Conditions: Uveitis
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 10
Healthy volunteers: no

Brief summary:
The purpose of this study is to assess the safety and efficacy of abatacept in the treatment of uveitis.

Detailed description:

Arms:
arm 1: 10 mg/kg abatacept (6 months). Then 5 mg/kg abatacept (18 months) arm 2: 10 mg/kg abatacept (6 months). Then 10 mg/kg abatacept (18 months)

Interventions: intervention 1: Abatacept
Intervention descriptions: intervention 1: Subjects will receive approximately 10 mg/kg rounded to the nearest 25 mg for the first 6 months of the trial. At 6 months subjects will then be randomized to receive either 5 mg/kg or 10 mg/kg.

Abatacept will be administered as a 30-minute intravenous infusion. Following the initial administration, abatacept will be given at 2 and 4 weeks after the first infusion and every 4 weeks thereafter for up to 2 years.

Protocol document:
Prot_SAP_000.pdf: 
Abatacept 
1 
 
STUDY TITLE: 
A phase I/II trial of Abatacept (Orencia) in the treatment of refractory 
non-infectious uveitis. 
 
 
Study Drug 
Abatacept  
 
Support Provided By 
Bristol-Myers Squibb, Co. 
 
Sponsor Investigator/Institution 
Eric B. Suhler 1,2, MD, MPH  
 
1Oregon Health & Science University 
2Portland VA Medical Center 
 
 
BMS Protocol: IM101-259 
Protocol Version/Date:  Version 3.5   1/13/2012 


 
Abatacept 
 
2
TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................... 2 
PROTOCOL SYNOPSIS ................................................................... 6 
1 
INTRODUCTION ............................................................... 10 
1.1 
Research Hypothesis ...................................................... 10 
1.2 
Product Development Rationale .................................... 10 
1.2.1 
Overview of Uveitis ......................................................................... 11 
1.3 
Summary of Results of Investigational Program .......... 12 
1.3.1 
Immunogenicity Experience with Abatacept ................................ 12 
1.4 
Overall Risk/Benefit Assessment .................................. 12 
1.5 
Study Rationale ............................................................... 14 
2 
STUDY OBJECTIVES ...................................................... 15 
2.1 
Primary Objective ............................................................ 15 
2.2 
Secondary Objectives ..................................................... 15 
3 
ETHICAL CONSIDERATIONS ......................................... 16 
3.1 
Good Clinical Practice .................................................... 16 
3.2 
Institutional Review Board/Independent Ethics 
Committee ....................................................................... 17 
3.3 
Informed Consent ........................................................... 17 
4 
INVESTIGATIONAL PLAN ............................................... 17 
4.1 
Study Design and Duration ............................................ 17 
4.2 
Study Population ............................................................. 18 
4.2.1 
Inclusion Criteria ............................................................................. 18 
4.2.2 
Exclusion Criteria ............................................................................ 20 
4.2.3 
Discontinuation of Subjects from Treatment ................................ 22 
5 
TREATMENTS .................................................................. 22 
5.1 
Study Treatment: Abatacept ........................................... 22 


 
Abatacept 
 
3
5.1.1 
Identification .................................................................................... 23 
5.1.2 
Storage, Handling, and Dispensing ............................................... 23 
5.1.3 
Additional Information for the Handling, Dispensing, and 
Storage of Abatacept ...................................................................... 24 
5.2 
Drug Accountability ........................................................ 25 
5.3 
Selection and Timing of Dose for Each Subject ........... 25 
5.3.1 
Dose Modifications in the Absence of Adverse Events ............... 25 
5.3.2 
Dose Modifications for Adverse Events ........................................ 26 
5.4 
Concomitant Treatments ................................................ 26 
5.4.1 
Prohibited and/or Restricted Treatments ...................................... 26 
5.4.2 
Other Restrictions and Precautions .............................................. 26 
5.4.2.1 
Immunizations ................................................................................. 26 
5.5 
Management of Possible Acute Hypersensitivity 
Reactions to Abatacept .................................................. 27 
6 
STUDY ASSESSMENTS AND PROCEDURES ............... 28 
6.1 
Time and Events Schedule ............................................. 28 
6.1.1 
Study Completion or Early Discontinuation Visit ......................... 28 
6.1.2 
Study Drug Discontinuation ........................................................... 28 
6.2 
Study Materials ................................................................ 30 
6.3 
Safety Assessments ....................................................... 30 
6.3.1 
Physical Examinations.................................................................... 30 
6.3.2 
Tuberculin Skin Testing .................................................................. 30 
6.4 
Efficacy Assessments .................................................... 31 
6.4.1 
Visual Acuity .................................................................................... 31 
6.4.2 
Graded Assessment of Ocular Inflammation ................................ 31 
6.4.3 
Measurement of Macular Thickness Using OCT .......................... 31 
6.4.4 
Fluorescein Angiography ............................................................... 31 
6.4.5 
Fundus Photography ...................................................................... 31 
6.5 
Other Assessments ........................................................ 32 
6.5.1 
Ocular Examinations ....................................................................... 32 


 
Abatacept 
 
4
6.5.2 
Subject and Physician Global Assessments of Disease ............. 32 
6.5.3 
Visual Analog Scale for Pain .......................................................... 32 
7 
ADVERSE EVENT REPORTING ...................................... 32 
7.1 
Adverse Events ............................................................... 32 
7.1.1 
Serious Adverse Events ................................................................. 32 
7.1.2 
Nonserious Adverse Events ........................................................... 33 
7.2 
Assignment of Adverse Event Intensity and 
Relationship to Abatacept .............................................. 34 
7.3 
Collection and Reporting ................................................ 34 
7.3.1 
Serious Adverse Events ................................................................. 35 
7.3.2 
Handling of Expedited Safety Reports .......................................... 36 
7.3.3 
Nonserious Adverse Events ........................................................... 37 
7.4 
Laboratory Test Abnormalities ...................................... 37 
7.5 
Pregnancy ........................................................................ 38 
7.5.1 
Requirements for Pregnancy Testing ............................................ 38 
7.5.2 
Reporting of Pregnancy .................................................................. 38 
7.6 
Other Safety Considerations .......................................... 39 
8 
STATISTICAL CONSIDERATIONS .................................. 39 
8.1 
Overview .......................................................................... 39 
8.2 
Datasets to be Analyzed ................................................. 39 
8.3 
Endpoint Definitions ....................................................... 40 
8.3.1 
Safety Endpoints ............................................................................. 40 
8.3.2 
Efficacy Endpoints .......................................................................... 40 
9 
ADMINISTRATIVE SECTION ........................................... 40 
9.1 
Compliance with the Protocol ........................................ 40 
9.2 
Records Retention .......................................................... 41 
9.3 
Destruction of Investigational Product .......................... 42 
10 
GLOSSARY OF TERMS ................................................... 43 
11 
LIST OF ABBREVIATIONS .............................................. 44 


 
Abatacept 
 
5
12 
APPENDICES ................................................................... 46 
13 
REFERENCES .................................................................. 49 
 
 


Abatacept 
6 
PROTOCOL SYNOPSIS 
Protocol Title: 
A phase I/II trial of Abatacept (Orencia) in the 
treatment of refractory non-infectious uveitis. 
Site Numbers & Names: 
1 Site 
Research Hypothesis: 
Among subjects with uveitis that are refractory to 
conventional immunosuppressive therapy, abatacept is a 
safe and effective treatment and a decreased dose is 
effective for maintenance of therapy. 
Study Rationale 
The majority of non-infectious uveitis cases are thought to 
be immune-mediated, possibly triggered by environmental 
stimuli and mediated primarily by T-cells in patients with an 
immunogenetic predisposition. The implication of cell-
mediated immunity in the pathogenesis of uveitis has 
provided a rationale for treatment with immunosuppressive 
medications such as corticosteroids, which have been 
shown to be effective in improving the signs and 
symptoms of ocular inflammation, as well as the prognosis 
for preservation of visual acuity. The well-known side 
effects of chronic corticosteroid therapy, however, have led 
ophthalmologists to employ corticosteroid-sparing agents 
to reduce the toxicity of long term corticosteroid use. 
Continuing effort is underway to identify more effective 
therapies, which would ideally focus on targeting the action 
of specific mediators of the immune response, allowing for 
increased efficacy and decreased side effects of 
treatment. 
Study Objectives: 
Primary: 
Secondary: 
 
To assess the safety of the study drug in patients with 
refractory, non-infectious uveitis. 
To assess the efficacy of the study drug in the treatment of 
subjects with refractory, non-infectious uveitis. 
Study Design: 
This is a randomized, controlled, dose-modification,  phase 
I/II, prospective clinical trial to examine the safety and 
efficacy of abatacept in treatment of uveitis.   
Study Schema 
Drugs / Doses /  
Length of Treatment) 
Subjects will receive approximately 10 mg/kg abatacept 
infusions at Day 1, Day 15, Day 30 and then every 4 
weeks for 6 months.Subjects will be randomized 
subsequently to receive either 5 mg/kg or 10 mg/kg doses 
every four weeks, and will continue receiving infusions for 
up to 2 years. 


 
Abatacept 
 
7
Accrual Goal: 
(Total number of subjects) 
20 subjects with non-infectious uveitis refractory to 
standard immunosuppression. 
Accrual Rate: 
(Number of subjects 
expected per month) 
  Enrollment expected at 1 subject per month. 
 
FPFV: 
LPFV: 
 3/2012 
3/2014 
Inclusion Criteria: 
Primary criteria are outlined below.  Please see 
section 4.2 for complete criteria. 
1. Patients with vision-threatening autoimmune 
uveitis. 
2. Failure to respond to prednisone and at least one 
other systemic immunosuppressive (such as 
methotrexate, azathioprine, mycophenolate mofetil, 
cyclosporine, chlorambucil, or a tumor-necrosis 
factor blocker or other biologic response modifier 
(BRM)), or intolerance to such medications due to 
side effects.  Washout periods will apply to all 
patients exposed to BRMs. 
3. Patients of both genders ≥ 6 years old. There is no 
upper age limit as long as there are no other 
disqualifying health conditions.  


 
Abatacept 
 
8
Exclusion Criteria: 
Primary criteria are outlined below.  Please see 
section 4.2 for complete criteria. 
1. Women of Childbearing Potential (WOCBP) who 
are unwilling or unable to use an acceptable 
method to avoid pregnancy for the entire study 
period and for up to 10 weeks after the last dose of 
study drug.  
2. Uveitis of infectious etiology. 
3. Subjects with current symptoms of severe, 
progressive, 
or 
uncontrolled 
renal, 
hepatic, 
hematologic, gastrointestinal, pulmonary, cardiac, 
neurologic, or cerebral disease. 
4. 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.  
5. Subjects with evidence of active or latent bacterial 
or viral infection, including subjects with evidence 
of human immunodeficiency virus (HIV) detected 
during screening. 
6. Subjects with herpes zoster or cytomegalovirus 
(CMV) that resolved less than 2 months before the 
informed consent document was signed. 
7. Subjects with evidence of current or prior 
tuberculosis (TB).  
8. Serious concomitant illness that could interfere with 
the subject’s participation in the trial. 
9. Subjects who are positive for hepatitis B surface 
antigen. 
10. Subjects who are positive for hepatitis C antibody 
11. Concomitant 
use 
of 
cyclophosphamide 
or 
cyclosporine (unless use is restricted to eye drops). 
12. Are taking other biologic medicines to treat RA or 
JIA such as: Enbrel® (etanercept), Humira® 
(adalimumab), Remicade® (infliximab), Kineret® 
(anakinra) or Rituxan® (rituximab). You may have 
a higher chance of getting a serious infection if you 
take ORENCIA with other biologic medicines. 


 
Abatacept 
 
9
Criteria for Evaluation: 
(Efficacy, safety, 
stopping rules, etc.) 
Safety assessments will be done at every visit including 
inquiring about systemic or ocular adverse events. Blood 
work and chest x-rays will be done as required for the 
study drug.  The following clinical assessments will provide 
outcome data at screening, week 12, 24,,52, 76, and at 2 
year study closure: Fluorescein Angiography, Ocular 
Coherence Tomography, graded assessment of anterior 
and posterior segment ocular inflammation, Best 
Corrected Visual Acuity, and patient and physician 
assessments of well-being utilizing Visual Analog Scales.  
Statistics: 
Safety measures will be assessed at every visit.  At weeks 
12, 24, 52, 76, and at study closure clinical efficacy will be 
assessed and compared to baseline values. If the subject 
is deemed a non-responder at this assessment, the 
subject will exit the study. For subjects who respond 
positively to treatment, clinical efficacy data will be 
collected at week 12, 24, 52, 76 and 104 and will be 
compared to the baseline values.  The primary efficacy 
endpoint will be at 52 weeks. 


 
Abatacept 
 
10 
1 
INTRODUCTION 
1.1 
Research Hypothesis 
Abatacept is a safe and effective treatment for subjects with uveitis refractory to 
conventional immunosuppressive therapy, and after induction with higher dose therapy 
(10 mg/kg/dose), will be able to be  safely and effectively managedwith maintenance 
therapy at 5 mg/kg/dose in these subjects. 
1.2 
Product Development Rationale 
Abatacept is a recombinant fusion protein consisting of the extracellular domain of 
human CTLA (cytotoxic T-lymphocyte antigen) 4 and a hinge fragment of the CH2-CH3 
portions 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-lymphocytes, also termed 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.1,2,3,4 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.5,6 In the 
presence of CD28, successful costimulation may occur, leading to T-cell activation.  
When modulation of the T-cell activation is required, one operative mechanism is to 
reduce costimulation via expression of CTLA4 on the surface of T-lymphocytes.  CTLA-
4expression, which may begin 24 to 48 hours following initial T-cell activation,  
successfully interferes 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.   


 
Abatacept 
 
11 
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.7 
1.2.1 
Overview of Uveitis 
The term uveitis is used clinically to describe a heterogeneous group of diseases having 
in common inflammation of intraocular structures. Despite accounting for <1% of ocular 
disease in most clinical settings, uveitis accounts for 10-15% of legal blindness in some 
series, and as many as a third of patients affected with the more severe manifestations of 
uveitis are blinded in series reported from tertiary centers8.  In addition, uveitis 
disproportionately affects a younger population compared to more prevalent blinding 
diseases such as glaucoma and macular degeneration, leading to loss of a 
disproportionately high number of productive person-years to society.  Therefore, despite 
its relative uncommonness, uveitis is a significant public health problem. 
Although frequently associated with systemic inflammatory or autoimmune diseases such 
as 
sarcoidosis, 
multiple 
sclerosis, 
Behçet's 
disease, 
and 
the 
seronegative 
spondylarthropathies, a significant number of cases defy disease classification and are 
labeled idiopathic.  In many such cases, disease may be limited to the eye.  In general, 
non-infectious cases of uveitis are thought to represent immune-mediated disease, 
possibly triggered by environmental stimuli and mediated primarily by T-cells in patients 
with an immunogenetic predisposition.9,10 
The implication of cell-mediated immunity in the pathogenesis of uveitis has provided a 
rationale for treatment with immunosuppressive medications such as corticosteroids, 
which have been shown to be effective in improving the signs and symptoms of ocular 
inflammation, as well as the prognosis for preservation of visual acuity.11  The well-
known side effects of chronic corticosteroid therapy, however, have led ophthalmologists 
to employ corticosteroid-sparing agents to reduce the toxicity associated with long term 
corticosteroid use.  Unfortunately, each of these agents may be associated with 
undesirable toxicity.12  Continuing effort is underway to identify more effective therapy, 


 
Abatacept 
 
12 
which would ideally focus on targeting the action of specific mediators of the immune 
response, allowing for increased efficacy and decreased side effects of treatment. 
1.3 
Summary of Results of Investigational Program 
The initial efficacy and safety of abatacept (previously known as CTLA4-Ig and 
BMS-188667) was established in clinical studies of rheumatoid arthritis (RA), psoriasis, 
and multiple sclerosis. Currently, there are no active registrational studies for psoriasis or 
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 (JIA in 
patients who have failed prior therapy with disease-modifying anti-rheumatic drugs 
(DMARDs).  There are no reported or registered studies of abatacept for the treatment of 
inflammatory eye diseases, although many of the above noted diseases may cause ocular 
inflammation, providing a rationale for studying this indication.  
1.3.1 
Immunogenicity Experience with Abatacept 
In the RA program, the frequency of development of anti-abatacept antibodies (ie, 
immunogenicity) was examined in 2337 subjects. Among all subjects, 62 of 2337 (2.8%) 
developed antibodies to abatacept. Overall, there was no apparent correlation of antibody 
development to clinical response or adverse events. However, the number of subjects that 
developed antibodies was too limited to make a definitive assessment. The potential 
clinical relevance of neutralizing antibody formation is not known.13,14 
1.4 
Overall Risk/Benefit Assessment 
Existing data exists on the safety or efficacy of abatacept for patients with inflammatory 
eye disease is limited to small case reports; however; The published experience in 
patients with other immune-mediated diseases is instructive, and will be discussed below. 
In 2010, Zulian and colleagues reported a series of 7 children with juvenile idiopathic 
arthritis and uveitis, all of whom had failed therapy with multiple standard 
immunosuppresssives and TNF blockers, and noted six treatment successes using 
monthly intravenous abatacept.  A respondent to this publication in February 2011 added 


 
Abatacept 
 
13 
two other successfully treated patients, along with a single case report of one successful 
case in 2008.15, 16  In the past decade, the development of biologic DMARDs such as 
TNF- inhibitors, along with other advances and new insights into rheumatoid disease 
progression, have led to a re-evaluation of management of RA to include earlier use of 
DMARD and combination DMARD therapy to limit the occurrence of functionally 
significant complications.  Similarly, early aggressive therapy of inflammatory eye 
disease may limit the occurrence of visually significant complications. The efficacy, 
tolerability, and safety profile of abatacept was demonstrated in the RA clinical 
development program. Abatacept, a biologic DMARD with a unique mechanism of 
action, has demonstrated a good efficacy/safety profile. Abatacept has been on the market 
in the US since January 2006 and in Europe since May 2007. 
The major identified risk of abatacept is an increased incidence of infections. The 
abatacept RA program identified both non-serious and serious infections, mainly 
bacterial (upper respiratory tract infections, pneumonias) and viral (herpes simplex), as 
occurring more frequently in abatacept-treated subjects than in subjects on placebo. Most 
infections responded appropriately to treatment, and no major differences in outcome 
were apparent between abatacept and placebo. The risk for serious infections did not 
increase with increasing exposure in the open-label periods of the clinical studies. 
The effect of increasing exposure on the risk of serious infections was assessed by 
comparing the incidence rate of serious adverse events in the “infections and infestations” 
classification over the cumulative double-blind and open-label study periods (10,365 
person-years) with that observed during the double-blind study periods alone 
(1688 person-years). This analysis revealed that that the incidence per 100 person-years 
(double-blind 
versus 
cumulative) 
remained 
stable 
for 
serious 
infections 
(3.47 versus 2.98).17 Opportunistic infections and tuberculosis (TB) were uncommon, 
although all subjects were screened for latent TB. 
The overall risk of malignancy for abatacept-treated subjects was comparable to that of 
placebo-treated subjects during the double-blind periods. The effect of increasing 
duration of exposure on the risk of malignancy was assessed by comparing the incidence 
rates of malignancies (per 100 person-years) in the cumulative double-blind and open-
label study periods (10,365 person-years as of December 2007) with that observed during 
the double-blind study periods alone (1688 person years). This analysis revealed that the 
incidence per 100 person-years (double-blind versus cumulative) remained stable for 
malignancies overall, excluding non-melanomatous skin cancer (0.59 versus 0.71). More 
specifically, the incidence rates for lung cancer (0.24 versus 0.16) and lymphoma (0.06 


 
Abatacept 
 
14 
versus 0.07) remained stable. In addition, in double-blind and cumulative study periods, 
the incidence rate of malignancy (per 100 person-years) for abatacept-treated subjects 
was similar to that seen in the double-blind placebo group and RA cohort overall and for 
major categories (skin, solid, hematologic). Clinical presentation and incidence over time 
do not suggest increased risk with abatacept.18 
Treatment with abatacept was associated with an excellent peri-infusional safety profile 
and a low level of immunogenicity. In the only existing study evaluating the safety and 
efficacy of abatacept or infliximab versus placebo (IM101-043, the ATTEST study), the 
safety and tolerability results through 1 year suggest that abatacept may have a superior 
safety and tolerability profile.19   
In summary, the potential overall benefit/risk ratio for abatacept-treated patients in this 
study appears to be favorable. The risks are probably no worse than those of infliximab 
therapy, which has been extensively studied in inflammatory eye disease, and may be 
superior.  To minimize the overall risk to participating patients, this protocol has 
inclusion and exclusion criteria appropriate to the population and proposed treatments, 
exclusionary screening tests, and specific follow up safety assessments. In addition, the 
adverse events and serious adverse events will be reviewed on an ongoing basis by the 
medical monitors and pharmacovigilance group to detect trends and any potential safety 
issues. 
1.5 
Study Rationale 
As noted previously, non-infectious cases of uveitis are thought to represent immune-
mediated disease, possibly triggered by environmental stimuli and mediated primarily by 
T-cells in patients with an immunogenetic predisposition. The implication of cell-
mediated immunity in the pathogenesis of uveitis has provided a rationale for treatment 
with immunosuppressive medications such as corticosteroids, which have been shown to 
be effective in improving the signs and symptoms of ocular inflammation, as well as the 
prognosis for preservation of visual acuity. The well-known side effects of chronic 
corticosteroid therapy, however, have led ophthalmologists to employ corticosteroid-
sparing agents to reduce the toxicity associated with long term corticosteroid use. 
Continuing effort is underway to identify more effective therapy, which would ideally 
focus on targeting the action of specific mediators of the immune response, allowing for 
increased efficacy and decreased side effects of treatment. 


 
Abatacept 
 
15 
2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
To assess the safety of the study drug in this patient population, ascertained by tracking 
the type, frequency, severity, and relationship of adverse events during study treatment, 
and where possible, determining whether or not a causal link exists between the event 
and study therapy. 
 
2.2 
Secondary Objectives 
 To assess the efficacy of the study drug in the treatment of subjects with refractory, non-
infectious uveitis and to assess the efficacy of a reduced dose as maintenance therapy.   
Refractory disease is defined as that which is unable to be successfully treated by 
corticosteroids and at least one “standard” immunosuppressive, or when toxicity makes 
such therapy untenable.  
Efficacy of the study drug will be assessed using a composite clinical endpoint  
comprised of 4 criteria.  Treatment will be judged to be successful if there is 
improvement in at least one of these criteria without significant worsening in any of 
them.  These criteria include: 
 Improvement by 2 or more lines of best-corrected ETDRS or Snellen visual acuity 
in at least one eye  
 Reduction in dose of systemic corticosteroid or other immunosuppressive therapy 
by at least 50% 
 Control of ocular inflammation, as judged on clinical criteria, according to 
standard methods 
o Reduction of anterior chamber cellular activity and/or vitreous haze by 2 
grades, and to a level of trace or less (SUN) 
o Reduction of chorioretinal infiltrates or reduction of retinal vasculitis 
(documented by fundus photography and fluorescein angiography) 
 Reduction of cystoid macular edema and/or retinal inflammation, as judged 
clinically and by fluorescein angiogram and/or optical coherence tomography. 
 


 
Abatacept 
 
16 
3 
ETHICAL CONSIDERATIONS 
3.1 
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. 


 
Abatacept 
 
17 
3.2 
Institutional Review Board/Independent Ethics 
Committee 
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. 
3.3 
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. 
The rights, safety, and well-being of the study subjects are the most important 
considerations and should prevail over interests of science and society. 
For minors, according to local legislation, one or both parents or a legally acceptable 
representative must be informed of the study procedures and must sign the informed 
consent form approved for the study before clinical study participation. The explicit wish 
of a minor who is capable of forming an opinion and assessing this information to refuse 
participation in, or to be withdrawn from, the clinical study at any time, should be 
considered by the investigator. Minors who are judged to be of an age of reason must also 
give their written assent. 
4 
INVESTIGATIONAL PLAN 
4.1 
Study Design and Duration 
This is a single-center, randomized, , dose-ranging, prospective clinical trial to examine 
the safety and efficacy of abatacept in treatment of refractory uveitis.  Subjects will 


 
Abatacept 
 
18 
receive 10 mg/kg intravenous infusions at Day 1, Day 15, Day 30 and every 4 weeks for 
6 months, then subjects will be randomized to receive either 5 mg/kg or 10 mg/kg 
infusions every 4 weeks for up to 1.5 years after to ascertain the effectiveness of the 
lower dose in maintaining control of inflammation.  Subjects will undergo efficacy 
assessments at weeks 12, 24, 52, 76, and 104 and non-responders will be removed from 
the study.   
The study will be split into 2 segments.  The first segment will be Weeks 0 through 24 in 
which the subjects will receive the standard, validated dose of 10 mg/kg and will undergo 
graded outcome assessments along with receiving study drug.  Upon completion of the 
first segment, subjects will be randomized to continue receiving study drug masked at 
either the standard dose of 10 mg/kg or at a reduced dose of 5 mg/kg.  Subjects may 
continue receiving infusions for an additional 1.5 years.After week 52, the subject will be 
followed as clinically necessary by the physician and will be seen for study grading visits 
at week 76 and week 104.  Concomitant medication exclusion criteria will still need to be 
followed during this period. 
Due to the inherent heterogeneity among this patient group, it is impractical to utilize a 
single primary end-point to assess effectiveness of the treatment.  Different patients are 
expected to show improvements in different aspects of the clinical assessments, which we 
would expect to be captured by use of the composite endpoint utilized in this trial.  It is 
because of this heterogeneity that we will enroll 20 subjects who would be expected to 
have a broad variety of autoimmune uveitides including the following: sarcoidosis, 
idiopathic 
intermediate, 
idiopathic 
posterior, 
idiopathic 
panuveitis, 
birdshot 
chorioretinopathy, pars planitis tubulointerstitial nephritis and uveitis (TINU), Vogt-
Koyanagi-Harada syndrome (VKH), juvenile idiopathic arthritis (JIA), multifocal 
choroiditis, retinal vasculitis, and sympathetic ophthalmia. 
A detailed description of procedures and timelines can be found in Section 6. 
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 
1. 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 


 
Abatacept 
 
19 
document to read. Then, if subjects consent to participate in the study, they will 
indicate that consent by signing and dating the informed consent document in the 
presence of study personnel. 
2) Target Population 
1. Patients with vision-threatening autoimmune uveitis. 
2. Refractory uveitis, defined as failure to effectively and durably respond to 
prednisone and at least one other systemic immunosuppressive (such as 
methotrexate, 
azathioprine, 
mycophenolate 
mofetil, 
cyclosporine, 
or 
chlorambucil), or intolerance to such medications due to side effects.   
3. Patients with bilateral disease with visual acuity of 20/40 or worse.  Vision may 
be better based on unacceptable doses of systemic immunosuppressive agents.  
Investigator discretion may apply here. 
4. Stable dose of corticosteroids and immunosuppression for at least four weeks.  In 
the case where corticosteroid doses are urgently raised in this time period to treat 
an inflammatory exacerbation, the “flare dose” of corticosteroid will be used as 
the baseline level of corticosteroids for the purposes of outcome determination.   
5. Screening laboratory test results should be acceptable to the Investigator prior to 
placing a subject on study drug. 
6. Must be willing and able to adhere to the study visit schedule and other protocol 
requirements. 
3) Age and Gender 
1. Men and women,  6 years of age.  There is no upper age limit as long as there 
are no other disqualifying health conditions. 
2. Women of childbearing potential (WOCBP) must be using an adequate method of 
contraception to avoid pregnancy throughout the study and for up to 10 weeks 
after the last dose of study drug to minimize the risk of pregnancy. 
WOCBP include any woman who has experienced menarche and who has not 
undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, 
or bilateral oophorectomy) or who is not post-menopausal. Post-menopause is 
defined as: 
 
Amenorrhea that has lasted for  12 consecutive months without another 
cause, or 
 
For women with irregular menstrual periods who are taking hormone 
replacement therapy (HRT), a documented serum follicle-stimulating 
hormone (FSH) level of greater than 35 mIU/mL. 
Women who are using oral contraceptives, other hormonal contraceptives 
(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 where their partner is sterile (eg, vasectomy) should be considered 
to be of childbearing potential. 


 
Abatacept 
 
20 
A male subject of fathering potential must use an adequate method of 
contraception to avoid conception throughout the study and for up to 10 weeks 
after the last dose of study drug to minimize the risk of pregnancy. 
4.2.2 
Exclusion Criteria 
4) Gender and Reproductive Status 
1. WOCBP who are unwilling or unable to use an acceptable method to avoid 
pregnancy for the entire study period and for up to 10 weeks after the last dose of 
study drug.  
2. Women who are pregnant or breastfeeding. 
3. Sexually active fertile men not using effective birth control if their partners are 
WOCBP. 
5) Target Disease Exceptions 
1. Uveitis of infectious etiology. 
6) Medical History and Concurrent Diseases 
1. Subjects who are impaired, incapacitated, or incapable of completing study-
related assessments. 
2. Subjects with current symptoms of severe, progressive, or uncontrolled renal, 
hepatic, hematologic, gastrointestinal, pulmonary, cardiac, neurologic, or cerebral 
disease, whether or not related to RA and which, in the opinion of the 
investigator, might place a subject at unacceptable risk for participation in the 
study. 
3. 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. 
4. 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. 
5. Subjects who currently abuse drugs or alcohol. 
6. History of opportunistic infections, including, but not limited to evidence of 
active cytomeglovirus, active Pneumocystis carinii, aspergillosis, or atypical 
mycobacterium infection within the previous 6 months. 
7. 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) detected during 
screening. 
8. Subjects with herpes zoster that resolved less than 2 months before the informed 
consent document was signed. 
9. Subjects who have received any live vaccines within 3 months of the anticipated 
first dose of study medication. 


 
Abatacept 
 
21 
10. 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). 
11. Subjects with evidence of current or prior tuberculosis. 
12. Serious concomitant illness that could interfere with the subject’s participation in 
the trial. 
13. Subjects with Multiple Sclerosis or Behcet’s Disease. 
7) Physical and Laboratory Test Findings 
1. Subjects must not be positive for hepatitis B surface antigen. 
2. 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. 
3. Subjects with any of the following laboratory values 
i) Hemoglobin < 9.0 g/dL 
ii) WBC < 2000/mm3 (< 2 x 109/L) 
iii) Platelets < 150,000/mm3 (< 150 x 109/L) 
iv) Serum creatinine > 1.5 times the ULN 
v) Serum ALT or AST > 2 times the ULN 
4. Any other laboratory test results that, in the opinion of the investigator, might 
place a subject at unacceptable risk for participation in the study. 
8) Prohibited Treatments and/or Therapies 
1. Subjects who have received treatment with any investigational drug within 
28 days (or less than 5 terminal half-lives of elimination) of the Day 1 dose. 
2. Concomitant use of cyclophosphamide (unless use is restricted to eye drops). 
3. Are concomitantly taking other biologic medicines to treat RA or JIA such as: 
Enbrel® (etanercept), Humira® (adalimumab), Remicade® (infliximab), 
Kineret® (anakinra) or Rituxan® (rituximab). You may have a higher chance of 
getting a serious infection if you take ORENCIA with other biologic medicines.  
Washout period required for adalimumab and etanercept is eight weeks, and for 
infliximab is 12 weeks. Washout period for Rituxan is until return of detectable 
circulating B-cells.  Washout period for calcineurin inhibitors, including 
cyclosporine, tacrolimus, and voclosporine, as well as for alkylating agents, will 
be four weeks.   
9) Other Exclusion Criteria 
1. 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. 


 
Abatacept 
 
22 
4.2.3 
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 
 Pregnancy 
 Instruct WOCBP to contact the investigator or study staff immediately if they 
suspect that they or their partner 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 or their 
partner 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. In this protocol, noninvestigational products 
include prednisone and other systemic immunosuppressives such as methotrexate, 
azathioprine, mycophenolate mofetil, cyclosporine, and chlorambucil. 


 
Abatacept 
 
23 
5.1.1 
Identification 
Abatacept (ORENCIA®) is supplied as a 250 mg/vial sterile, white, preservative-free, 
lyophilized powder for parenteral administration. Following reconstitution with 10 mL of 
Sterile Water for Injection, USP, the solution is clear, colorless to pale yellow, with a pH 
range of 7.0 to 8.0. 
Product: Abatacept for Injection (Abatacept = BMS-188667 + CTLA4Ig) 
Potency: 250 mg/vial 
Appearance: White to off-white, whole or fragmented cake in a vial 
In addition, Norm-Ject® non-siliconized syringes and in-line filters will be supplied. 
Each investigator will be responsible for supplying any intravenous admixture solutions 
(Sterile Water for Injection, 5% Dextrose in Water Injection, 0.9% Sodium chloride 
Injection) needed for the reconstitution and dilution of investigational product identified 
in the protocol. 
5.1.2 
Storage, Handling, and Dispensing 
The investigational product should be stored in a secure area according to local 
regulations. 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. 
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.  


 
Abatacept 
 
24 
5.1.3 
Additional Information for the Handling, Dispensing, and Storage 
of Abatacept 
A pharmacist or qualified personnel at the site will reconstitute the drug for intravenous 
(IV) administration. All reconstitution and dilutions must be performed using 
polypropylene nonsiliconized syringes (Norm-Ject®) manufactured by Henke Sass Wolf 
in Germany (to be provided by BMS). 
NOTE: A separate needle and syringe must be used for each vial reconstituted. 
Abatacept vials are sealed under vacuum. If any vials are found without this vacuum, 
they should be segregated and not used. These vials must be retained until reconciliation 
by your Study Drug Monitor. 
NOTE: The vial should NOT be vented prior to reconstitution. To avoid foam formation 
following the addition of SWFI (Sterile Water for Injection), the vial should be gently 
swirled until the contents are completely dissolved. Upon complete dissolution of the 
lyophilized powder, the vial should then be vented with a needle to dissipate any foam 
that may be present. 
Each vial of abatacept for injection, 250 mg/vial, should be reconstituted with 10 mL of 
Sterile Water for Injection (without bacteriostatic agent) to yield a concentration of 
25 mg/mL. In order to minimize foaming, the stream of SWFI should be directed to the 
sides of the vial. 
A sufficient excess of abatacept is incorporated into each vial to account for withdrawal 
losses so that 10 mL of the reconstituted solution containing 250 mg can be withdrawn 
for parenteral administration. After reconstitution of the product the solution must be 
diluted further with 5% Dextrose in Water Injection (D5W) or 0.9% Sodium Chloride 
(Normal Saline). For all doses the final total volume for infusion is 100 mL. 
The continuous infusion solution must be filtered upon administration using an in line, 
sterile, non-pyrogenic, low protein-binding filter with a pore size of 1.2 μm. This infusion 
should be administered in a fixed volume of 100 mL over a period of not less than 
30 minutes. Any unused portion of the infusion solution should not be stored for reuse. 
No data is available on the compatibility of abatacept with other intravenous substances. 
Abatacept should be administered in a separate intravenous line whenever possible and 
not mixed with other medications. Assure adequate and appropriate flushing between any 
other drug substances if other drugs are administered through the same line sequentially. 
No incompatibilities have been observed with glass bottles or polyvinyl chloride bags and 


 
Abatacept 
 
25 
administration sets. Care must be taken to assure sterility of the prepared solution, as the 
drug product does NOT contain any antimicrobial preservatives or bacteriostatic agents. 
Vials of abatacept for injection, 250 mg/vial, should be stored under refrigeration (28°C) 
and should be protected from long-term exposure to light. Intact vials are stable for at 
least one year under these conditions. 
All dilutions of abatacept for injection must be used within the 24 hours after 
reconstitution of the original vial. 
 Specific stability guidelines for each dilution are as follows: 
 Reconstituted abatacept for injection, 25 mg/mL, may be stored at temperatures from 
15°- 25°C and room light or at refrigeration (2°-8°C) for up to 24 hours in the original 
vial. 
 Dilutions of reconstituted abatacept for injection from 1 to 25 mg/mL in NS or D5W 
in polyvinyl chloride (PVC) or non-PVC IV bags may be stored at temperatures from 
15°-25°C and room light or at refrigeration (2°-8°C) for no more than 24 hours from 
the time of initial reconstitution. 
 Diluted solutions of abatacept for injection are compatible with standard PVC IV 
infusion sets. 
5.2 
Drug Accountability 
Please refer to Section 9.2 (Records Retention) for details on drug accountability 
requirements. 
5.3 
Selection and Timing of Dose for Each Subject 
During the first 24 weeks, all subjects will receive approximately 10 mg/kg calculated 
based on the patient’s body weight at each administration, rounded to the nearest 25 mg.  
 
Abatacept will be administered as a 30-minute intravenous infusion. Following the initial 
administration, abatacept will be given at 2 and 4 weeks after the first infusion and every 
4 weeks thereafter for up to 2 years. Any unused portions in the vials must be 
immediately discarded. 
 
After the 24 week infusion, subjects who have responded to treatment will be randomized 
to receive either the standard 10 mg/kg dose or a reduced dose of 5 mg/kg, rounded to the 
nearest 25 mg. 
 
5.3.1 
Dose Modifications in the Absence of Adverse Events 
In the absence of adverse events deemed at least possibly related to abatacept, subjects 
will complete their scheduled infusions as prescribed per protocol. For visits scheduled 


 
Abatacept 
 
26 
for Day 15 and Day 29, the dose may be administered within 72 hours (± 3 days) before 
or after the target date to adjust for the subject’s or site personnel’s convenience. For all 
subsequent doses, a window of ± 7 days is acceptable. 
5.3.2 
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 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 
Concomitant Treatments 
5.4.1 
Prohibited and/or Restricted Treatments 
The following medications are prohibited throughout the complete study period: 
 Any biologic DMARD (such as but not limited to: anakinra, infliximab, etanercept, 
adalimumab, rituximab or any other investigational biologic). 
 Cyclophosphamide, Cyclosporine 
 Live vaccines. 
 Use of any investigational drug other than study medication. 
5.4.2 
Other Restrictions and Precautions 
5.4.2.1 
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 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 


 
Abatacept 
 
27 
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. 
5.5 
Management of Possible Acute Hypersensitivity 
Reactions to Abatacept 
Hypersensitivity or acute allergic reactions may occur as a result of the protein nature of 
abatacept. In this study, subjects’ vital signs will be monitored before and following 
administration of abatacept. Appropriate emergency equipment and qualified personnel 
must be available where the subjects are treated in the event of a serious anaphylactic 
reaction. 
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 abatacept. Care should be taken to treat any acute toxicities 
expeditiously, should they occur. The following equipment and supplies should be 
readily available when abatacept is administered: a portable tank or wall source of 
oxygen, endotracheal intubation set, oral airway, mask, manual resuscitation bag, 
syringes, injectable epinephrine, injectable antihistamine, and injectable glucocorticoids. 
Signs and management of potential acute hypersensitivity reactions: 
Sign 
Management 
Symptomatic 
Hypotension 
Discontinue the abatacept infusion. Place the subject in 
the Trendelenburg position and administering IV fluid. 
Administer epinephrine, glucocorticoids, antihistamines, 
and pressor agents as indicated. 
Dyspnea 
Discontinue the abatacept infusion. 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. 
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 


 
Abatacept 
 
28 
appropriately. Study medication should be withheld, and restarted only when the 
infection is clinically resolved. 
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. 
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. 
 


 
 
 
Abatacept 
 
29 
a. Lab tests include: HIV, Hep B surface antigen, Hep C antibody, Hemoglobin, WBC, Platelets, Serum Creatinine, ALT/AST, HCG 
b. Lab tests include:  Hemoglobin, WBC, Platelets, Serum Creatinine, ALT/AST 
c. Weeks 8, 16 and Weeks 24, 32, 40. 
Table 1: 
Time and Events Schedule for Protocol  
Procedure 
Screening 
 
Day 1 
 
Day 15 
 
Weeks 4, 8  Week 12 
Week 16, 20 
 
Week  24 
Weeks 28, 32, 
36, 40, 44, 48 
Week 52 
Week 76,  104 
Eligibility Assessments 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
TB Test 
X 
 
 
 
 
 
 
 
 
 
Safety Assessments 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse Events Assessment 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Laboratory Tests 
Xa 
 
 
 
 
 
 
 
Xb 
 
Pregnancy Test 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy Assessments 
 
 
 
 
 
 
 
 
 
 
OCT 
X 
 
 
 
X 
 
X 
 
X 
X 
FA/FP 
X 
 
 
 
X 
 
X 
 
X 
X 
Inflammation Grading 
X 
 
 
Xc 
X 
Xc 
X 
Xc 
X 
X 
Eye Exam/Visual Acuity 
X 
 
 
Xc 
X 
Xc 
X 
Xc 
X 
X 
Visual Analogue Scale 
X 
 
 
 
X 
 
X 
 
X 
X 
Clinical Drug Supplies 
 
 
 
 
 
 
 
 
 
 
Infusion (every 4 weeks) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
 
 
 
 
 
 
X 
 
 
 


 
 
Abatacept 
 
30 
6.2 
Study Materials 
Bristol-Myers Squibb (BMS) will provide abatacept at no cost for this study. 
6.3 
Safety Assessments 
All subjects who receive a dose of abatacept will be evaluated for safety at every visit. 
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. 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. 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 
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 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 vaccinations,20,21 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. 


 
 
Abatacept 
 
31 
6.4 
Efficacy Assessments 
The efficacy assessments during the treatment phase of the study will be done at the 
intervals specified in the Schedule of Assessments.  The following clinical assessments 
will provide outcome data:  visual acuity, graded assessment of ocular inflammation, 
optical coherence tomography (OCT), fluorescein angiography (FA), and fundus 
photography. 
6.4.1 
Visual Acuity 
Snellen best corrected visual acuity will be measured at screening/baseline, week 8, 16, 
24, 32, 40, 52, 76 and 104.  If the subject cannot read or is unfamiliar with the Roman 
alphabet, then the tumbling E chart will be used.   
6.4.2 
Graded Assessment of Ocular Inflammation 
The grading of ocular inflammation will be performed at screening/baseline, week 8, 16, 
24, 32, 40, 52, 76 and 104.  The scales for vitreous haze and anterior chamber cells will 
be based off of the Nussenblatt scoring system and the SUN nomenclature (Appendices 
A, B). 
6.4.3 
 Measurement of Macular Thickness Using OCT 
OCT assessments will be used to document changes in macular thickness.   OCT exams 
will be performed at the baseline visit and weeks 12, 24,52, 76 and 104.  This assessment 
can be performed whenever clinically indicated. 
6.4.4 
Fluorescein Angiography 
Fluorescein angiography will be performed at the baseline visit and weeks 12, 24, 52, 76 
and 104.  This assessment can be performed whenever clinically indicated.  Fluorescein 
angiography will be used to document inflammatory signs by accepted criteria. 
6.4.5 
Fundus Photography 
Fundus photography will be performed at the baseline visit and weeks 12, 24, 52, 76 and 
104.  This assessment can be performed whenever clinically indicated.  Fundus 
photography will be used to document chorioretinal infiltrates and/or retinal vasculitis 


 
 
Abatacept 
 
32 
6.5 
Other Assessments 
6.5.1 
Ocular Examinations 
Ocular exams will be performed using slit lamp and dilated fundus exams according to 
the Table. 
6.5.2 
Subject and Physician Global Assessments of Disease 
The Subject and Physician Global Assessments of Disease Activity will be performed 
during baseline, week 12, 24, 52, 76 and 104  The assessments will be recorded on the 
subject’s chart as a single vertical mark on a 100-mm VAS.  The distance from the mark 
to the left-hand boundary of the scale will be recorded on the CRF. 
6.5.3 
Visual Analog Scale for Pain 
The VAS for Pain will be completed during baseline, week 12, 24, 52, 76 and 104.  The 
subject will be asked to place a vertical line on a 100-mm scale on which the left-hand 
boundary represents “no pain,” and the right-hand boundary represents “pain as severe as 
can be imagined.”  The distance from the mark to the left-hand boundary will be recorded 
on the CRF. 
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) 


 
 
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33 
 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 that may not be 
immediately life-threatening or result in death or hospitalization but, based on 
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 above. Examples of such events include but are not limited to 
intensive treatment in an emergency department or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization. 
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 overdose and cancer are not always serious by regulatory definition, these 
events 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) 
 elective surgery planned before signing consent 
 admissions as per protocol for a planned medical/surgical procedure 
 routine health assessment requiring admission 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. 


 
 
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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. 
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. 


 
 
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35 
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/. 
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/ 


 
 
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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 


 
 
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37 
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 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 until completion of the study. 
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. 


 
 
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38 
7.5 
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 
 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.  
7.5.1 
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. 
7.5.2 
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 


 
 
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39 
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.  
7.6 
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. 
8 
STATISTICAL CONSIDERATIONS 
8.1 
Overview 
This is a pilot study.  The primary safety endpoint will be measured by tracking the type, 
frequency, severity, and relationship of adverse events to study treatment.  The secondary 
efficacy analysis is to test whether at least 50% of patients show clinical improvement in 
our composite clinical endpoint, comprised of 1) improvement of visual acuity, 2) 
reduction of systemic corticosteroid and other immunosuppressive therapy, 3) improved 
control of inflammation, and/or 4) reduction of cystoid macular edema.  Patients will 
serve as their own controls, and descriptive statistics will be utilized to determine effect 
of treatment within-patients and in the study cohort as a whole.  
8.2 
Datasets to be Analyzed 
Visual acuity will be used to determine improvement by 2 or more lines of visual acuity.  
Concomitant medications will be used to monitor systemic corticosteroid and other 
immunosuppressive therapy.  Grading of ocular inflammation using the anterior chamber 
cellular activity and protein flare, vitreous cellular activity and haze as well as the fundus 
photography will be used to analyze improved control of ocular inflammation.  OCT and 


 
 
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40 
FA will be used to analyze the reduction of cystoid macular edema and signs of retinal 
inflammation.  Corticosteroid reduction from baseline will also be ascertained.  
8.3 
Endpoint Definitions 
8.3.1 
Safety Endpoints 
This will be measured by tracking the type, frequency, severity, and relationship of 
adverse events to study treatment. 
8.3.2 
Efficacy Endpoints 
The composite clinical endpoint for success will be comprised of 4 criteria.  The primary 
efficacy endpoint will be at one year.  Treatment will be judged to be successful if there 
is improvement in at least one of these criteria without significant worsening in any of 
them.  These criteria include: 
 Improvement by 2 or more lines of best-corrected ETDRS or Snellen visual acuity 
in at least one eye 
 Reduction in dose of systemic corticosteroid or other immunosuppressive therapy 
by at least 50% 
 Control of ocular inflammation, as judged on clinical criteria, according to 
standard methods 
o Reduction of anterior chamber cellular activity and vitreous haze by at 
least two grades and to a level of trace or less (SUN) 
o Reduction of chorioretinal infiltrates or reduction of retinal vasculitis 
(documented by fundus photography and fluorescein angiography) 
 Reduction of cystoid macular edema, as judged clinically and by fluorescein 
angiogram and/or optical coherence tomography. 
 
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. 
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 


 
 
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41 
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. 


 
 
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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 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  
AE 
Adverse event 
ALT 
Alanine Transaminase  
APC 
Antigen-Presenting Cell  
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  
FDA 
Food and Drug Administration 
FSH 
Follicle-Stimulating Hormone  
GCP 
Good Clinical Practice  
HCG 
Human Chorionic Gonadotropin  
HIV 
Human Immunodeficiency Virus  
HRT 
Hormone Replacement Therapy 
IB 
Investigator Brochure 
ICH 
International Conference on Harmonisation  
IEC 
Independent Ethics Committee  


 
 
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IL 
Interleukin  
IND 
Investigational New Drug (Application) 
IRB 
Independent Review Board  
IST 
Investigator-Sponsored Trial 
IU 
International Unit  
IV 
Intravenous  
JRA 
Juvenile Rheumatoid Arthritis  
MRI 
Magnetic Resonance Imaging  
NS 
Normal Saline  
NSAE 
Non-Serious Adverse Event 
NSAID 
Non-Steroidal Anti-inflammatory Drug  
OA 
Osteoarthritis  
PCR 
Polymerase Chain Reaction  
PPD 
Purified Protein Derivative  
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  
WBC 
White Blood Cell  
WOCBP 
Women of Childbearing Potential  


 
 
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12 
APPENDICES 
Appendix A:  
Nussenblatt Scoring System 
Nussenblatt RB, et al., Ophthalmology 92:467-471, 1985.  
 
Grade of Vitreous Haze 
0 
0.5+ 
1+ 
2+ 
3+ 
4+ 
Clear 
Trace 
Few opacities, 
mild blurring of 
optic nerve and 
retinal vessels 
Significant 
blurring of 
optic nerve and 
retinal vessels 
but still visible 
Optic nerve 
visible, borders 
blurred, no 
retinal vessels 
seen 
Dense opacity 
obscuring optic 
nerve head 
 
Standardized photographs illustrating the above may be found in the 
referenced 
article.


 
 
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Appendix B: 
Standardization of Uveitis Nomenclature (SUN) 
Standardization of Uveitis Nomenclature for Reporting Clinical Data. Results of the First 
International Workshop.  American Journal of Ophthalmology, Volume 140, Issue 
3, Pages 509-516  
TABLE 1. The SUN Working Group Anatomic Classification of Uveitis  
Type 
Primary Site of Inflammation 
Includes 
Anterior uveitis 
Anterior chamber 
Iritis 
Iridocyclitis 
Anterior cyclitis 
Intermediate 
uveitis 
Vitreous 
Pars planitis 
Posterior cyclitis 
Hyalitis 
Posterior 
uveitis 
Retina or choroid 
Focal, multifocal, or diffuse 
h
idi i
Chorioretinitis 
Retinochoroiditis 
Retinitis 
Neuroretinitis 
Panuveitis 
Anterior chamber, vitreous, and retina or 
h
id
  
TABLE 2. The SUN Working Group Descriptors of Uveitis  
TABLE 3. The SUN Working Group Grading Scheme for Anterior Chamber Cells  
Grade 
Cells in Field† 
0 
<1 
0.5+ 
1–5 
1+ 
6–15 
2+ 
16–25 
3+ 
26–50 
4+ 
>50 
† Field size is a 1 mm by 1 mm slit beam.  
 
Category 
Descriptor 
Comment 
Onset 
Sudden 
  
Insidious 
Duration 
Limited 
≤3 months duration 
Persistent 
>3 months duration 
Course 
Acute 
Episode characterized by sudden onset and limited duration 
Recurrent  
Repeated episodes separated by periods of inactivity without treatment ≥3 months in duration 
Chronic 
Persistent uveitis with relapse in <3 months after discontinuing treatment 


 
 
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TABLE 4. The SUN Working Group Grading Scheme for Anterior Chamber Flare  
Grade 
Description 
0 
None 
1+ 
Faint 
2+ 
Moderate (iris and lens details clear) 
3+ 
Marked (iris and lens details hazy) 
4+ 
Intense (fibrin or plastic aqueous) 
TABLE 5. The SUN Working Group Activity of Uveitis Terminology  
Term 
Definition 
Inactive 
Grade 0 cells 
Worsening 
activity 
Two step increase in level of inflammation (e.g. anterior chamber cells, vitreous haze) or 
increase from grade 3+ to 4+ 
Improved 
activity 
Two step decrease in level of inflammation (e.g. anterior chamber cells, vitreous haze) or 
decrease to grade 0 
Remission 
Inactive disease for ≥3 months after discontinuing all treatments for eye disease 
 
 


 
 
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13 
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4. Linsley PS, Greene JL, Brady W, et al. Human B7-1 (CD80) and B7-2 (CD86) bind with 
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14. ORENCIA® (abatacept) Prescribing Information. Bristol-Myers Squibb Company; 
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