Collection of all SAEs 
must continue for 30 days after the last administration of the investigational product. If applicable, 
SAEs must be collected that relate to any later protocol-specified procedure. The investigator 
should notify BMS of any SAE occurring after this time period that is believed to be related to the 
investigational product or protocol-specified procedure. 
All SAEs, whether considered related or unrelated to abatacept, must be reported to BMS (by the 
investigator or designee) within 24 hours of study personnel becoming aware of the event. If only 
limited information is initially available, follow-up reports are required. The original SAE form 
must be kept on file at the study site. 
All SAEs should be faxed or emailed to BMS at: 
Global Pharmacovigilance & Epidemiology 
Bristol-Myers Squibb Company 
Fax Number: 609-818-3804 
Email: Worldwide.safety@bms.com 
For studies conducted under an Investigator IND, any event that is both serious and unexpected 
must be reported to the Food and Drug Administration (FDA) as soon as possible and no later 
than 7 days (for a death or life-threatening event) or 15 days (for all other SAEs) after the 
investigator’s or institution’s initial receipt of the information. BMS will be provided with a 
simultaneous copy of all adverse events filed with the FDA. SAEs should be reported on 
MedWatch Form 3500A, 
which 
can 
be 
accessed 
at: 
http://www.accessdata.fda.gov/scripts/medwatch/. 


 
Protocol Amendment 1, November 30, 2015 
47 
 
MedWatch SAE forms should be sent to the FDA at: 
MEDWATCH 
5600 Fishers Lane 
Rockville, MD 20852-9787 
Fax: 1-800-FDA-0178 (1-800-332-0178) 
http://www.accessdata.fda.gov/scripts/medwatch/ 
All SAEs should simultaneously be faxed or e-mailed to BMS at: 
Global Pharmacovigilance & Epidemiology 
Bristol-Myers Squibb Company 
Fax Number: 609-818-3804 
Email: Worldwide.safety@bms.com 
Serious adverse events, whether related or unrelated to abatacept, must be recorded on the SAE 
page and reported within 24-hours to BMS (or designee) to comply with regulatory requirements. 
An SAE report should be completed for any event where doubt exists regarding its status of 
seriousness.  
All SAEs must be reported within 24-hours by confirmed facsimile transmission (fax) and mailing 
of the completed SAE page. In some instances where a facsimile machine is not available, overnight 
express mail may be used. If only limited information is initially available, follow-up reports are 
required. (Note: Follow-up SAE reports should include the same investigator term(s) initially 
reported.) In selected circumstances, the protocol may specify conditions that require additional 
telephone reporting. 
If the investigator believes that an SAE is not related to the investigational product but is potentially 
related to the conditions of the study (such as withdrawal of previous therapy, or a complication of 
a study procedure), the potential relationship should be specified in the narrative section of the SAE 
report. 
If an ongoing SAE changes in its intensity or relationship to the investigational product, a follow-up 
SAE report should be sent within 24 hours to BMS. As follow-up information becomes available 
it should be sent within 24 hours using the same procedure used for transmitting the initial SAE 
report. All SAEs should be followed to resolution or stabilization. 
7.3.2 
Handling of Expedited Safety Reports 
In accordance with local regulations, BMS will notify investigators of all SAEs that are suspected 
(related to the investigational product) and unexpected (ie, not previously described in the 
Investigator Brochure). In the European Union, an event meeting these criteria is termed a 
Suspected Unexpected Serious Adverse Reaction (SUSAR). BMS will send investigators an 
expedited safety report (ESR) to notify them of such an event. 
Other important findings that BMS may report as ESRs include increased frequency of a clinically 
significant expected SAE, an SAE considered associated with study procedures that could modify 
the conduct of the study, lack of efficacy that poses significant hazard to study subjects, clinically 
significant safety findings from a nonclinical (eg, animal) study, important safety recommendations 


 
Protocol Amendment 1, November 30, 2015 
48 
 
from a study data monitoring committee, or the decision by BMS to end or temporarily halt a 
clinical study for safety reasons. 
Upon receiving an ESR from BMS, the investigator must review and retain the ESR with the 
Investigator Brochure. Where required by local regulations or when there is a central IRB/IEC for 
the study, BMS will submit the ESR to the appropriate IRB/IEC. The investigator and IRB/IEC 
will determine if the informed consent requires revision. The investigator should also comply with 
the IRB/IEC procedures for reporting any other safety information. 
In addition, BMS will report suspected serious adverse reactions (whether expected or unexpected) 
to the relevant health authorities in all concerned countries according to local regulations (either as 
expedited and/or in aggregate reports). 
7.3.3 
Nonserious Adverse Events 
The investigator will begin collecting nonserious adverse event (NSAE) information once 
administration of the investigational product is initiated. This NSAE information should also be 
collected from the start of a placebo lead-in period or other observational period intended to 
establish a baseline status for the subjects. 
All identified NSAEs must be recorded and described in the medical record. If an ongoing NSAE 
worsens in its intensity, or if its relationship to the investigational product changes, a new NSAE 
entry for the event should be completed. NSAEs should be followed to resolution or stabilization, 
or reported as SAEs if they become serious. Follow-up is also required for NSAEs that cause 
interruption or discontinuation of investigational product, or those that are present at the end of 
study participation. Subjects with NSAEs at study completion should receive post-treatment 
follow-up as appropriate. 
7.4 
Laboratory Test Abnormalities 
All laboratory test results captured as part of the study should be recorded following institutional 
procedures. When reporting a test result that constitutes an adverse event, the clinical term should 
be used; for example, the event should be reported as “anemia” not “low hemoglobin.” Test results 
that constitute SAEs should be documented and reported as such. 
7.5 
Overdose 
An overdose is defined as the accidental or intentional ingestion or infusion of any dose of a product 
that is considered both excessive and medically important. All occurrences of overdose must be 
reported as an SAE. 
7.6 
Pregnancy 
Sexually active WOCBP must use an effective method of birth control during the course of the 
study, in such a manner that the risk of failure is minimized. (See Section 4.2.1 for the definition 
of WOCBP.) Before enrolling WOCBP in this study, investigators must review the BMS-provided 
information about study participation for WOCBP, which can also be found in the GCP Manual 
for Investigators. The topics include the following:  
 
General Information 
 
Informed Consent Form 


 
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 
Pregnancy Prevention Information Sheet 
 
Drug Interactions with Hormonal Contraceptives 
 
Contraceptives in Current Use 
 
Guidelines for the Follow-up of a Reported Pregnancy. 
Before study enrollment, WOCBP must be advised of the importance of avoiding pregnancy during 
study participation and of the potential risk factors for an unintentional pregnancy. The subject 
must sign an informed consent form documenting this discussion.  
7.6.1 
Requirements for Pregnancy Testing 
All WOCBP MUST have a negative pregnancy test within 72 hours before receiving 
abatacept. The minimum sensitivity of the pregnancy test must be 25 IU/L or equivalent units of 
HCG. If the pregnancy test is positive, the subject must not receive abatacept and must not continue 
in the study. 
In addition, all WOCBP must be instructed to contact the investigator and/or other study 
personnel immediately if they suspect they might be pregnant (eg, missed or late menstrual 
period) at any time during study participation. 
7.6.2 
Reporting of Pregnancy 
If, following initiation of the investigational product, it is subsequently discovered that a study 
subject is pregnant or may have been pregnant at the time of investigational product exposure, 
including during at least 6 half-lives after administration, the investigational product will be 
permanently discontinued in an appropriate manner (eg, dose tapering if necessary for subject 
safety). The investigator must immediately notify BMS of this event and record the pregnancy on 
the Pregnancy Surveillance Form (not on an SAE form). Initial information on a pregnancy must 
be reported immediately to BMS, and information on the outcome provided once it is available. 
Completed Pregnancy Surveillance Forms must be forwarded to BMS according to SAE reporting 
procedures.  
Note: Any pregnancy that occurs in a female partner of a male study subject must be reported to 
BMS using the Pregnancy Surveillance Form. 
Protocol-required procedures for study discontinuation and follow-up must be performed for the 
subject unless contraindicated by pregnancy (eg, x-ray studies). Other appropriate pregnancy 
follow-up procedures should be considered if indicated. Information regarding the course of the 
pregnancy, including perinatal and neonatal outcome, must be reported to BMS on the Pregnancy 
Surveillance Form. Infants should be followed for a minimum of 8 weeks.  
7.7 
Other Safety Considerations 
Any significant worsening noted during interim or final physical examinations, electrocardiograms, 
x-rays, and any other potential safety assessments, whether or not these procedures are required by 
the protocol, should also be recorded in the medical record. 
7.8 
Safety Data Reconciliation 


 
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The investigator will reconcile the clinical database SAE cases transmitted to BMS Global 
Pharmacovigilance (GPV&E). Frequency of reconciliation will be determined prior to study 
commencement but will occur no less than once prior to study database lock. BMS GPV&E will 
e-mail upon request from the investigator, the GPV&E reconciliation report. Requests for 
reconciliation should be sent to aepbusinessprocess@bms.com. The data elements listed on the 
GPV&E reconciliation report will be used for case identification purposes. If the investigator 
determines a case was not transmitted to BMS GPV&E, the case will be sent immediately. 
8 
STATISTICAL CONSIDERATIONS 
8.1 
Sample Size Determination 
We based our sample sizes on the preliminary data (unpublished): SLE patients with arthritis at 
the start of a treatment had a mean score on 66-joint count of 21 ± 8.2.  There was a decrease to a 
mean of 2.0 ± 1.5 after 12 weeks of various interventions in patients who reported they improved. 
For the study proposed here, if 67% of abatacept pts will achieve 20% improvement in swollen 
and tender joints vs. 30% of controls  by week 16, n=28 per group (with p=0.05, power=0.8).  
Thus we plan 32 patients for abatacept over 16 weeks and 32 patients for placebo over 16 weeks, 
a total of 64. The dropout rate in the abatacept non-nephritis lupus trial was 35% (over 12 
months). We anticipate one-third that in a 4 month trial, proposed, here – i.e. 12%. If we begin 
with 64 patients we should have 56 completers, thus approximately 28 in each group. 
 
 Thus, we will plan to recruit 32 SLE patients at UCLA and an additional 32 at UCSD (separate 
contract).  
 
 
8.2 
Populations for Analyses 
The study analyses will be performed at the termination of the study; once the last visit of the last 
patients has been recorded.  The analyses will be performed on the 64 SLE patients enrolled in the 
study based on the inclusion and exclusion criteria as stated above. 
8.3 
Endpoint Definitions 
Starting at baseline and at each visit, the SLEDAI 2K, BILAG, and joint count will be recorded.  
In addition the patient and physician Global Assessment will be recorded.  These are all validated 
measures to evaluate SLE disease activity and response to therapy.  In addition, the US 28-joint 
synovitis and power Doppler scores will be compared to baseline.  


 
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8.3.1 
Demographics and Baseline Characteristics 
All subjects who receive a dose of study drug will be evaluated for safety. Safety outcomes 
include adverse events, clinically significant changes in vital signs, laboratory test abnormalities, 
and clinical tolerability of the drug. The investigator will determine the severity of each adverse 
event as mild, moderate, severe, or very severe.  Descriptive statistics (mean, standard deviation, 
median, inter-quartile range, and frequency distribution) of safety data will be generated to 
characterize the study participants by treatment arm.  The Chi-square test or Fisher’s exact test 
will be used to compare the percent of subjects presenting with AEs (analyzed separately as SAE, 
any AE) between the two groups. 
 
8.4.3 Efficacy Analyses 
The Fisher’s exact test will be used to compare the percent of subjects achieving primary and 
secondary outcomes between two groups. Wilcoxon rank sum tests will be used to compare 
ordinal and quantitative outcomes between groups. Logistic regression will also be used to adjust 
for baseline clinical presentation and demographic factors. A site by treatment interaction effects 
will be included in the model to account for possible differences in treatment efficacy between 
our two sites. Bivariate analysis and nonparametric analysis (for example local polynomial 
regression or generalized additive model analysis) will be carried out to inspect the relationship 
between outcome and covariates. The goodness-of-fit of logistic models will be evaluated using 
the Hosmer-Lemeshow test.  With the quantitative outcomes such as joint counts, ultrasound 
measurements, etc we will use Poisson regression to assess the treatment effect or linear 
regression for continuous outcomes.  Poisson regression is a special case of generalized linear 
model and robust pseudo likelihood inference will be used in the analysis.  We also will use 
multiple imputation technique to accommodate possible missing data at 12 and 24 weeks due to 
patients lost to follow up. The imputation model will include all baseline 12 week and 24 week 
outcomes and covariates to impute the missing outcomes 23. Analyses will be done with and 
without imputation.  


 
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8.4.4Other Analyses 
NA 
9 
ADMINISTRATIVE SECTION 
9.1 
Compliance with the Protocol 
The study must be conducted as described in the final IRB/IEC-approved protocol. Documentation 
of approval, signed by the IRB/IEC chairperson or designee, will be sent to the BMS protocol 
manager. The study will be monitored by an individual outside the study team chosen by the PI.  
All protocol amendments and revisions to the informed consent will be submitted to the BMS 
protocol manager and to the IRB/IEC. No protocol amendments will be implemented until written 
approval has been given by the IRB/IEC, except when necessary to eliminate an immediate hazard 
to study subjects. Administrative letters should also be sent to the BMS protocol manager and 
IRB/IEC; however, they do not require approval. 
If a protocol amendment mandates a revision to the informed consent, the revised consent must be 
used to obtain consent from subjects currently enrolled in the study if it affects them (eg, if it 
contains new information regarding safety), and the revised consent must be used to obtain consent 
from new subjects before enrollment.  
9.2 
Records Retention 
The investigator will retain, in a confidential manner, all data pertinent to the study for all treated 
subjects as well as those entered as control subjects. The investigator will retain source documents 
and accurate case histories that record all observations and other data pertinent to the investigation 
(eg, the medical record) for the maximum period required by applicable regulations and guidelines 
or following institutional procedures. If the investigator withdraws from the study (eg, relocation 
or retirement), the records will be transferred to a mutually agreed upon designee, such as another 
investigator or an IRB. Written documentation of such transfer will be provided to BMS. 
The investigator will ensure that a current record of disposition of investigational product is 
maintained at each study site where the investigational product is inventoried and disposed. 
Records or logs must comply with applicable regulations and guidelines and should include: 
 
amount received and placed in storage area 
 
amount currently in storage area 
 
label identification number or batch number and use date or expiry date 
 
dates and initials of person responsible for each inventory entry/movement 
 
amount dispensed to and returned by each subject, including unique subject identifiers 
 
amount transferred to another area/site for dispensing or storage 
 
non-study disposition (eg, lost, wasted, broken), and 
 
amount destroyed at study site. 
9.3 
Destruction of Investigational Product 
If the investigational product is to be destroyed on site, it is the investigator’s responsibility to 
ensure that arrangements have been made for disposal, and that procedures for proper disposal have 


 
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been established according to applicable regulations, guidelines, and institutional procedures. 
Appropriate records of the disposal must be maintained. 


 
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10 
GLOSSARY OF TERMS 
Term 
Definition 
Adverse Reaction 
An adverse event that is considered by either the investigator 
or the sponsor to be related to the investigational product 
Expedited Safety Report 
Rapid notification to investigators of all SAEs that are 
suspected (related to the investigational product) and 
unexpected (ie, not previously described in the Investigator 
Brochure), or that could be associated with the study 
procedures.  
SUSAR 
Suspected, Unexpected, Serious Adverse Reaction as termed 
by the European Clinical Trial Directive (2001/20/EC).  
Unexpected Adverse Reaction 
An adverse reaction, the nature or severity of which is not 
consistent with the applicable product information (eg, 
Investigator Brochure for an unapproved investigational 
product) 
 


 
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11 
LIST OF ABBREVIATIONS 
AB 
Antibody  
ACR 
American College of Rheumatology  
AE 
Adverse event 
ALT 
Alanine Transaminase  
APC 
Antigen-Presenting Cell  
ARA 
American Rheumatology Association  
AST 
Aspartate Transaminase  
BCG 
Bacillus Calmette-Guérin  
BMS 
Bristol-Myers Squibb  
BUN 
Blood Urea Nitrogen  
CBC 
Complete Blood Count  
CDC-ACID  
Centers for Disease Control and Prevention Advisory Committee on 
Immunization Practices  
CFR 
Code of Federal Regulations  
CI 
Confidence Interval  
CMV 
Cytomegalovirus  
CRF 
Case Report Forms  
CRP 
C-Reactive Protein  
CTLA 
Cytotoxic T-Lymphocyte Associated  
CXR 
Chest X-Ray  
DMARD 
Disease-Modifying Antirheumatic Drug  
DNA 
Deoxyribonucleic Acid  
D5W 
Dextrose (5%) in Water  
EC 
European Commission  
ESR 
Expedited Safety Report  
EULAR 
European League Against Rheumatism  
FDA 
Food and Drug Administration 
FSH 
Follicle-Stimulating Hormone  
GCP 
Good Clinical Practice  
GGT 
Gamma-Glutamyltransferase  
GM-CSF 
Granulocyte Macrophage Colony-Stimulating Factor  
HCG 
Human Chorionic Gonadotropin  
HIV 
Human Immunodeficiency Virus  
HLA 
Histocompatibility Leukocyte Antigen  


 
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HRT 
Hormone Replacement Therapy 
IB 
Investigator Brochure 
ICH 
International Conference on Harmonisation  
IEC 
Independent Ethics Committee  
IL 
Interleukin  
IND 
Investigational New Drug (Application) 
IRB 
Independent Review Board  
IST 
Investigator-Sponsored Trial 
IU 
International Unit  
IV 
Intravenous  
JRA 
Juvenile Rheumatoid Arthritis  
MHC 
Major Histocompatibility Complex  
MRI 
Magnetic Resonance Imaging  
NPV 
Negative Predictive Value  
NS 
Normal Saline  
NSAE 
Non-Serious Adverse Event 
NSAID 
Non-Steroidal Anti-inflammatory Drug  
OA 
Osteoarthritis  
PCR 
Polymerase Chain Reaction  
PPD 
Purified Protein Derivative  
PPV 
Positive Predictive Value  
PVC 
Polyvinylchloride  
RA 
Rheumatoid Arthritis  
RF 
Rheumatoid Factor  
SAE 
Serious Adverse Event  
Se 
Sensitivity  
SLE 
Systemic Lupus Erythematosus  
SmPC 
Summary of Product Characteristics  
Sp 
Specificity  
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
SWFI 
Sterile Water For Injection  
TB 
Tuberculosis  
TNF 
Tumor Necrosis Factor  
ULN 
Upper Level of Normal  
VAS 
Visual Analog Scale  


 
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WBC 
White Blood Cell  
WOCBP 
Women of Childbearing Potential  


 
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12 
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Appendix 1 ACR Criteria 


 
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Appendix 2 – SLICC 


 
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BILAG 


 
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SLEDAI 2 K 


 
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Physician Global 


 
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Patient Global