Clinical trial NCT02018042
Conditions: Alopecia Areata
Keywords: Alopecia Areata AA
Sponsor: Columbia University
Start date: 2013-09-01; Completion date: 2017-07-31
Enrollment: 15 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Alopecia areata (AA) is a common disease of the immune system, known as an "autoimmune" disease. In this disease, the immune system mistakenly destroys the hair follicle, causing hair to fall out. Despite many people having this disease, research into its cause and into new, better ways to treat Alopecia Areata has lagged far behind other similar diseases of the immune system. Currently, there are no Federal Drug Administration approved drugs for Alopecia Areata.

Abatacept (made by Bristol-Myers Squibb) is a safe intervention known to effectively treat rheumatoid arthritis, another "autoimmune" disease, by fighting inflammation. There are some genetic and chemical similarities between those with active rheumatoid arthritis and Alopecia Areata, suggesting that treatment with the same drug is likely to be effective. In mice specially designed for testing drugs for the treatment of human alopecia, this medication worked to prevent the disease Alopecia Areata from starting.

To test Abatacept, we are going to treat 15 patients with moderate to severe Alopecia Areata for 6 months. Each person enrolling into this study will receive the active study drug. The effectiveness of the medication will be measured by changes in hair re-growth as determined by physical exam and photography, as well as by patient and physician scoring. Patients will be followed for another 6 months off of the drug to see if the effects of treatment last and if there is delayed response. We have recently changed the study to allow testing of abatacept in a few patients with alopecia totalis and universalis.

Small scalp biopsies and peripheral blood will be taken at the beginning of the study before treatment and then after 4,12 and 24 weeks. The chemical analysis of these skin samples and blood will help us to understand how the disease happens, how the treatment works, and perhaps even guide us to better treatments in the future.

Detailed description:
Among patients with alopecia areata, patients with higher disease burdens are unlikely to have satisfactory outcomes with current therapies. Our hypothesis is that CTLA4-Ig will be effective therapy in moderate-severe alopecia areata by blocking re-activation of CD8+ memory T cells, thereby aborting the cytotoxic T cell inflammatory response underlying alopecia areata.

Alopecia areata (AA) is a common autoimmune disease resulting from immune destruction of the hair follicle and subsequent hair loss. Despite its high prevalence, research into the pathogenesis and the development of innovative therapies in Alopecia Areata has lagged far behind other autoimmune diseases. Currently, there are no FDA approved drugs for Alopecia Areata. Abatacept is a safe intervention known to block costimulation and inflammatory responses in rheumatoid arthritis, which shares several susceptibility genes in common with Alopecia Areata. Both diseases share the involvement of CTLA4, which is the rationale for selecting Abatacept for evaluation in this clinical trial. CTLA4-Ig has been shown to prevent the onset of Alopecia Areata in the C3H-HeJ animal model of Alopecia Areata, demonstrating preclinical proof of concept data in Alopecia Areata.

We will conduct an open label pilot study of 15 patients with moderate to severe Alopecia Areata treated with SC abatacept 125mg once per week for 6 months. A few subjects with alopecia totalis or universalis will also be included. Subjects will be followed for another 6 months to evaluate durability of response following the treatment phase. The primary efficacy outcome will be the proportion of responders after 6 months of treatment compared to the historically known rate of response in untreated/placebo-treated subjects of 8 to 10%. Punch biopsies and peripheral blood will be obtained at baseline prior to treatment and then after 4, 12 and 24 weeks for immunomonitoring and molecular studies.

The safety of and incidence of adverse events related to abatacept in this population of patients will also be analyzed as a secondary endpoint.

Arms: arm 1: Patients will be treated with abatacept 125mg subcutaneous (SC) self-administered each week. Treatment will be continued for 6 months to provide adequate time to assess the short-term efficacy and safety of abatacept in patients with alopecia areata. Patients will then be followed for an additional 6 months to assess the timing and incidence of relapse.
Interventions: intervention 1: Abatacept
Intervention descriptions: intervention 1: After the screening period, subjects will begin weekly self-administered subcutaneous abatacept and will continue treatment for 6 months. Patients will be instructed in self-administration of study medication at baseline (week zero) and will be observed self-administering medication at each visit. Instructions regarding study drug administration will be reinforced as needed.

The 6-month treatment period is expected to provide adequate time to assess the short-term efficacy and safety of abatacept in patients with moderate to severe AAP. Responders will then be followed for 6 months off drug.

Protocol documents:
Prot_SAP_000.pdf: 
Abatacept in alopecia areata 
April 10, 2015 
1 
AN OPEN-LABEL SINGLE-ARM CLINICAL TRIAL TO EVALUATE THE 
EFFICACY OF ABATACEPT IN MODERATE TO SEVERE PATCH TYPE 
ALOPECIA AREATA AND ALOPECIA TOTALIS AND UNIVERSALIS 
 
Investigators: 
 
Julian Mackay-Wiggan, M.D., M.S. 
Assistant Professor and Director, Clinical Trials Unit 
Department of Dermatology 
Columbia University 
jc299@columbia.edu 
 
Joan Bathon, M.D. 
Professor in Medicine and Chief Division of Rheumatology 
Columbia University 
jmb2311@columbia.edu 
 
Bibhas Chakraborty 
Associate Professor in Biostatistics 
Columbia University 
bc2425@columbia.edu 
Angela Christiano, Ph.D. 
Professor in Dermatology and Genetics 
Vice-Chair for Research in Dermatology 
Columbia University 
amc65@columbia.edu 
 
Raphael Clynes, M.D., Ph.D. 
Associate Professor in Pathology, Medicine and Dermatology 
Director of the Immunogenetics and Cellular Immunology Laboratory 
Columbia University 
rc645@columbia.edu 
 
Columbia University  
Department of Dermatology - Clinical Research Unit 
161 Fort Washington Avenue, 12th Fl, Rm 1264 
NY, NY 10032 
Tel #: 212-305-6953 
Fax #: 212-305-0286 
 
[Protocol Version/Date: April 10, 2015] 
 
 


 
Abatacept in alopecia areata 
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Table of Contents 
 
PROTOCOL SYNOPSIS ....................................................................................................5 
 
1 
INTRODUCTION ..........................................................................................13 
 
1.1 
Research Hypothesis .......................................................................................13 
1.2 
Product Development Rationale .....................................................................13 
1.2.1 
Overview of Alopecia Areata .........................................................................14 
1.2.2 
Pathology and role of T cells in human Alopecia Areata ...............................16 
1.2.3 
Preclinical Studies: CTLA4-Ig prevents onset of Alopecia Areata in 
the C3H-HeJ mouse model .............................................................................17 
1.2.4 
Genetics of Alopecia Areata ...........................................................................17 
1.2.5 
Haplotype Analysis for CTLA4 Modulation with Abatacept Therapy ..........19 
1.3 
Summary of Results of Investigational Program ............................................21 
1.3.1 
Core Efficacy Studies of Abatacept in Rheumatoid Arthritis ........................21 
1.3.2 
Pharmacokinetics of Subcutaneous Formulation ............................................23 
1.3.3 
Overall Safety of Abatacept ............................................................................25 
1.3.4 
Safety of SC Formulation of Abatacept..........................................................26 
1.4 
Overall Risk/Benefit Assessment ...................................................................28 
1.5 
Study Rationale ...............................................................................................29 
 
2 
STUDY OBJECTIVES ..................................................................................30 
 
2.1 
Primary Objective ...........................................................................................30 
2.2 
Secondary Objectives .....................................................................................30 
3 
ETHICAL CONSIDERATIONS....................................................................31 
3.1 
Good Clinical Practice ....................................................................................31 
3.2 
Institutional Review Board/Independent Ethics Committee ..........................32 
3.3 
Informed Consent ...........................................................................................32 
4 
INVESTIGATIONAL PLAN .........................................................................32 
4.1 
Study Design and Duration .............................................................................32 
4.2 
Study Population .............................................................................................35 
4.2.1 
Inclusion Criteria ............................................................................................35 
4.2.2 
Exclusion Criteria ...........................................................................................36 
4.2.3 
Women of Childbearing Potential ..................................................................39 
4.3 
Concomitant Treatments .................................................................................40 
4.3.1 
Prohibited and/or Restricted Treatments ........................................................40 
4.3.2 
Other Restrictions and Precautions .................................................................40 
4.4 
Discontinuation of Subjects from Treatment ..................................................40 
5 
TREATMENTS ..............................................................................................41 
5.1 
Study Treatment: Abatacept ...........................................................................41 
5.1.1 
Identification ...................................................................................................41 
5.1.2 
Storage, Handling, and Dispensing ................................................................41 


 
Abatacept in alopecia areata 
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5.1.3 
Additional Information for the Handling, Dispensing, and Storage of 
Abatacept ........................................................................................................42 
5.2 
Method of Assigning Subjects to a Treatment ...............................................42 
5.3 
Selection and Timing of Dose for Each Subject .............................................42 
5.3.1 
Dose Modifications for Adverse Events .........................................................42 
5.4 
Blinding/Unblinding .......................................................................................42 
5.5 
Concomitant Treatments .................................................................................43 
5.5.1 
Prohibited and/or Restricted Treatments ........................................................43 
5.5.2 
Other Restrictions and Precautions .................................................................43 
5.6 
Treatment Compliance ....................................................................................43 
6 
STUDY ASSESSMENTS AND PROCEDURES ..........................................44 
6.1 
Time and Events Schedule ..............................................................................44 
6.1.1 
Study Completion or Early Discontinuation Visit ..........................................48 
6.1.2 
Study Drug Discontinuation ...........................................................................48 
6.2 
Study Materials ...............................................................................................50 
6.3 
Safety Assessments .........................................................................................50 
6.3.1 
Physical Examinations ....................................................................................50 
6.3.2 
Tuberculin Skin Testing .................................................................................50 
6.4 
Efficacy Assessments .....................................................................................51 
6.4.1 
Primary Efficacy Assessment .........................................................................51 
6.4.2 
Secondary Efficacy Assessments ...................................................................52 
6.4.3 
Other Assessments ..........................................................................................53 
6.5 
Adverse Events ...............................................................................................57 
6.5.1 
Serious Adverse Events ..................................................................................57 
6.5.2 
Nonserious Adverse Events ............................................................................58 
6.6 
Assignment of Adverse Event Intensity and Relationship to Abatacept ........58 
6.7 
Collection and Reporting ................................................................................59 
6.7.1 
Serious Adverse Events ..................................................................................59 
6.7.2 
Handling of Expedited Safety Reports ...........................................................60 
6.7.3 
Nonserious Adverse Events ............................................................................61 
6.8 
Laboratory Test Abnormalities .......................................................................61 
6.9 
Overdose .........................................................................................................61 
6.10 
Pregnancy .......................................................................................................62 
6.10.1 
Requirements for Pregnancy Testing ..............................................................62 
6.10.2 
Reporting of Pregnancy ..................................................................................62 
6.11 
Other Safety Considerations ...........................................................................63 
7 
STATISTICAL CONSIDERATIONS ...........................................................63 
7.1 
Sample Size Determination ............................................................................63 
7.2 
Populations for Analyses ................................................................................63 
7.3 
Endpoint Definitions .......................................................................................63 
7.4 
Analyses ..........................................................................................................64 
7.4.1 
Demographics and Baseline Characteristics ...................................................64 
7.4.2 
Safety Analyses ..............................................................................................64 
7.4.3 
Efficacy Analyses ...........................................................................................64 


 
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8 
ADMINISTRATIVE SECTION ....................................................................65 
8.1 
Compliance with the Protocol ........................................................................65 
8.2 
Records Retention ...........................................................................................65 
8.3 
Destruction of Investigational Product ...........................................................66 
9 
GLOSSARY OF TERMS ...............................................................................66 
10 
LIST OF ABBREVIATIONS.........................................................................67 
11 
REFERENCES ...............................................................................................70 


 
 
 
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PROTOCOL SYNOPSIS 
Protocol Title: 
An Open-Label Single-Arm Clinical Trial to Evaluate the 
Efficacy of Abatacept in Moderate to Severe Patchy Type 
Alopecia Areata and alopecia totalis and universalis 
Site Numbers & Names: 
Clinical Research Unit 
Department of Dermatology 
Columbia University Medical Center 
Research Hypothesis: 
Among patients with alopecia areata, patients with higher 
disease burdens are unlikely to have satisfactory outcomes 
with current therapies. Our hypothesis is that CTLA4-Ig will 
be effective therapy in moderate-severe alopecia areata by 
blocking re-activation of CD8+ memory T cells, thereby 
aborting the cytotoxic T cell inflammatory response 
underlying alopecia areata.   


 
 
 
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Study Rationale 
Alopecia areata (AA) is a common autoimmune disease 
resulting from autoimmune attack on the hair follicles. The 
histopathology clearly identifies the “swarm of bees”, 
comprised of T cells encircling the human hair follicle. 
Costimulatory blockade with Abatacept (CTLA4-Ig, a 
soluble receptor that blocks costimulatory molecules) has 
recently emerged as an effective therapy in human T cell 
mediated diseases. Abatacept is FDA-approved for the 
treatment of Rheumatoid Arthritis and Juvenile Idiopathic 
Arthritis and is under study for many other autoimmune 
conditions. 
     There is genetic evidence for the importance of the 
costimulatory pathway in human AA. Our recent GWAS 
studies identified several genetic susceptibility alleles that 
included CTLA4 as well as HLA, IL-2 and its receptor and 
NKG2D ligands (Petukhova et al, 2010).  Many of these AA 
susceptibility alleles are shared by other common 
autoimmune diseases including Celiac Disease, Type I 
Diabetes, and Rheumatoid Arthritis. These autoimmune 
states may share common pathogenic mechanisms and may 
respond to common treatments.  
      Our recent studies point to a dominant role for activated 
NKG2D-bearing CD8 T cells as the likely culprit 
autoaggressive cellular effector(Petukhova et al, 2010).  
CD8+NKG2D+ effector T cells dominate the peribulbar 
infiltrate in human AA and are intimately associated with 
dermal sheath cells aberrantly expressing NKG2D ligands. 
Our unpublished data in the mouse has confirmed the human 
pathological findings (Petukhova et al, 2010), identifying 
activated NKG2D bearing CD8 T cells both adjacent to the 
hair follicle and in the draining lymph nodes.  Thus, the 
immunopathogenesis of the C3H mouse model faithfully 
recapitulates human alopecia. Consistent with a primary role 
for autoimmune T cells in the C3H mouse model of alopecia 
areata, disease can be induced in normal unaffected mice by 
transfer of T cells from affected mice or humans (Sundberg 
et al, 1994; Gilhar et al, 2003; McElwee et al, 2005). It is 
important therefore that proof-of-concept has already been 
provided for CTLA4-Ig as a treatment in the C3H alopecic 
mouse model (Carroll et al, 2002).   
     Based on these pre-clinical proof-of-concept studies in the 
relevant animal model, the genetic evidence for the relevance 
of the CTLA4 pathway in human alopecia areata, and the 


 
 
 
Abatacept in alopecia areata 
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lack of existing evidence-based data for any treatment in 
alopecia areata, there is a strong rationale for testing CTLA4-
Ig treatment in this disease.   
Study Objectives: 
Primary: 
Secondary: 
The study’s primary efficacy endpoint will be the proportion 
of responders after 6 months of treatment, with response 
defined as 50% or greater hair re-growth from baseline as 
assessed by SALT score at week 24. This is a relatively strict 
definition for defining responders and non-responders and was 
chosen to minimize the potential for spontaneous remission, in 
which fewer than 10% are expected to achieve this magnitude 
of hair regrowth spontaneously. 
 
As secondary endpoints, efficacy will be measured by changes 
in hair re-growth as a continuous variable as determined by 
physical exam and Canfield photography, as well as patient 
and physician global evaluation scores. To assess the 
durability of responses, patients will continue to be followed 
for an additional 6 months off treatment or until it is 
determined that relapse has occurred. Additionally, patient 
reported outcomes, safety measures, incidence and timing of 
relapse will be important secondary outcomes. We will also 
explore the efficacy of treating 2 patients with current alopecia 
totalis or universalis, and in doing so, will compare, on an 
exploratory basis, the rate of occurrence of hair regrowth in 
patients with moderate to severe patch type alopecia areata 
compared to those with current alopecia totalis or universalis.  
 
In addition, response to abatacept treatment will be examined 
on an exploratory basis for correlation with the presence or 
absence of the AA GWAS risk haplotype. 
Study Design: 
Open label pilot study of 6 months of abatacept 125mg SC per 
week in the treatment of moderate to severe AA and current 
alopecia totalis or universalis, followed by 6 months follow-
up off drug to assess the incidence and timing of recurrence of 
disease. Treatment may be extended by up to 6 additional 
months beyond the initially planned 6 months of treatment if 
clinically indicated at the discretion of the investigator. 
Study Schema 
Drugs / Doses /  
Length of Treatment) 
A fixed dose of abatacept (125mg) will be self-administered 
subcutaneously weekly for 24 weeks, with an option to 
extend treatment for up to an additional 24 weeks at the 
discretion of the investigator. A loading IV dose will not be 
employed. 


 
 
 
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Accrual Goal: 
(Total number of 
subjects) 
15 
Accrual Rate: 
(Number of subjects 
expected per month) 
1-3 
FPFV: 
LPFV: 
Follow Up: 
(dd-mm-yy) 
 May, 1, 2013 
 March 31, 2015 
 12 months 
Correlative Studies: 
(PK/PD, etc.) 
Our published work and previous studies in human AA have 
reported increased NKG2DL expression and augmented 
expression of IFN response genes in the target hair follicle 
end organ, and elevated NKG2D expression in circulating 
CD8 T cells and NK cells (Ito et al, 2008; Petukhova et al, 
2010). 
Clinical Correlative Studies 
Our study will include longitudinal assessment of AA 
biomarkers at baseline and during treatment to correlate 
treatment and disease status with;  
1) histological improvement with reduced T cell peribulbar 
infiltrates. 
2) declines in circulating and peribulbar CD8+NKG2D+ 
infiltration and in follicular hair follicle NKG2DL 
expression.  
3) reduced IFN inflammatory biomarkers in the skin and 
blood. 
4) presence or absence of AA GWAS risk haplotype 


 
 
 
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Inclusion Criteria: 
Patients between 18 to 75 years of age. 
 
Patients with a diagnosis of moderate-to-severe patch type 
alopecia areata. 
 
Patients will have ≥30% and <95% total scalp hair loss at 
baseline as measured using the SALT score. 
 
Patients with alopecia totalis/universalis can be included as 
long as the current episode of hair loss meets the criteria of 
30 to 95% hair loss (i.e. they are not currently AT or AU), 
and as long as in the opinion of the investigator there appears 
to be potential for regrowth.  
Two to five patients with current episodes of alopecia totalis 
/or universalis (100% scalp hair loss) may be included in this 
study at the discretion of the investigator.  
 
Duration of hair loss greater than 3 months without an 
upper limit of duration as long as there is reason to 
believe that regrowth is possible in the opinion of the 
investigator. 
 
No evidence of active/ongoing regrowth present at baseline. 
Patients may be naïve to treatment or unresponsive to 
intralesional (IL) steroids or other treatments for alopecia 
areata. 


 
 
 
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Exclusion Criteria: 
Two to five patients with alopecia totalis/universalis at the 
time of enrollment at the discretion of the investigator. 
Patients with a history of or active skin disease on the scalp 
such as psoriasis or seborrheic dermatitis. 
Patients in whom the diagnosis of alopecia areata is in 
question. 
Patients with active medical conditions or malignancies 
(except adequately treated basal or squamous cell carcinoma) 
that in the opinion of the investigator would increase the 
risks associated with study participation, including patients 
with a history of recurrent infections. 
Women of childbearing potential who are unable or 
unwilling to use two forms of birth control for the study 
duration. 
Women who are pregnant or nursing. 
Patients with COPD 
Patients known to be HIV or hepatitis B or C positive. 
Patients with history or evidence of hematopoietic 
abnormality. 
Patients with history of immunosuppression or history of 
recurrent serious infections. 
Patients unwilling or unable to discontinue treatments known 
to affect hair regrowth in AA. 


 
 
 
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Criteria for Evaluation: 
(Efficacy, safety, 
stopping rules, etc.) 
EFFICACY 
Primary endpoint: SALT (Severity of Alopecia Tool) Scores: 
The proportion of scalp involvement is determined by 
dividing the scalp into 4 quadrants and estimating the 
percentage of the scalp surface that all the alopecic areas 
would occupy if placed together. 
 
Secondary endpoint:  Changes in hair re-growth as a 
continuous variable will be determined using physical exams 
and Canfield photography, as well as patient and physician 
global evaluation scores. 
 
Differences in the incidence of regrowth between patients 
with patch type AA vs patients with alopecia totalis or 
universalis will also be analyzed on an exploratory basis. 
 
In addition, response to abatacept treatment will be examined 
on an exploratory basis for correlation with the presence or 
absence of the AA GWAS risk haplotype. 
 
Additionally, patient reported outcomes, safety measures, 
incidence and timing of relapse will be important secondary 
outcomes.  
 
To assess safety, frequent and close monitoring of clinical and 
laboratory findings have been implemented. Adverse events 
will be captured and analyzed as a secondary endpoint. 
 
All physical examination findings, vital sign abnormalities, 
and clinical laboratory abnormalities, will be captured as AEs 
when deemed medically significant by the investigator. A 
qualified physician associated with the study will be available 
to assess clinical signs and symptoms that may be indicative 
of an adverse event. Safety will be assessed by summarizing 
the incidence and type of AEs. The proportion of patients who 
discontinued treatment will be summarized. 
 


 
 
 
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Statistics: 
This is a small exploratory open label pilot study to identify an efficacy 
signal in alopecia areata.  
 
Based on two recently completed randomized trials (Strober et al, 2008; 
Price et al, 2009) in similar patient populations (moderate to severe AA) 
we expect placebo response rates to be between 6% (>50% improvement 
in SALT score (Olsen et al, 1999)) and 12% (>25% improvement). We 
have chosen our primary endpoint conservatively (proportion of patients 
with >50% improvement in SALT index) as a relatively strict criteria that 
should minimize placebo response rates to 10% or less (0-2 of 15 subjects). 
This allows a higher degree of confidence that appreciable response rates 
are attributable to drug rather than spontaneous remission.  
 
Power analysis. Assuming a historically known placebo response rate of 
10% and the usual 5% level of significance (alpha), the sample size of 15 
would provide 80.7% power to detect a difference of 30% in the response 
rate between the experimental treatment group and the historical placebo 
group. 
 
Since this is a small open label proof of concept study, we recognize that 
it will likely lack adequate power to conclusively demonstrate small 
efficacy signals (particularly if the assumed detectable difference of 30% 
is not met).  Yet, descriptive summaries of all the primary and secondary 
efficacy outcomes (proportions for binary outcomes, means for continuous 
outcomes) will provide a preliminary indication of the effect size (even if 
smaller than 30%) that will aid design of subsequent efficacy trials.  
 
Differences in the incidence of regrowth between patients with patch type 
AA vs patients with alopecia totalis or universalis will also be analyzed on 
an exploratory basis. In addition, response to abatacept treatment will be 
examined on an exploratory basis for correlation with the presence or 
absence of the AA GWAS risk haplotype. 
 
To assess safety as a secondary endpoint, we will summarize via 
descriptive statistics, the occurrence of adverse events for the study group.  
 
Accrual projections. The Dermatology clinic and private practice at 
CUMC currently sees 600 AA patients yearly, of which we anticipate 20-
30% would be eligible (>40% hair loss). Accrual will be greatly facilitated 
by targeted recruitment through our existing NAAF registry which 
includes 400 AA patients in the New York area, the majority of which have 
patchy type disease. Thus, complete accrual of 15 subjects should be 
feasible within 1 year from a pool of >100 eligible subjects yearly. 
 


 
 
 
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1 
INTRODUCTION 
1.1 
Research Hypothesis 
Among patients with alopecia areata, patients with higher disease burdens are unlikely to have 
satisfactory outcomes with current therapies. Our hypothesis is that CTLA4-Ig will be effective 
therapy in moderate-severe alopecia areata by blocking re-activation of CD8+NKG2D+ memory 
T cells, thereby aborting the cytotoxic T cell inflammatory response underlying alopecia areata. 
1.2 
Product Development Rationale  
Abatacept is a recombinant fusion protein consisting of 
the extracellular domain of human CTLA4 and a 
fragment (hinge- CH2-CH3 domains) of the Fc domain 
of human IgG1 that has been modified to prevent 
complement fixation and antibody-dependent cellular 
cytotoxicity. 
Abatacept is the first drug in a new class of agents 
termed 
“selective 
costimulation 
modulators.” 
Abatacept binds specifically to the CD80 and CD86 
molecules, proteins prominently displayed on the 
surface of antigen-presenting cells (APCs) (Figure 1). 
Activation of naive T cells during an immune response 
requires two stimuli from APCs. The first signal is 
antigen-specific; antigens are presented by APCs, with 
the signal transmitted to the T cell through the T cell’s antigen receptor. The second, or 
costimulatory, signal is not antigen-specific and is delivered following the engagement of a 
costimulatory ligand on the APC with a cognate receptor on the T cell. 
A key costimulatory receptor on T cells is CD28. CD28 is constitutively expressed on resting 
T cells and binds to both CD80 (B7-1) and CD86 (B7-2) on the APC (Azuma et al, 1993; Freeman 
et al, 1993; Peach et al, 1994; Linsley et al, 1994) 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 (Skak et al, 2003; Oliveira dos Santos et al, 1999). At 24 to 48 hours 
following T cell activation, the T cell expresses CTLA4 on its surface, which engages the CD80 
and CD86 molecules on the APC surface interfering with CD28’s ability to bind to its ligands on 
the APC; CD80 and CD86 preferentially bind to CTLA4 with a much higher avidity than with 
CD28. Although the precise mechanisms are as yet unclear, CTLA4 expression is associated with 
a decrease in T cell activation. 
After the T cell activity has been dampened, the CTLA4 recycles into the T cell’s cytoplasm. The 
CTLA4 section of abatacept binds specifically to CD80 and CD86 (B7-1 and B7-2, respectively) 
and down-modulates the CD28-mediated costimulation of T cells. Thus, abatacept uses a segment 
 
Figure 1.  Mechanism of Action.  Abatacept 
disrupts ‘signal 2’, blocking the costimulatory 
pathway and preventing autoimmunity. 


 
 
 
Abatacept in alopecia areata 
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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 (Davis et al, 2007). 
Costimulatory blockade and its rationale as treatment for autoimmunity   
 
Initial studies with CTLA4Ig fusion molecules demonstrated inhibition of naive CD4 T cell 
activation and proliferation (Linsley et al. 1992; Wells et al. 1997), and prevention of 
autoimmunity and inhibition of graft rejection in animal models (Knoerzer et al. 1995; Pearson et 
al. 1996). By contrast, it was generally accepted that memory T cells did not require CD28/B7-
derived costimulation for recall responses (Salomon and Bluestone 2001). If this were true, then 
an exclusive activity of CTLA4Ig on naïve T cell activation would limit its use as a treatment of 
ongoing autoimmune diseases, which requires the reversal of injury mediated by effector and 
memory T cells, previously activated by self-antigens.  However, we now know that memory T 
cell responses remain costimulation dependent.  This is likely due to effector T cell regeneration 
from self-reactive memory T cell precursors by B7-expressing APCs in the lymph node and target 
tissues. Reactivation of antiviral memory T cells is impaired in the absence of B7/CD28 
costimulation (Borowski et al. 2007; Fuse et al. 2008; Duttagupta et al. 2009; Garidou et al. 2009; 
Teijaro et al. 2009; Grujic et al. 2010). In mouse models, CTLA4-Ig limits effector T cell responses 
from memory cell precursors (Ndejembi et al. 2006) and alleviates ongoing autoimmunity (Finck 
et al. 1994; Khoury et al. 1995), while anti-CTLA4 enhances CD8 T cell memory responses 
(Pedicord et al. 2011) potentially a driver in its therapeutic effects in cancer (Wolchok and Saenger 
2008; Hodi et al. 2010).  In humans, CTLA4-Ig is effective therapy in diseases known to be 
driven by memory T cells (Abrams et al. 1999; Kremer et al. 2005), and moreover the 
therapeutic effect is correlated with a decrease in CD8 T cell effectors (CD8+CD28- T cells) 
(Scarsi et al. 2010), as we would hope to accomplish using Abatacept therapy in alopecia 
areata.  
1.2.1 
Overview of Alopecia Areata 
Alopecia areata (AA) is a major medical problem and 
is the most prevalent autoimmune disease in the US, 
with a lifetime risk of 1.7%, affecting both males and 
females across all ethnic groups (Safavi et al. 1995). 
Additionally, AA represents the second most common 
form of human hair loss, second only to androgenetic 
alopecia, 
and 
causes 
significant 
disfigurement and psychological distress 
to 
affected 
individuals  
(Figure 2).  
Figure 2. Clinical manifestations of AA.  Patchy disease (a and b), In b, 
the patient is in a spontaneous regrowth phase.  For patients with alopecia 
universalis, there is a complete lack of body hair and scalp hair (c), while 
patients with alopecia totalis lack scalp hair but not body hair.  In d, the 
randomness of hair regrowth is observed, with regrowth in the parietal 
region but not either the occipital or temporal regions. 


 
 
 
Abatacept in alopecia areata 
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15
Alopecia Areata usually presents with patchy hair loss. Approximately one-third of these patients 
will experience spontaneous remissions within the first year. However, many patients will develop 
waxing and waning disease with some progressing to alopecia totalis (total scalp hair loss) or 
alopecia universalis (loss of all body hair). This population that suffers from a disfiguring disease 
represents a significant unmet medical need (Alkhalifah et al, 2010a,b).   
 
Alopecia totalis/universalis seldom, if ever, remits spontaneously or with current treatment. In our 
targeted population of moderate-severe patch-type alopecia placebo response rates in other clinical 
studies have been in the 6-12% range (Price et al, 2008; Strober et al, 2009). 
 
Clinical development of innovative therapies in AA has lagged far behind other autoimmune 
conditions.  This may be due in part to the perception that AA is merely a cosmetic disorder.  In 
reality, AA carries one of the highest burdens amongst all skin diseases, particularly among 
children and adolescents whose self-image is so closely linked to their appearance (Bickers et al. 
2006).   
 
There are no evidence-based treatments for AA. A comprehensive Cochrane analysis assessment 
of seventeen randomized clinical trials (RCTs) involving a total of 540 participants found no 
proven treatment of AA (Delamere et al. 2008).  Each trial included from 6 to 85 participants and 
assessed a range of interventions that included topical and oral corticosteroids, topical cyclosporin, 
photodynamic therapy and topical minoxidil. Overall, none of the interventions showed significant 
treatment benefit in terms of hair growth when compared with placebo. It was concluded that the 
effectiveness of few (if any) treatments for AA are proven. No RCTs on the use of diphencyprone, 
dinitrochlorobenzene, intralesional corticosteroids or dithranol were found, although these drugs 
are commonly used for the treatment of AA. Similarly, although topical corticosteroids and 
minoxidil are widely prescribed and appear to be safe, there is no convincing evidence that they 
are beneficial in the long-term. Most trials have been poorly reported and/or are so small that any 
important clinical benefits are inconclusive.    
 
This study will provide a first efficacy study of Abatacept in alopecia areata. One clear 
advantage of immunotherapeutic studies in the skin is the relative ease of access of the target 
organ. Thus, our studies here examining the skin could provide important insight into the 
mechanism(s) of action of Abatacept in related diseases (see “Common Cause” section 1.2.4), 
which in turn could impact our understanding of autoimmune diseases in which the target organ is 
not accessible. Shared genetic and common pathological pathways provide strong rationale 
for increasing the scope of approved pharmaceuticals (such as Abatacept) for novel 
indications (such as AA).  Studies of abatacept in Type I diabetes are underway (TrialNet 
T1D, Clinicaltrials.gov).  Indeed, positive studies in any one of these autoimmune diseases that 
share a common cause could serve as the basis for advancing common treatments.  
 
 
 


 
 
 
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16
1.2.2 
Pathology and role of T cells in human Alopecia Areata 
CD8+ Killer T cells in Human AA  
Alopecia areata results from autoimmune attack on the 
hair follicles. The relevant autoantigens are unknown, 
but the histopathology clearly identifies the “swarm of 
bees” encircling the human hair follicle. Infiltrates 
containing both CD4 and CD8 T cells have been 
described, but our recent studies pointed to a dominant 
role for activated NKG2D-bearing CD8 T cells that are 
the likely culprit autoaggressive cellular effectors1. 
We recently demonstrated that CD8+NKG2D+ 
effector T cells dominate the peribulbar infiltrate in 
human AA that are intimately associated with dermal 
sheath cells aberrantly expressing NKG2D ligands 
(Figure 3). 
Interferon driven Th1-response in human AA 
 
Consistent with a pathogenic cellular immune 
response, AA has been viewed as a Th1-driven disease 
(Arca et al, 2004; Barahmani et al, 2009; Kuwano et al, 2007); for instance elevated Th1 
cytokines/chemokines (Figure 4) are seen in the peripheral blood of AA patients and IFN-inducible 
gene signatures have been described in the skin of AA patients (Ghoreishi, et al, 2010). 
  
FiFigure 3. NKG2D axis in human AA:  
Top panels: The NKG2DL ULBP3 is 
upregulated in human AA hair follicles but not in 
control subjects. Bottom panels: 
Immunostaining of a HF bulb shows dense 
infiltration with NKG2D staining CD8 T cells. 
IFN-gamma
control
AAP
AU
0
20
40
60
80
pg/ml
IP-10
control
AAP
AU
0
200
400
600
800
1000
pg/ml
*
IL-8
control
AAP
AU
0
5000
10000
15000
pg/ml
IL-8
*
*
*
Figure 4. Elevated Serum 
Chemokines and Cytokines 
in Human AA. Interferon- 
and IFN-induced chemokines 
(IP-10/CXCL10) are elevated 
in the serum of human AA, in 
some cases correlating with 
disease severity, i.e. patchy 
disease (AAP) vs. universalis 


 
 
 
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17
 
1.2.3 
Preclinical Studies: CTLA4-Ig prevents onset of Alopecia Areata in the C3H-
HeJ mouse model 
C3H/HeJ mice develop spontaneous alopecia areata and the histopathological changes are identical 
to human alopecia including the importance of IFN-γ producing CD8+ NKG2D bearing T cells 
which are present in alopecic skin, and are massively expanded and activated in AA cutaneous 
lymph nodes (data not shown). As with human alopecia we have demonstrated that IFN-response 
genes are highly upregulated in C3H/HeJ alopecic skin but in non-lesional skin and is normalized 
in mice with treated with effective therapy (data not shown). 
Consistent with a primary role for autoimmune T cells, in C3H mice disease can be induced in 
normal unaffected mice by transfer of T cells (either or both CD4 and CD8 T cells) from affected 
mice or humans (Sundberg et al, 1994; Gilhar et al, 2003; McElwee et al, 2005). Thus the 
immunopathogenesis of the C3H mouse model faithfully recapitulates human alopecia and 
provides the rationale for preclinical studies in the C3H/HeJ mouse. Proof-of-concept has been 
provided for CTLA4-Ig as a treatment in the C3H alopecic mouse model.  As published by 
our consultant Carroll et al. (2002), in the AA skin-graft model, CTLA4-Ig treatment prevented 
alopecia in 13/15 or 14/15 graft recipients (10% overall disease incidence) when given for 1 week 
or 4 weeks respectively whereas alopecia developed in all 35/35 untreated graft recipients (100% 
disease incidence).  Our hypothesis is that CTLA4-Ig blocks re-activation of CD8+NKG2D+ 
memory T cells, aborting the cytotoxic T cell inflammatory response underlying AA.  
 
1.2.4 
Genetics of Alopecia Areata 
Common Cause Hypothesis in Autoimmune Diseases 
The ‘Common Cause’ theory of autoimmunity is well-supported by decades of research using 
various methodologies and provides strong support for the existence of shared disease 
mechanisms.  Epidemiological studies first demonstrated that some autoimmune diseases cluster 
within families, suggesting shared pathogenesis. More recently, hypothesis-free research strategies 
in genetics have shifted away from linkage studies in families, to genome-wide association studies 
(GWAS) in population-based cohorts. The results of these studies have provided tremendous 
support to the "common cause hypothesis" (Karopka et al. 2006) and have importantly identified 
susceptibility alleles in specific genes that underlie grouped sets of autoimmune diseases, 
arguing for unifying/general mechanisms that dysregulate tolerance at one of several 
multiple end organ sites, with autoimmune destruction in the pancreas, joint, or skin, etc., 
the potential final disease outcome. In fact, outside of the HLA, at least 23 such genes have been 
associated with two or more autoimmune diseases in a GWAS (Gregersen and Olsson 2009; 
Zhernakova et al. 2009). The majority of these shared genes can be mapped onto a discrete set of 
immunological molecular pathways.  Among these, the costimulatory pathway is one such 
shared mechanism. 


 
 
 
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CTLA4 is a ‘Common Cause’ Gene within the Costimulatory Locus 
Prior to identification of the ‘costimulatory 
locus’ across GWAS studies, a number of 
candidate gene studies had provided extensive 
evidence for the involvement of CTLA4 in 
numerous autoimmune diseases. In fact, the CDC-
based Human Genome Epidemiology Network 
(http://www.hugenavigator.net) 
maintains 
a 
database of genetic association studies, and no less 
than 650 publications report associations of CTLA4 
to 198 disease terms.  This includes 384 reports for 
36 autoimmune conditions, some of which we have 
summarized in Table 1. 
The costimulatory locus resides on human 
chromosome 2q33 and is comprised of a ~300kB 
region containing three genes, CD28, CTLA4 and ICOS, which likely arose as sequential gene 
duplication events (Gough et al. 2005). The expression of the three costimulatory genes is 
differentially regulated insofar as CD28 is constitutively present on naïve T cells, whereas CTLA4 
and ICOS become displayed only following T-cell activation, either at the level of transcriptional 
upregulation and/or endosomal trafficking to the plasma membrane. The engagement of CD28 
also influences the expression of CTLA4 and ICOS, suggestive of long-distance and coordinated 
regulation at multiple levels.  
 
The regulation of immune responses occurs through a balance of activating and inhibitory signals 
to generate effective immune responses, but prevent autoimmune disease. Despite their 
colocalization in the genome and evolutionary relationship and 20% sequence homology in their 
ligand binding domains (Gough et al. 2005), the functions of CD28 and CTLA4 are almost 
directly opposite with respect to autoimmunity (Scalapino and Daikh 2008). CD28 is an 
activatory/stimulatory signal (an accelerator), and engages as part of ‘signal 2’ by binding CD80 
and CD86 on the surface of antigen presenting cells. CTLA4, on the other hand, is an inhibitor of 
T-cell costimulation (a brake), and binds to the same receptors with 100x greater avidity than 
CD28, serving to dampen the immune response, although the mechanism(s) by which this occurs 
are incompletely understood. In addition to this activity, CTLA4 is also known to play a role in 
reverse-signaling to the antigen presenting cell once it is engaged, as well as in the generation of 
regulatory T cells, indicating pleiotropic roles in immune modulation (Scalapino and Daikh 2008). 
 
GWAS Implicates the CTLA4 Region on Chromosome 2q33.2 in AA/AT/AU 
In accordance with the common cause hypothesis of autoimmune diseases, our GWAS on AA 
(Petukhova et al. 2010) revealed a number of risk loci shared with other forms of autoimmunity, 
such as RA, T1D, CeD, SLE, MS and psoriasis, in particular, CTLA4, IL2/IL2RA, IL21, 
NKG2D ligands and genes critical to Treg function. The genetic commonality with RA, T1D, 
and CeD is especially noteworthy in light of the pathogenic significance of the expression of an 
Table 1.  Genetic association studies for CTLA4 
annotated in a CDC database.


 
 
 
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19
NK ligand in the end organ (synovial fluid, islets, gut and skin), and the involvement of the 
NKG2DL/NKG2D pathway in the pathogenesis of each of these three diseases.   
Interestingly, according to the NIH database of GWAS (http://www.genome.gov/gwastudies), to 
date, six GWAS have identified significant associations with CTLA4 across four diseases: 
our own study in AA (Petukhova et al. 2010), RA (Gregersen et al. 2009; Stahl et al. 2010), T1D 
(Cooper et al. 2008; Barrett et al. 2009) and CeD (Dubois, Trynka et al. 2010). The results of all 
published SNPs at these loci are shown in Figure 5. Guided by our GWAS findings and 
immunobiological studies, 
our goal is to develop 
treatments to fill the unmet 
needs of patients with AA. 
Importantly, since our 
original publication, 
CTLA4 has been 
replicated as a bona fide 
AA locus in an 
independent cohort (John 
et al, 2011). 
  
Overall, these results implicate CTLA4 genetically in the pathogenesis of several 
autoimmune diseases, and suggest that genetic variation at this locus may influence 
transcriptional and splicing regulation of CTLA-4 resulting in aberrant control of T cell 
activation. CTLA4 variants that are associated with AA have been correlated with decreased 
expression levels, providing further evidence for the involvement of costimulatory pathways in 
AA pathogenesis. 
 
1.2.5 
Haplotype Analysis for CTLA4 Modulation with Abatacept Therapy 
Autoimmune diseases that are common in the population, as is alopecia areata, are complex 
disorders and can arise from a multitude of causes that may not always be aligned within a single 
pathway.  This is thought to, in turn, to contribute to heterogeneity in treatment response. For 
example, if disease arises in an individual because of perturbations in a particular pathway, drugs 
that target alternative disease pathways will ultimately not effect molecular corrections and 
disease will remain unresolved for the patient. 
The costimulatory pathway has demonstrated perturbations in a number of autoimmune 
diseases.  We and others have identified haplotypes at the costimulatory locus that confer risk for 
autoimmunity and alopecia areata in particular (Petukhova et al, Butty et al.). We hypothesize 
that variants carried on these haplotypes perturb the costimulatory axis and patients carrying 
Figure 5.  GWAS results for CTLA4.  Four diseases have implicated CTLA4 in a 
GWAS. The dotted line indicates the threshold for genome-wide statistical 
significance (p=5x10-7).


 
 
 
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20
such risk variants in particular will receive benefit from therapies specifically targeted to this 
pathway. 
Long range haplotype analysis using a small set of common SNPs across the costimulatory locus 
revealed two predominating haplotypes in European populations, termed 15-2-4 and 5-1-4 that 
are associated with autoimmune protection or risk respectively.  Our own targeted deep 
sequencing across the locus in a cohort of 122 alopecia areata patients revealed significant 
overlap between 15-1-4 haplotype and the risk haplotypes identified in our alopecia areata 
GWAS, such that all chromosomes carrying the 15-1-4 haplotype also carried an AA GWAS risk 
haplotype.  Therefore, while the causal variants are not yet completely elucidated, we propose 
that patients carrying at least one copy of this haplotype will benefit from abatacept therapy.  In 
our dataset of 244 chromosomes, we identified 47 (20%) with this risk haplotype.  Furthermore, 
we identified 166 chromosomes that did not carry either the 15-1-4 haplotype or an AA risk 
haplotype (67%).      
In this study we will analyze the rate of response as correlated with the presence or absence of 
the risk haplotype.  If there appears to be a correlation, future studies of abatacept in AA may be 
designed to test and enroll subjects a priori based on the presence or absence of the risk 
haplotype enabling a more direct analysis of response to treatment in relationship to risk 
haplotype presence or absence. 
Table 1. 
 
Alopecia Areata 
Haplotype 15-2-
4 
Protective 15-1-
4 
Risk- Other 
Haplotype- Total 
GWAS risk 
Haplotype 
1 
47 
36 
84 
No GWAS risk 
Haplotype 
46 
 
114 
160 
Total 
47 
47 
150 
244 
Haplotype, Butty et al., 2007 
Table 1. The costimilatory locus was targeted for deep sequencing in 122 alopecia areata patients 
(Chr2: 204544318-204841364), revealing 1209 variants that passed stringent quality control. 
Variants were phased to reveal sequence for 244 chromosomes, 47 of which carry the 15-1-4 
haplotype that increases risk for autoimmunity and 150 of which do not carry this risk haplotype. 


 
 
 
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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 RA, psoriasis, and multiple sclerosis. Currently, there are no 
active registrational studies for psoriasis. There is currently an active IST in multiple sclerosis. 
The subsequent registrational program was in juvenile idiopathic arthritis (JIA), with data being 
collected from the ongoing long-term extension portion. Current active registrational programs for 
abatacept include studies in systemic lupus erythematosus (SLE) including lupus nephritis, and 
psoriatic arthritis. 
A full development program conducted in adult RA led to regulatory approval in the United States 
for this indication in December 2005, in Canada in June 2006, and in Europe in May 2007. In the 
US, abatacept now has two indications: (1) treatment of moderate to severe active RA in adults, 
and (2) treatment of moderate to severe juvenile idiopathic arthritis (JIA) in patients who have 
failed prior therapy with disease-modifying anti-rheumatic drugs (DMARDs).  
 
1.3.1 
Core Efficacy Studies of Abatacept in Rheumatoid Arthritis 
The RA clinical program consisted of five core studies: IM101-100, IM101-101, IM101-102, 
IM101-029, and IM101-031 (N=2944) (Kremer et al, 2003a,b; Genovese et al, 2005; Kremer et 
al, 2006; Weinblatt et al, 2006).  Each study had a double-blind placebo-controlled period of 
6 months or 1 year. In Study IM101-100, subjects received abatacept 2 mg/kg, 10 mg/kg, or 
placebo. In the other studies, subjects received abatacept 10 mg/kg or a fixed dose that 
approximated 10 mg/kg or placebo. 


 
 
 
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22
Subjects who completed the double-blind period were offered 
entry into an uncontrolled, open-label period, in which all subjects 
received abatacept (in a fixed dose that approximated 10 mg/kg). 
A total of 2624 subjects in the core RA studies received the 
approved abatacept dose (10 mg/kg or a fixed dose that 
approximated 10 mg/kg) in the combined double-blind and open-
label periods, representing 4603 person-years of exposure (i). 
The efficacy of abatacept at a weight-tiered dose approximating 
10 mg/kg was demonstrated in placebo-controlled studies in adult 
subjects with active RA and an inadequate response to 
methotrexate (IM101-100, IM101-102, and IM101-043), and in 
one study in adult subjects with active RA and an inadequate 
response to at least one TNF-blocking agent (etanercept and/or 
infliximab; IM101-029) (Kremer et al, 2003a,b; Genovese et al, 
2005; Kremer et al, 2006; Weinblatt et al, 2006).   Other studies 
have provided additional supportive evidence of efficacy. 
Abatacept (10 mg/kg or a fixed dose approximating 10 mg/kg) 
was significantly more effective than placebo in reducing the 
signs and symptoms of RA, including induction of major clinical 
response, improving physical function, slowing the progression of 
structural damage, and improving the quality of life in subjects 
with moderately to severely active RA. 
In Studies IM101-102 and IM101-029, improvement in signs and symptoms assessed by the 
American College of Rheumatology (ACR) 20 response rate versus placebo was observed after 
administration of the first dose, as measured at Day 15, and it was maintained through the double-
blind study phase and for up to 3 years (in IM101-029 and IM101-102) and up to 5 years (in 
IM101-100) (Westhovens et al, 2007; Kremer et al, 2007). In the open-label extensions of 
IM101-100, IM101-102, and IM101-029, durable and sustained ACR20, ACR50, and ACR70 
responses have been observed through 48, 24, and 18 months, respectively, of abatacept treatment 
(Westhovens et al, 2007; Genovese et al, 2008; Kremer et al, 2008). 
 
Clinical Trials of Abatacept in other Autoimmune Diseases 
Given the established safety and efficacy of abatacept in rheumatoid arthritis, the drug is currently 
being tested in a variety of autoimmune diseases (Table 2), as well as for organ transplantation. At 
present there are 79 clinical trials either in progress or completed using abatacept, of which 
66 involve an autoimmune disease (www.clinicaltrials.gov). These include safety, 
pharmacodynamics and efficacy studies and their primary purpose is mostly treatment, but also 
prevention in a smaller number of studies.  
  
 
 
Table 2. Abatacept clinical trials for 
autoimmune diseases 
(www.clinicaltrials.gov). 


 
 
 
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23
1.3.2 
Pharmacokinetics of Subcutaneous Formulation 
Subcutaneous (SC) formulation in adult population 
Single SC doses of abatacept (50 to 150 mg) demonstrated approximately dose proportional PK in 
healthy adult subjects(ii). Following administration of single doses of 50 to 150 mg of abatacept, 
the mean Cmax increased from 3.5 to 10.7 μg/mL and the geometric mean AUC(INF) increased 
from 1490 to 4270 μghour/mL. The median time to occurrence of Cmax (Tmax) following SC 
administration ranged between 48 and 168 hours. Mean T1/2 values in healthy subjects ranged from 
11.2 to 14.7 days. T1/2 values from this study were comparable with the T1/2 values obtained with 
abatacept administered IV to subjects with RA (13 to 14 days)(iii). The fact that T1/2 values 
following SC dosing were comparable to T1/2 values obtained after IV dosing suggests that the 
elimination characteristics of abatacept were not altered following SC administration. 
A double-blind, randomized, placebo-controlled, parallel-group, multiple-dose study (IM101063) 
assessed the steady-state trough serum concentrations of abatacept following SC administration in 
subjects with RA(iv). Subjects were randomized to receive either abatacept or placebo in 1 of 5 
parallel groups based on body weight obtained at the screening visit (Table 1.3.2A). The SC dose 
regimens were selected to target trough levels between 10-30 ug/ml, which was associated with 
efficacy with the IV formulation. 
Table 1.3.2A 
IM101063 Treatment Groups Based on Body Weight 
Treatme
nt Group 
Subject 
weight (kg) 
IV dose on  
Day 1 (mg) 
SC dose weekly 
for 12 weeks (mg) 
SC injection volume 
(mL) 
1 
< 60 
500 
75 
0.6 
2 
< 60 
500 
125 
1 
3 
60 - 100 
750 
125 
1 
4 
> 100 
1000 
125 
1 
5 
> 100 
1000 
200 
0.6 + 1.0 
Source: IM101063 CSR 
On Day 1, subjects received a single IV infusion (loading dose) of abatacept or placebo, based on 
their weight range. Approximately 1 hour after the completion of the IV infusion, subjects received 
their assigned SC dose of abatacept or placebo. Abatacept or placebo was administered weekly by 
the SC route, at the same dose as the SC dose on Day 1, for a total of 12 SC injections. Blood 
samples for PK analysis were collected on Day 1 prior to and at the end of the IV infusion. In 
addition, blood samples were collected prior to each weekly SC dose of abatacept. 
Steady-state trough serum concentrations were achieved after ~ 4 to 5 weeks following the 
combined regimen of a single IV loading dose and weekly SC injections. With the exception of 
Treatment group 4 (abatacept 125 mg SC weekly dose for subjects weighing > 100 kg), the mean 
steady-state trough concentrations across all other treatment groups appeared to be comparable.  


 
 
 
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24
However, to truly represent the steady-state serum levels from SC administration without the 
contribution of the IV loading dose, Cmin values on Days 71-85 were selected, since contribution 
from IV was expected to be negligible. Comparison of mean steady-state trough concentrations on 
Day 71, 78 and 85 indicated that abatacept did not appear to accumulate following weekly dosing 
(Table 1.3.2B). 
Table 1.3.2B 
Summary Statistics for Abatacept Steady-State Cmin Values 
on Days 71, 78, and 85 - IM101063 
Treatment Group 
Study 
Day 
n 
Cmin (g/mL) 
Geometric Mean 
(CV%) 
Cmin (g/mL) 
Median (Min, Max) 
1 (500 mg IV / 75 mg 
SC) 
71 
7 
22.64 (20.13) 
20.92 (17.06, 29.84) 
 
78 
7 
21.66 (19.99) 
22.40 (16.01, 28.93) 
 
85 
7 
23.62 (31.63) 
21.91 (18.24, 39.60) 
2 (500 mg IV / 125 mg 
SC) 
71 
4 
28.03 (42.13) 
32.57 (13.73, 43.30) 
 
78 
3 
34.17 (29.49) 
33.10 (25.97, 46.40) 
 
85 
3 
36.73 (31.64) 
37.50 (26.26, 50.30) 
3 (750 mg IV / 125 mg 
SC) 
71 
26 
24.05 (40.65) 
26.53 (7.97, 54.11) 
 
78 
23 
24.41 (52.35) 
27.54 (5.40, 68.90) 
 
85 
25 
24.93 (38.42) 
26.01 (9.57, 53.80) 
4 (1000 mg IV / 125 mg 
SC) 
71 
3 
16.22 (24.39) 
15.15 (13.37, 21.07) 
 
78 
5 
11.57 (32.25)  
13.20 (6.89, 16.33) 
 
85 
5 
13.01 (41.35) 
13.30 (6.66, 22.73) 
5 (1000 mg IV / 200 mg 
SC) 
71 
5 
26.52 (56.53) 
26.20 (8.68, 55.20) 
 
78 
5 
29.21 (52.96) 
40.40 (8.04, 57.10) 
 
85 
5 
27.53 (58.87) 
29.01 (8.74, 62.00) 
Source:  IM101063 CSR, Supplemental Table S.8.2.2 
n=number of observations 
 


 
 
 
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25
Steady-state pharmacokinetic parameters of abatacept after weekly SC administration were 
determined between the SC dosing interval from Day 71 to 78. Cmax and AUC(TAU) appear to 
be comparable in Treatment Groups 1, 3 and 5 (Table 1.3.2C). 
Table 1.3.2C 
Summary Statistics for Abatacept Steady-State 
Pharmacokinetic Parameters - IM101063 
Treatment Group 
Pharmacokinetic Parameter 
Cmax (µg/mL)  
Geometric Mean (CV%) 
AUC(TAU) (µg*h/mL) 
Geometric Mean (CV%) 
1 (500mg IV / 75mg 
SC) 
n = 7  
26.3 (29.5) 
n = 7 
4066 (22.2) 
2 (500mg IV / 125mg 
SC) 
n = 4 
34.9 (46.6) 
n = 3 
6699 (20.7) 
3 (750mg IV / 125mg 
SC) 
n = 26 
31.9 (42.8) 
n = 24 
4607 (38.6) 
4 (1000mg IV / 125mg 
SC) 
n = 5 
14.7 (44.3) 
n = 4 
2555 (30.1) 
5 (1000mg IV / 200mg 
SC) 
n = 5 
41.7 (41.2) 
n = 5 
5849 (40.5) 
Source: IM101063 CSR, Supplemental Table S.8.2.3 
n = number of subjects, TAU = 7 days 
Cmax and AUC(TAU) were calculated between a SC dosing interval from Day 71 to Day 78 
profile. The dose determined by IM101063 was then tested in a large SC program including 
IM101174, the pivotal efficacy study demonstrating non-inferiority of SC to IV including over 
1,400 paitents.  SC abatacept was approved based on this and other supportive safety studies in 
2011. 
 
1.3.3 
Overall Safety of Abatacept 
The risks that may be associated with the use of abatacept include infections, some of which may 
be serious or fatal, infusion related reactions, and an increase in respiratory adverse events and 
infections in patients with chronic pulmonary obstructive disease (COPD). Other potential risks 
may include the development of malignancies or autoimmune disorders, but an increased risk of 
these types of events have not been observed. As with the use of any protein therapeutic, 
antibodies against abatacept (immunogenicity) may develop. The rate of immunogenicity has 
generally been low and there has not been an apparent effect on safety, efficacy, or 
pharmacokinetics (PK). A recent safety analysis of 5 randomized, placebo-controlled double 
blind abatacept clinical trials was performed, which included 1955 patients during the double 
blind period and 2688 during the cumulative double blind and open label periods.  The overall 


 
 
 
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26
frequencies of adverse events, serious adverse events, and malignancies were similar between the 
patients receiving abatacept and those in the placebo arms of the studies.  Safety data through 
cumulative exposure showed no evidence of increased incidence of serious infections or 
malignancies with increasing exposure to abatacept, suggesting an acceptable safety profile in 
this population (Sibilia and Westhovens 2007). Similar findings supporting its safety in children 
6 years and older with juvenile idiopathic arthritis have been reported.  A randomized, double-
blind placebo controlled trial reported no difference in the frequency of adverse events between 
the treatment groups during the double-blind period.  Furthermore, there were no reports of 
serious adverse events in the treatment group (Ruperto et al. 2008).  
1.3.4 
Safety of SC Formulation of Abatacept  
SC formulation in adult population 
IM101013 
In Study IM101013(ii) a double-blind, randomized (within dose), placebo-controlled, 
parallel-group, single-dose study in healthy subjects weighing  100 kg, single SC doses of 
abatacept were well-tolerated by healthy adult subjects. There were no deaths, no discontinuations, 
and no SAEs reported. All AEs were mild to moderate in intensity. In general, there was no 
difference between the frequency and types of AEs reported by the abatacept (all abatacept groups 
combined, n = 40) and placebo (all placebo groups combined, n = 8) groups. The most common 
type of AEs reported by abatacept and placebo subjects were injection site reactions including 
erythema, swelling, and tenderness. Infections were commonly reported by both the abatacept and 
placebo groups and were not more common in abatacept-treated subjects than in placebo-treated 
subjects. One (1) abatacept-treated subject had laboratory abnormalities (increases in alanine 
aminotransferase and gamma-glutamyl transferase levels) that were considered by the investigator 
to be clinically significant and were reported as AEs. 
Overall, 11 of the 40 subjects (27.5%) developed antibodies to the CTLA4 region of the abatacept 
molecule, with endpoint titers in healthy subjects followed for 71 days ranging from Day 33 to 
Day 872. Only 1 of the 11 subjects developed antibodies that had abatacept neutralization activity. 
The earliest onset of seroconversion was at Day 43 (seen in 1 subject), after approximately 3 to 4 
half-lives of abatacept and accounting for over 94% of the drug being eliminated from the vascular 
system. The presence of an immune response resulted in increased clearance of abatacept from the 
vascular system. This resulted in a shorter T1/2 (range = 3.2 to 7.5 days) compared with the T1/2 for 
subjects who did not exhibit an immune response to abatacept (range = 11.2 to 14.7 days). The 
incidence rate of seroconversion in subjects receiving a single SC dose of abatacept (27.5%) was 
higher compared with subjects who discontinued IV abatacept treatment (7.4%) in the Phase 2/3 
development program of IV abatacept for RA. The development of immunogenicity did not appear 
to be associated with adverse safety outcomes; the safety profile of abatacept in subjects with and 
without an immune response was comparable. 
IM101063 


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


 
 
 
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than 3% of treated subjects had an infection AE(s) that was serious or required discontinuation of 
abatacept treatment.  
In IM101173, one previously un-labelled SAE was reported: severe grade 4 Pneumocystis jiroveci 
pneumonia(vii).. The subject had been on study for 3 months, receiving 125 mg of abatacept SC 
once a week and developed bilateral pneumonia with severe respiratory failure. The subject was 
hospitalized to receive treatment for the infection and severe respiratory failure; the subject 
recovered and was discharged 1 month later. Safety data frp, IM101174, the large, pivotal efficacy 
study is consistent with the overall IV experience and with the other SC studies. 
 
1.4 
Overall Risk/Benefit Assessment 
The efficacy of abatacept in alopecia areata is uncertain and determination of any activity in this 
disease is the objective of this pilot study. The long term safety profile of abatacept is reassuring 
and confirms the potential for a favorable positive benefit/risk of abatacept in the treatment of 
alopecia areata.  
 
Current therapeutic options for Alopecia Areata 
There is no FDA approved drug for alopecia areata.  A recent Cochrane report (Delamere et 
al, 2008) concluded that there was no evidenced based support for any intervention in this disease.  
Standard of care remains observation for mild disease, and lesional/oral steroids for more advanced 
cases (Alkhalifah et al, 2010a,b). In our targeted population of moderate-severe alopecia 
areata placebo response rates have been in the 6-12% range (Price et al, 2008; Strober et al, 
2009).  Spontaneous regrowth is extremely rare in patients with alopecia totalis or universalis. 
Intralesional steroid responses are unpredictable and occur less frequently in subjects with higher 
disease burdens. This population that suffers from a disfiguring disease represents a significant 
unmet medical need (Alkhalifah et al, 2010a,b).  Evidence-based and steroid-sparing interventions 
are needed.  
 
Use of subcutaneous Abatacept carries potential risks, including treatment-associated infection 
and injection site reactions.  Alopecia areata patients as a whole are young (median age 23-30) 
and otherwise healthy, which should mitigate risk of adverse effects.  The target population in 
this proposed study is subjects with greater than 30% hair loss is unusually extensive disease, 
affecting fewer than 30% of all alopecia subjects, with disfiguring consequences and severe 
psychosocial morbidity. Although AA does not cause physical pain, several studies have noted 
that AA seriously impairs quality of life (QoL), mainly by altering self-perception and self-esteem, 
both of which interfere with social life.  Because AA is chronic, visible to others, and often 
difficult to treat, its impact on quality of life is underappreciated (Bickers et al, 2006; Hanan 
et al, 2008; Dubois et al, 2010) and comparable to psoriasis (Bickers et al, 2006). Patient advocacy 
groups, including National Alopecia Areata Foundation have developed an active disease registry 
of over 10,000 subjects to document the impact on quality of life and encourage clinical 
investigation in this disease.  
 


 
 
 
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1.5 
Study Rationale 
Alopecia areata is a prevalent disease with high unmet need with significant psychosocial 
morbidity and no current evidence-based treatments. Preclinical studies have set the stage for 
evaluation of abatacept in alopecia areata. Importantly, CTLA4-Ig prevents disease onset in the 
C3H-HeJ mouse model.  Furthermore based on our GWAS studies (Petukhova et al, 2010) and an 
independent replication study (John et al, 2011), we know that CTLA4 is relevant in human AA. 
Based on this clear rationale and the relative safety of abatacept in this young, otherwise-healthy 
motivated population, we propose an exploratory pilot study to evaluate abatacept as a therapeutic 
in AA.  
 
To our knowledge, abatacept has never been examined in human AA. Specifically, we propose an 
exploratory trial using weekly fixed dose of SC abatacept to establish initial efficacy data in 15 
subjects with moderate-severe AA. This initial clinical experience with abatacept, if positive, 
would provide the basis for considering and designing subsequent larger and appropriately 
powered RCTs. 
 
The study proposed here targets the identical moderate-severe AA patient population as two other 
preceding RCT studies that also evaluated therapeutic effects of immune biologics (alefacept and 
efalizumab) (Price et al, 2008; Strober et al, 2009). Moderate-to-severe AA carries significant 
psychosocial burden and is likely a much more reversible disease process than AA 
totalis/universalis.   
 
Prior interventional trials in AA have been criticized for inclusion of a heterogeneous participant 
population with wide disease severity and duration (Delamere et al, 2008). To overcome these 
sources of patient heterogeneity: 
 
1. Patients who currently have alopecia totalis or universalis (AT/AU) were initially 
excluded in this pilot study since their response rate was expected to be lower. Patients with 
alopecia totalis/universalis can be included if the current episode of hair loss meets the criteria of 
30 to 95% hair loss (i.e. they may have had a previous episode of AT or AU which demonstrated 
regrowth of hair, and they are not currently AT or AU), and as long as in the opinion of the 
investigator there does appear to be potential for regrowth. Based on the early promising results 
seen to date in our treatment of moderate-severe patch type AA with ruxolitinib, we will enroll at 
the investigator’s discretion 2 to 5 patients with current AT/AU to preliminarily explore the 
effect of abatacept in these most severe cases of AA.  
 
2. Patients with mild disease are excluded since natural remission is considerably more likely in 
the early stages of disease or in mild disease (involving less than 25% hair loss) where spontaneous 
successful regrowth has been reported in up to 50% of individuals34. In more extensive disease, 
remissions are less likely and are usually restricted to incomplete hair regrowth involving a 
minority of scalp areas. Thus to minimize placebo response rates this study is specifically 


 
 
 
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30
focused on subjects with moderate to severe alopecia areata with greater than 30% hair loss 
and disease duration greater than 3 months.   
 
We have adopted the following study plan to identify a treatment “signal” in alopecia areata: The 
standard dosing schedule of SC abatacept of 125mg per week used in rheumatoid arthritis 
treatment will also be used here to treat moderate and severe alopecia areata for a period of 6 
months. Treatment may be extended by up to an additional 6 months beyond the initial 6 months 
of treatment if clinically indicated at the discretion of the investigator. 
 
2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
The study’s primary efficacy endpoint will be the proportion of responders after 6 months of 
treatment, with response defined as 50% or greater hair re-growth from baseline as assessed by 
SALT score (Olsen et al, 1999) at week 24. This is a relatively strict definition for defining 
responders and non-responders and was chosen to minimize the potential for spontaneous 
remission, in which fewer than 10% are expected to achieve this magnitude of hair regrowth 
spontaneously. To assess the durability of responses, patients who achieve 50% regrowth from 
baseline during the first 6 months, will continue to be followed for an additional 6 months off 
treatment or until it is determined that relapse has occurred 
 
2.2 
Secondary Objectives 
As secondary endpoints, efficacy will be measured by changes in hair re-growth as a continuous 
variable as determined by physical exam and Canfield photography, as well as patient and 
physician global evaluation scores. To assess the durability of responses, patients will continue to 
be followed for an additional 6 months off treatment.  The occurrence of adverse events will also 
be captured as a secondary endpoint. 
 
Secondary efficacy outcomes in detail 
1. Percent hair regrowth from baseline determined by SALT measurements following 24 
weeks of treatment, up to an optional 48 weeks of treatment at the discretion of the 
investigator, and during the 6 month period following discontinuation of treatment. 
2. Comparison of the proportion of responders in the experimental group with the 
historically known placebo response rate, with response defined as 50% change in SALT 
score (50% regrowth) from baseline, at the end of treatment (at week 24, optional 
treatment up to week 48, as well as any endpoint between the end of treatment and 6 
months after end of treatment, as applicable), and the end of the follow up period 6 
months after discontinuation of treatment (week 48, optional end of study up to week 72). 
3. Comparison of the proportion of subjects in the experimental group and the proportion of 
subjects in the historical control group attaining global overall improvement SALT score 


 
 
 
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31
of A5 (100% coverage) supported by </= SALT 25 at weeks 12, 24, 36 and 48; optional 
up to weeks 30, 36, 42, 48, 60, 72 for subjects getting optional additional treatment 
beyond initial 6 months of treatment, at the discretion of the investigator. 
4. Change in PGA (Physician Global Assessment) based on evaluation of live evaluations 
and standardized photographs between baseline, week 12, 24, 36 and 48; up to week 72 
for subjects receiving optional additional treatment. 
5. Differences in the incidence of regrowth between patients with patch type AA vs patients 
with alopecia totalis or universalis will also be analyzed on an exploratory basis. 
6. Response to abatacept treatment will be examined on an exploratory basis for correlation 
with the presence or absence of the AA GWAS risk haplotype. 
7. Change in patient global assessment between baseline, Week 12, 24, 36 and 48; up to 
week 72 for subjects receiving optional additional treatment. 
8. Change in patient quality of life assessment from baseline to weeks 12, 24, 36 and 48; up 
to week 72 for subjects receiving optional additional treatment. 
9. Frequency of occurrence and timing of relapse (as defined above) in responders followed 
for 6 months off therapy. 
10. Safety will be assessed by summarizing the incidence and type of AEs. The proportion of 
patients who discontinued treatment will be summarized. 
 
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 Harmonization (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 (e.g, 
loss of medical licensure; debarment). Systems with procedures that ensure the quality of every 
aspect of the study will be implemented. 
 


 
 
 
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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 (e.g, 
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 (e.g, 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. 
 
4 
INVESTIGATIONAL PLAN 
4.1 
Study Design and Duration 
Screening  
A complete medical history will be taken. Patients will be screened for pre-existing renal (basic 
metabolic and urine analysis), hematologic (CBC with differential and reticulocytes) or hepatic 
dysfunction or COPD; lipid panel; prior exposure to tuberculosis (PPD and CXR) or hepatitis; 
pregnancy tests will be done in women of childbearing potential.  
 
Assessments: Baseline assessments of disease severity will be done. This will include SALT 
score (Severity of Alopecia Tool, Addendum 1), Physician global assessment (PGA), patient 
global assessment and patient quality of life assessment. In order to minimize or eliminate inter-
rater variability, every effort will be made to have the same investigator evaluate an individual 
subject at each visit. Whenever possible the same investigator (the PI or her designee) will 
examine the patient’s scalp, determine the SALT score, and grade the photographic images.  
 
Visit Schedule and Assessments  
Screening assessments and all scheduled study visits are outlined in the Table of Study  


 
 
 
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33
 
Assessments 
 
Baseline to Week 24 (period on study medication) 
 
Patients will be seen at baseline, and at weeks 4, 8, 12, 18 and 24 weeks.  Assessments of disease 
severity will be conducted including SALT (Severity of Alopecia ToolAddendum2 26)36, Physician 
global assessment (PGA) at weeks 4,8,12, 18, 24, 36, and 48, and patient global assessment and 
patient quality of life assessment at weeks 0, 12, 24, 36, and 48. Patients receiving optional 
additional treatment, at the discretion of the investigator, will continue to be seen every 6 weeks 
after week 24 while on treatment. 
 
PGA and patient evaluations will be based on similar 100mm visual analog scales with 0 labeled 
as no scalp hair loss and 100 labeled as complete scalp hair loss. Patients and physicians will place 
a vertical mark along the horizontal line depending on their assessment of the degree of hair loss 
present at the time of assessment. 
 
Patient quality of life assessments will be based on changes in the Dermatology Life Quality Index 
DLQI (Finlay et al, 2004), which we have previously used for patient evaluation in the AA registry.  
 
Photography will be performed at every scheduled visit; skin biopsies will be performed at baseline 
and weeks 4, 12 and 24; blood draws for safety parameters and immune studies will be done based 
on the attached table of study procedures. 
 
Patients will be instructed in study medication administration at baseline (week zero) and will be 
observed self-administering medication at each visit. Instructions regarding study drug 
administration will be reinforced as needed. Study medication will be evaluated in order to assess 
compliance and medication will be dispensed as needed.   
 
Additional biopsies and blood draws may be obtained as clinically indicated. Since the timeline to 
regrowth may vary from subject to subject, unscheduled biopsies and blood draws will insure that 
tissue and blood samples are obtained at optimal time points to evaluate the changes occurring at 
the onset of growth or in the event of any unexpected clinical change. In addition, areas that are 
resistant to treatment may be biopsied to determine the cellular and immunologic differences of 
those areas compared to areas that are responding to treatment. The patient will be given the option 
to agree to, or decline, the additional biopsies and blood draws. 
 
Adverse events will be assessed at every visit. 
 
Week 25 to 48 (follow-up period off study medication)  
All patients will be seen at week 36 and 48, after completion of 6 months of study drug, to 
determine durability of response or evidence for a delayed effect. Importantly patients who 
achieved >or = 50% regrowth as measured by SALT score (responders) will be seen at week 36, 


 
 
 
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34
and 48 after end of study treatment in order to assess the frequency and timing of relapse or to 
capture the occurrence of further regrowth. 
 
Relapse will be defined as any recurrence of hair loss in responders (subjects achieving greater 
than 50% decrease in SALT score from baseline during the first 6 months of the study) who had 
achieved stable regrowth without continued loss for at least 2 months; and loss of >/= 25% of 
regrowth in patients who had achieved 50% regrowth during treatment but still had chronic low 
grade hair loss.  
 
Nonresponders will also continue follow-up in order to assess for delayed response.  
 
Efficacy evaluations: SALT, PGA, Patient global assessment and patient quality of life 
assessment will be performed at Weeks 36, and 48.  
 
Blood draws for safety parameters will be conducted at week 30 if deemed necessary to assess 
normalization of any previously abnormal values.  
 
Week 25 up to 72 (for subjects receiving optional additional treatment extension) 
Patient receiving an optional additional treatment extension of up to 6 months, at the discretion 
of the investigator, will continue to be seen every 6 weeks after week 24 while on the study 
medication, then at 12 weeks and 24 weeks after completion of up to 12 months of study drug, to 
determine durability or response or evidence for a delayed effects. 
 
Efficacy evaluations: SALT, PGA, Patient global assessment and patient quality of life 
assessment will continued to be performed at every visit during optional additional treatment 
extension. 
 
Blood draws for safety parameters will be conducted at 12 weeks after completion of study drug 
if deemed necessary to assess normalization of any previously abnormal values.  
 
Adverse events will be assessed at every visit.  
 
Standardized photographs of the subject’s scalp will be done at every scheduled visit and will be 
used to support determination of percent hair regrowth. Photography will be performed using a 
high-resolution digital camera with Intellistudio system from Canfield Scientific, Inc. Patients will 
be positioned using a laser guide, after which photographs of the entire scalp will be taken at 
standardized locations and at a fixed distance. Close-up photographs may also be taken using an 
epiluminescent attachment in order to assess for the presence of early regrowth. 
 
 


 
 
 
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Unscheduled Visits  
An unscheduled visit can occur at any time during the study for instance as prompted by signs of 
infection or local injection site reactions. A source document must be maintained for these 
unscheduled visits. The date for the visit and any data generated must be recorded on the 
appropriate CRF. At treatment discontinuation/early termination subjects will undergo end off 
study evaluations per the Schedule of Assessments. 
 
Telephone contact/retention  
Patients will be contacted on a monthly basis, between the planned study visits at weeks 36 and 
48, in the observational phase (Weeks 25 to 48, up to Week 72 for subjects receiving treatment 
extension) of the study to ascertain the occurrence of adverse events as well as to assess the status 
of hair growth or loss.  
 
Any concerns or questions the patient may have will also be addressed. If deemed necessary, the 
subject may be asked to come in for an unscheduled visit.  
 
Duration of Treatment  
 
After the screening period, subjects will begin weekly self-administered subcutaneous abatacept 
and will continue treatment for 6 months. Patients will be instructed in self-administration of 
study medication at baseline (week zero) and will be observed self-administering medication at 
each visit. Instructions regarding study drug administration will be reinforced as needed.  
The 6-month treatment period is expected to provide adequate time to assess the short-term 
efficacy and safety of abatacept in patients with moderate to severe AAP. Responders will then be 
followed for 6 months off drug. 
 
Treatment may be extended by up to an additional 6 months beyond the initial 6 months of 
treatment if clinically indicated at the discretion of the investigator. 
 
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  
Before any study procedures are performed, subjects will have the details of the study 
described to them, and they will be given a written informed consent document to read. 


 
 
 
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36
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) Must be between 18 and 75 years of age.  
3) Must have a diagnosis of moderate to severe AA - defined as the presence of equal to or more 
than 30% and equal to or less than 95% total scalp hair loss at baseline as measured using the 
SALT score. Five patients with current alopecia totalis/universalis may be included in this study 
at the investigator’s discretion. 
4) Duration of hair loss greater than 3 months without an upper limit of duration as long as there is 
reason to believe that regrowth is possible in the opinion of the investigator. 
5) No evidence of active, ongoing regrowth present at baseline. 
6) Patients with alopecia totalis/universalis can be included as long as the current episode of hair 
loss meets the criteria of 30 to 95% hair loss (i.e. they may have had a previous episode of AT or 
AU which demonstrated regrowth of hair, and they are not currently AT or AU), and as long as in 
the opinion of the investigator there does appear to be potential for regrowth. two to five patients 
with current episodes of alopecia totalis/universalis may be included in this study at the 
investigator’s discretion.  
7) Subjects may be naïve to treatment or unresponsive to intralesional (IL) steroids or other 
treatments for AA.  
8) Must be willing to avoid live vaccines while on the study medication, and within 3 
months of its discontinuation. 
9) Women of childbearing potential (WOCBP) must use highly effective methods of birth 
control [for up to 12 weeks after the last dose of investigational product] to minimize the 
risk of pregnancy]. WOCBP must follow instructions for birth control for the entire 
duration of the study including a minimum of 90 days after dosing has been completed. 
a. Acceptable methods of highly effective birth control include:  
i. Condom with spermicide  
ii. Diaphragm and spermicide  
iii. Cervical cap and spermicide  
b. The use of intrauterine devices, (IUDs) shall be at the discretion of the 
investigator.  
c. Women must have a negative serum or urine pregnancy test (minimum sensitivity 
25 IU/L or equivalent units of HCG) within 24 hours prior to the start of 
investigational product.  
d. Women must not be breastfeeding  
10) Sexually active fertile men must use highly effective birth control if their partners are 
WOCBP. Men that are sexually active with WOCBP must follow instructions for birth 
control for the entire duration of the study and a minimum of 90 days after dosing has 
been completed.  
 
4.2.2 
Exclusion Criteria 
1) Sex and Reproductive Status 


 
 
 
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a. 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.  
b. WOCBP using a prohibited contraceptive method.  
c. Women who are pregnant or breastfeeding. 
d. Women with a positive pregnancy test on enrollment or before administration of 
abatacept. 
e. Sexually active fertile men not using effective birth control if their partners are 
WOCBP. 
2) Target Disease Exceptions  
a. Two to five patients with current alopecia totalis/universalis at the time of 
enrollment (i.e. 100% scalp or 100% scalp and body loss, respectively) may be 
enrolled. The remaining patients most must have 30 to 95% hair loss due to 
alopecia areata.  
b. Patients with a history of or active skin disease on the scalp such as psoriasis or 
seborrheic dermatitis. 
c. Patients in whom the diagnosis of alopecia areata is in question. 
d. Patients with active medical conditions or malignancies (except adequately 
treated basal or squamous cell carcinoma) that in the opinion of the investigator 
would increase the risks associated with study participation, including patients 
with a history of recurrent infections. 
e. Patients with COPD 
f. Patients known to be HIV or hepatitis B or C positive. 
g. Patients with history or evidence of hematopoietic abnormality. 
h. Patients with history of immunosuppression or history of recurrent serious 
infections. 
i. Patients unwilling or unable to discontinue treatments known to affect hair 
regrowth in AA 
3) Coexisting disease or concurrent medications 
a. Patients taking TNF antagonists or other biological therapy such as anakinra. 
b. Patients known to be HIV or hepatitis B or C positive. 
c. Patients with evidence of infection or active/untreated skin cancer. 
d. Patients who have been treated with intralesional steroids, systemic steroids, 
anthralin, squaric acid, DPCP (diphenylcycloprophenone), protopic, minoxidil or 
other medication which in the opinion of the investigator may affect hair regrowth 
within one month of the baseline visit. 


 
 
 
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38
e. Subjects who are impaired, incapacitated, or incapable of completing study-
related assessments. 
f. Subjects with current symptoms of severe, progressive, or uncontrolled renal, 
hepatic, hematologic, gastrointestinal, pulmonary, cardiac, neurologic, or cerebral 
disease, which, in the opinion of the investigator, might place a subject at 
unacceptable risk for participation in the study. 
g. Female subjects who have had a breast cancer screening that is suspicious for 
malignancy and in whom the possibility of malignancy cannot be reasonably 
excluded by additional clinical, laboratory, or other diagnostic evaluations. 
h. Subjects with a history of cancer in the last 5 years, other than non-melanoma 
skin cancers cured by local resection or carcinoma in situ. Existing non-melanoma 
skin cancers should be removed, the lesion site healed, and residual cancer ruled 
out before administration of the study drug. 
i. Subjects who currently abuse drugs or alcohol. 
j. Subjects with evidence (as assessed by the investigator) of active or latent 
bacterial or viral infections at the time of potential enrollment, including subjects 
with evidence of human immunodeficiency virus (HIV) detected during 
screening. 
k. Subjects with herpes zoster or cytomegalovirus (CMV) that resolved less than 2 
months before the informed consent document was signed. 
l. Subjects who have received any live vaccines within 3 months of the anticipated 
first dose of study medication. 
m. Subjects with any serious bacterial infection within the last 3 months, unless 
treated and resolved with antibiotics, or any chronic bacterial infection (eg, 
chronic pyelonephritis, osteomyelitis, or bronchiectasis). 
n. Subjects at risk for tuberculosis (TB). Specifically excluded from this study will 
be subjects with a history of active TB within the last 3 years, even if it was 
treated; a history of active TB greater than 3 years ago, unless there is 
documentation that the prior anti-TB treatment was appropriate in duration and 
type; current clinical, radiographic, or laboratory evidence of active TB; and 
latent TB that was not successfully treated (≥ 4 weeks). 
4) Physical and Laboratory Test Findings 
a. Subjects must not be positive for HIV, hepatitis B or C. 
b. 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. 
c. Subjects with any of the following laboratory values 


 
 
 
Abatacept in alopecia areata 
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39
i. Hemoglobin < 10.0 g/dL 
ii. WBC < 3500/mm3 (< 3 x 109/L) 
iii. Platelets < 120,000/mm3 (< 3 x 109/L) 
iv. Serum creatinine > 2 times the ULN 
v. Serum ALT or AST > 2 times the ULN 
vi. Any other laboratory test results that, in the opinion of the investigator, 
might place a subject at unacceptable risk for participation in the study. 
5) Prohibited Treatments and/or Therapies 
a. Subjects who have at any time received treatment with any investigational drug 
within 28 days (or less than 5 terminal half-lives of elimination) of the Day 1 
dose. 
b. Any concomitant biologic DMARD, such as anakinra.  
c. Subjects who have been treated with intralesional steroids, systemic steroids, 
anthralin, squaric acid, DPCP (diphenylcycloprophenone), protopic, minoxidil or 
other medication which in the opinion of the investigator may affect hair regrowth 
within one month of the baseline visit.  
6) Other Exclusion Criteria 
a. Prisoners or subjects who are involuntarily incarcerated. 
b. Subjects who are compulsorily detained for treatment of either a psychiatric or 
physical (e.g, infectious disease) illness. 
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
subjects and to ensure that the results of the study can be used. It is imperative that subjects fully 
meet all eligibility criteria. 
 
4.2.3 
Women of Childbearing Potential 
Women of childbearing potential (WOCBP) include any female who has experienced menarche 
and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, 
or bilateral oophorectomy), and who is not postmenopausal. Post menopause is defined as:  
 Amenorrhea ≥ 12 consecutive months without another cause, and a documented serum 
follicle stimulating hormone (FSH) level > 35 mIU/mL or  
 Women with irregular menstrual periods and a documented serum follicle stimulating 
hormone 
(FSH) 
level 
> 
35 
mIU/mL 
or 
NOTE: FSH level testing is not required for women  62 years old with amenorrhea of  1 
year 
 Women on hormone replacement therapy (HRT) 


 
 
 
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Women who are using oral or other hormonal contraceptives, such as vaginal products, skin 
patches, or implanted or injectable products, or mechanical products, such as an intrauterine device 
or barrier methods (diaphragm, condoms, spermicides), to prevent pregnancy or who are practicing 
abstinence or who have a sterile (e.g., vasectomy) partner should be considered to be of 
childbearing potential. 
Not Applicable. 
4.3 
Concomitant Treatments 
4.3.1 
Prohibited and/or Restricted Treatments 
Any medication known to affect hair growth in Alopecia areata including but not limited to topical, 
intralesional 
or 
systemic 
steroids, 
squaric 
acid, 
anthralin, 
protopic, 
minoxidil, 
diphenylcyclopropenone, cyclosporine and any other medications, which in the judgment of the 
investigator, may affect hair growth in patients with alopecia areata. 
 
4.3.2 
Other Restrictions and Precautions 
Not applicable. 
4.4 
Discontinuation of Subjects from Treatment 
Subjects MUST discontinue study treatment and withdraw from the study for any of the following 
reasons: 
Withdrawal of informed consent (subject’s decision to withdraw for any reason) 
Any clinical adverse event (AE), laboratory abnormality, or intercurrent illness which, in the 
opinion of the investigator, indicates that continued participation in the study is not in the best 
interest of the subject 
Pregnancy 
 Instruct WOCBP to contact the investigator or study staff immediately if they suspect 
they might be pregnant (eg, missed or late menstrual period) at any time during study 
participation. Institutional policy and local regulations should determine the frequency 
of on-study pregnancy tests for WOCBP enrolled in the study. 
 The investigator must immediately notify BMS if a study subject becomes pregnant. The 
mechanism for reporting pregnancy is described in Section 7.6. 
Termination of the study by BMS. 
Loss of ability to freely provide consent through imprisonment or involuntarily incarceration for 
treatment of either a psychiatric or physical (eg, infectious disease) illness. 
 


 
 
 
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41
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 being tested or used as a 
reference in a clinical study, including products already with a marketing authorization but used 
or assembled (formulated or packaged) in a way different from the authorized form, or used for an 
unauthorized indication, or when used to gain further information about the authorized form. In 
this protocol, the investigational product is abatacept. 
Other medications used in the study as support or escape medication for preventative, diagnostic, 
or therapeutic reasons as components of a given standard of care are considered noninvestigational 
products.  
5.1.1 
Identification 
Abatacept Injection, 125 mg/Syringe (125 mg/mL), is a sterile solution for SC administration, 
which contains approximately 126 mg abatacept, 171 mg sucrose, 8 mg Poloxamer 188, 0.28 mg 
monobasic sodium phosphate, monohydrate, and 0.84 mg dibasic sodium phosphate, anhydrous, 
in Water for Injection. It is packaged in 1 mL long glass syringe barrel staked with a 29 gauge 
stainless steel needle and stoppered with a 7.1 mm rubber stopper. The composition of this solution 
has a ratio of monobasic sodium phosphate, monohydrate, and dibasic sodium phosphate, 
anhydrous, used to achieve the target pH of 7.2. 
 
5.1.2 
Storage, Handling, and Dispensing 
The 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 


 
 
 
Abatacept in alopecia areata 
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42
be inspected visually for particulate matter prior to administration. Refer to the Investigator 
Brochure for additional information regarding handling, preparation, and storage of abatacept.  
 
5.1.3 
Additional Information for the Handling, Dispensing, and Storage of Abatacept 
Abatacept injection, 125 mg/syringe (125 mg/mL) for SC administration are ready to use solutions 
provided in pre-filled siliconized syringes with a 29 gauge needle. No special drug preparation is 
required prior to administering to patients. A sufficient amount of abatacept solution is 
incorporated into each syringe so that 1 ml of solution will be administered upon administration. 
Abatacept SC formulations (prefilled syringes) should be stored under refrigeration 
(approximately 2 to 8C) and protected from long-term (more than 24 hours) exposure to light. Do 
not freeze. 
Additional information on the use of the abatacept combination product is found in the Appendix. 
5.2 
Method of Assigning Subjects to a Treatment 
This will be an open label study. All subjects will receive active drug for the duration of the 6 
month treatment period. 
 
5.3 
Selection and Timing of Dose for Each Subject 
Patients will be treated with abatacept 125mg SC self-administered each week. Treatment will be 
continued for 6 months to provide adequate time to assess the short-term efficacy and safety of 
abatacept in patients with alopecia areata.  Patients will then be followed for an additional 6 months 
to assess the timing and incidence of relapse. 
5.3.1 
Dose Modifications for Adverse Events 
If there is evidence of toxicity, as determined by laboratory tests or by clinical assessment that 
could place the subject at increased risk in the judgment of the investigator, administration of 
abatacept should be interrupted and the investigator should notify BMS. Subjects may be 
considered eligible to continue with abatacept treatment only if full resolution of the adverse event 
is documented. If the adverse event completely resolves and the next dose of abatacept cannot be 
administered within 14 days of the target date, then that scheduled dose should be skipped. The 
next dose of abatacept should then be administered on the next targeted day for administration. 
5.4 
Blinding/Unblinding 
Not applicable. 


 
 
 
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43
5.5 
Concomitant Treatments 
5.5.1 
Prohibited and/or Restricted Treatments 
The following medications are prohibited throughout the complete study period: 
Any medications known to affect hair growth in alopecia areata including but not limited to topical, 
intralesional or systemic steroids, anthralin, squaric acid, diphenylcyclopropenone, protopic, 
cyclosporine or any other medications which in the opinion of the investigator may affect hair 
growth in AA. 
Live vaccines. 
Use of any investigational drug other than study medication. 
Corticosteroid use at unstable dose and/or superior to the equivalent of prednisone 10 mg/day is 
not permitted. 
5.5.2 
Other Restrictions and Precautions 
5.5.2.1 
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 than 2 weeks). 
In view of the long half-life of abatacept, study subjects should not be administered a live virus 
vaccine for a minimum of 3 months following the last dose of abatacept. 
5.6 
Treatment Compliance 
Compliance will be documented via the use of patient diaries to record the date and time of self-
administration of medication at home.  Study drug reconciliation will be performed at each visit 
during the treatment period. 
 


 
 
 
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44
6 
STUDY ASSESSMENTS AND PROCEDURES 
6.1 
Time and Events Schedule 
The Time and Events Schedule (Section 6, Table 3) summarizes the frequency and timing of 
various measurements. 
 
Pre-screening procedures 
Written informed consent will be obtained for this study by the principal investigator or his/her 
designee from all patients prior to any protocol-specific procedures. The study will be conducted 
in accordance with the Food and Drug Administration (FDA) approved revision of the Declaration 
of Helsinki, current FDA regulations, and International Conference on Harmonization (ICH) 
guidelines.  
 
Procedures Performed Prior to Treatment Screening (Day -28 to -1):  
The following screening evaluations will be performed within 4 weeks prior to enrollment: 
 Informed consent, inclusion/exclusion criteria, prior concomitant medications 
 Medical history, physical examination, including a dermatological exam 
 Vital signs, body weight 
 Assessments of disease severity will be conducted including SALT (Severity of Alopecia 
Tool) 
 Physician’s global assessment (PGA) 
 Clinical laboratory evaluation (complete blood count, basic metabolic profile, hepatic 
panel and urinalysis), hepatitis B and C screening panel, HIV test, lipid profile, serum 
pregnancy test 
 Tuberculosis testing (PPD skin test or quantiferon test) 
 Chest X ray 
 
A visit will be scheduled 48-72 hours after placement of the PPD for reading of the test results.  If 
possible, this visit will be combined with the baseline visit. The results of all assessments/tests 
listed above must be reviewed prior to enrollment to ensure that the patient meets entry criteria 
and that no exclusion criteria are present. 
 
 Baseline (Day 0) Procedures Performed Prior to treatment 
 Review of inclusion/exclusion criteria 
 Vital signs, body weight 
 Adverse events reporting, concomitant medication review 
 Photography 
 Physician evaluation utilizing the PGA and SALT scale 
 Patient global assessment and quality of life assessment 
 Urine pregnancy testing for WOCBP 


 
 
 
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45
 Blood collection for immunological studies including assessment of presence or absence 
of AA GWAS risk haplotype 
 Scalp biopsy (4mm punch biopsy) 
 Training of subject in Subcutaneous administration of medication followed by observed 
patient self-administration of medication 
 
Weeks 4, 8, and 12 (Days 28, 56 and 84) 
Visit days will have an acceptable window of ±3 day. 
 Vital signs, body weight 
 Adverse events reporting, concomitant medication review 
 Photography 
 Physician evaluation utilizing the PGA and SALT scale 
 Patient global assessment and quality of life assessment (week 12 only) 
 Urine pregnancy testing for WOCBP 
 Physical and dermatological examination (week 12 only) 
 Clinical laboratory evaluation (only weeks 4 and 12) 
 Scalp biopsy (4mm punch biopsy) (only weeks 4 and 12) 
 Blood collection for immunological studies (only weeks 4 and 12) 
 Optional Scalp biopsy (4mm punch biopsy) in addition to weeks 4 and 12 – at the 
discretion of the investigator and with the consent of the subject, based upon perceived 
utility in context of individual patient response to therapy and durability of that response.  
 Optional Blood collection for immunological studies in addition to weeks 4 and 12, at the 
discretion of the investigator and with the consent of the subject.   
 Training/reinforcement of training for self-administered SQ injection 
 Patient observed self-administering study medication 
 
Week 18 (Day 126±1) 
 Vital signs, body weight 
 Adverse events reporting, concomitant medication review 
 Photography 
 Physician evaluation utilizing the PGA and SALT scale 
 Urine pregnancy testing for WOCBP 
 Optional Scalp biopsy (4mm punch biopsy)  - at the discretion of the principal 
investigator and with the consent of the subject, based upon perceived utility in context of 
individual patient response to therapy. 
 Optional Blood collection for immunological studies, at the discretion of the principal 
investigator and with the consent of the subject.   
 Training/reinforcement of training for self-administered SQ injection 
 Patient observed self-administering study medication 
 
Week 24 (Day 168±7) – End of Treatment  


 
 
 
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46
 Vital signs, body weight 
 Physical and dermatological examination 
 Adverse events reporting, concomitant medication review 
 Photography 
 Physician evaluation utilizing the PGA and SALT scale 
 Patient global assessment and quality of life assessment 
 Urine pregnancy testing for WOCBP  
 Clinical laboratory evaluation 
 Scalp biopsy (4mm punch biopsy) 
 Blood collection for immunological studies  
 
 Weeks 36 and 48 (Days 252 and 336 ±7 days) – Observational Period 
 Vital signs, body weight 
 Physical and dermatological examination (only week 48) 
 Adverse events reporting, concomitant medication review 
 Photography 
 Physician evaluation utilizing the PGA and SALT scale 
 Patient global assessment and quality of life assessment 
 Optional Scalp biopsy (4mm punch biopsy) – at the discretion of the principal 
investigator and with the consent of the subject, based upon perceived utility in context of 
individual patient response to therapy and durability of that response.  
 Optional Blood collection for immunological studies, at the discretion of the principal 
investigator and with the consent of the subject.   
 
Weeks 30, 36, 42, 48 (Extension Option) 
Visit days will have an acceptable window of ±7 days. 
 Vital signs, body weight 
 Adverse events reporting, concomitant medication review 
 Photography 
 Physician evaluation utilizing the PGA and SALT scale 
 Patient global assessment and quality of life assessment 
 Urine pregnancy testing for WOCBP 
 Physical and dermatological examination (week 36) 
 Clinical laboratory evaluation, if indicated (at 12 weeks after end of study treatment) 
 Optional Scalp biopsy (4mm punch biopsy) – at the discretion of the investigator and 
with the consent of the subject, based upon perceived utility in context of individual 
patient response to therapy and durability of that response.  
 Optional Blood collection for immunological studies in addition to weeks 4 and 12, at the 
discretion of the investigator and with the consent of the subject.   
 
 


 
 
 
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47
Weeks 40 to 72 (Observational Period after Extension Option) 
Visit days will have an acceptable window of ±7 days. 
 Patient will be observed at 12 and 24 weeks after completing study medication  
 Vital signs, body weight 
 Physical and dermatological examination (at end of study) 
 Adverse events reporting, concomitant medication review 
 Photography 
 Physician evaluation utilizing the PGA and SALT scale 
 Patient global assessment and quality of life assessment 
 Optional Scalp biopsy (4mm punch biopsy) – at the discretion of the principal 
investigator and with the consent of the subject, based upon perceived utility in context of 
individual patient response to therapy and durability of that response.  
 Optional Blood collection for immunological studies, at the discretion of the principal 
investigator and with the consent of the subject.   
 
 
Early Termination 
 Vital signs, body weight 
 Physical and dermatological examination 
 Adverse events reporting, concomitant medication review 
 Photography 
 Physician evaluation utilizing the PGA and SALT scale 
 Patient global assessment and quality of life assessment 
 Clinical laboratory evaluation 
 Optional Scalp biopsy (4mm punch biopsy)  - at the discretion of the principal 
investigator and with the consent of the subject, based upon perceived utility in context of 
individual patient response to therapy. 
 Optional Blood collection for immunological studies, at the discretion of the principal 
investigator and with the consent of the subject.   
 The reason for early withdrawal/study drug discontinuation must be documented 
 
Unscheduled Visits 
An unscheduled visit can occur at any time during the study.  A source document must be 
maintained for these unscheduled visits. The date for the visit and any data generated must be 
recorded on the appropriate CRF. At treatment discontinuation/early termination subjects will 
undergo study evaluations per the Schedule of Assessments.  
 
Duration of Treatment 
Treatment will be continued for 6 months to provide adequate time to assess the short-term efficacy 
and safety of abatacept in patients with alopecia areata. Patients will then be followed for an 
additional 6 months to assess the timing and incidence of relapse of AA.   
 


 
 
 
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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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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Table 3: Schedule of Assessments 
Visit 
Screening 
PPD 
reading 
Base-
line 
 
Week 
4 
Week 
8 
Week 
12 
Week 
18 
Week 
24/ET 
Week 
30, 36, 
42, 48 
(optional) 
12 
Weeks 
after 
end tx 
24 
Weeks 
after 
end tx 
Day 
-28 to -1 
 
0 
28±1 
56±1 
84±1 
126±1 
168±7 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
 
X 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
Body Weight 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical/Cutaneous 
Exam 
X 
 
 
 
 
X 
 
X 
 
 
X 
Vital Signs 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
Medications 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Photography 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SALT evaluation 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physician global 
assessment 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Patient quality of life 
assessment 
 
 
X 
 
 
X 
 
X 
X 
X 
X 
Patient global 
assessment 
 
 
X 
 
 
X 
 
X 
X 
X 
X 
Clinical laboratory 
evaluation* 
X 
 
 
X 
 
X 
 
X 
X 
 
 
Hepatitis screening 
panel, HIV test 
X 
 
 
 
 
 
 
 
 
 
 
Lipid Profile 
X 
 
 
 
 
 
 
 
 
 
 
PPD test and reading 
X 
X 
 
 
 
 
 
 
 
 
 
Serum pregnancy test 
X 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Scalp Biopsy 
 
 
X 
X 
(X)c 
X 
(X)c 
X 
(X)c 
(X)c 
(X)c 
Phlebotomy for 
immunological studies 
 
 
Xd 
X 
(X)c 
X 
(X)c 
X 
(X)c 
(X)c 
(X)c 
Training/reinforcement 
of training for self-
administered 
SQ 
injection 
Patient observed self-
administering 
study 
medication 
 
 
 
Xb 
X 
X 
X 
X 
X 
X 
 
 
Chest X ray-1 view 
X 
 
 
 
 
 
 
 
 
 
 


 
 
 
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aClinical laboratory evaluation consists of CBC, BMP, hepatic panel, and urinalysis.  Additional 
evaluations will only be performed if needed to verify normalization of previously abnormal lab 
values.  
bBaseline dose will be subcutaneous administration of abatacept. 
c Optional additional Scalp biopsies (4mm punch biopsy) may be performed at the discretion of 
the investigator and with the consent of the subject, based upon perceived utility in context of 
individual patient response to therapy and durability of that response.  Optional Blood collection 
for immunological may be performed at the discretion of the investigator and with the consent of 
the subject.   
d Includes testing for AA GWAS risk haplotype 
 
6.2 
Study Materials 
Bristol-Myers Squibb (BMS) will provide abatacept and laboratory testing at no cost for this study. 
6.3 
Safety Assessments 
Analysis of safety is included as a secondary endpoint.  All subjects who receive a dose of 
abatacept will be evaluated for safety. Safety outcomes include adverse events, clinically 
significant changes in vital signs, laboratory test abnormalities, and clinical tolerability of the drug. 
The investigator will determine the severity of each adverse event as mild, moderate, severe, or 
very severe. Laboratory findings that the investigator feels are clinically relevant should be 
recorded as adverse events. In addition, the investigator will determine the relationship of the 
adverse event to the administration of the study drug. Any occurrence of a SAE from time of 
consent forward, up to and including follow-up visits will be reported. See Section 6.5 for the SAE 
reporting procedures. 
 
6.3.1 
Physical Examinations 
During the treatment period, the physical examination is to be performed before administration of 
abatacept. While the interim physical examination may not be as comprehensive as the complete 
physical examination, important body systems should be included as deemed clinically indicated 
by the investigator. These body systems may include lymph nodes, liver, spleen, and breast. An 
interim physical examination may note any changes in the subject’s condition since the last 
assessment and does not preclude examination of any of the body systems as clinically indicated. 
6.3.2 
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 


 
 
 
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51
vaccinations(viii,ix),or who have a prior positive test). Tuberculin skin testing is not contraindicated 
for persons who have been vaccinated with BCG. 
QuantiFERON® testing is an acceptable alternative when tuberculin skin testing is not 
appropriate. A tuberculin skin test is not required if one was performed within 6 months of 
screening and documentation of testing is on file. If tuberculin skin testing is performed at 
screening, then the 72-hour reading must be completed before administration of abatacept. 
6.4 
Efficacy Assessments 
6.4.1 
Primary Efficacy Assessment 
The study’s primary efficacy endpoint will be the proportion of responders after 6 months of 
treatment, with response defined as 50% or greater hair re-growth from baseline as assessed by 
SALT score (Figure 6) at week 24. Treatment may be extended by up to an additional 6 months 
beyond the initial 6 months of treatment if clinically indicated at the discretion of the investigator. 
 
This is a relatively strict definition for defining responders and non-responders and was chosen 
to minimize the potential for spontaneous remission, in which fewer than 10% are expected to 
achieve this magnitude of hair regrowth spontaneously. 


 
 
 
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SALT – Severity of Alopecia Tool 
A. The proportion of scalp involvement is determined by 
dividing the scalp into 4 quadrants and estimating the 
percentage of the scalp surface that all the alopecic areas would 
occupy if placed together. The following groups will be used: 
 
S: Scalp hair loss 
 
_____S0 = No hair loss  
    _____S4 = 76%-99% hair loss 
_____S1 = <25% hair loss 
    _____a = 76%-95% hair loss 
_____S2 = 26%-50% hair loss   _____b = 96%-99% hair loss 
_____S3 = 51%-75% hair loss   _____S5 = 100% hair loss 
 
Body hair loss 
B0 = No body hair loss 
B1 = some body hair loss 
B2 = total (100%) body hair loss 
 
Nail involvement 
N0 = No nail involvement 
N1 = some nail dystrophy 
N1a = 20 nail dystrophy 
 
Percentage change from baseline (% 
regrowth) =  
[(SALT BL – SALT F/U)/ SALT 
BL]  x 100% = % change from 
baseline 
Absolute regrowth = SALT BL – 
SALT F/U = absolute change from 
BL 
6.4.2 
Secondary Efficacy 
Assessments 
As secondary endpoints, efficacy will be measured by changes 
in hair re-growth as a continuous variable as determined by 
physical exam and Canfield photography, as well as patient 
and physician global evaluation scores. To assess the durability of responses, patients will 
continue to be followed for an additional 6 months off treatment. To assess the durability of 
response and the incidence of relapse, patients who achieve 50% regrowth from baseline (50% 
reduction in baseline SALT score) will continue to be followed for an additional 6 months off 
treatment or until it is determined that relapse has occurred.  Relapse will be defined as any 
Figure 6. SALT score. The 
percentage of hair loss in any 
one of the four views (areas) of 
the scalp = the percentage hair 
loss x percent surface area of 
the scalp in that area. The 
SALT score then equals the 
sum of the scalp hair loss in 
each area. 
(a) Top (left side view) = 95% x 
.18 = 17.1 
(b) Second (right side view) = 
90% x .18 = 16.2 
(c) Third (top of scalp) = 95% x 
.40 = 38 (realizing that most of 
hair loss is probably male 
pattern hair loss) 


 
 
 
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53
recurrence of hair loss in responders (subjects achieving greater than 50% decrease in SALT 
score from baseline during the first 6 mths of the study) who had achieved stable regrowth 
without continued loss for at least 2 mths; and loss of >/= 25% of regrowth in patients who had 
achieved 50% regrowth during treatment but still had chronic low grade hair loss. Nonresponders 
to 6 months study treatment (defined as failure to achieve 50% improvement in SALT score 
compared to baseline) will not be required to participate in the 6mth follow-up period.. Partial 
responders will continue to be followed to assess for delayed achievement of complete response. 
Analysis of safety is included as a secondary endpoint.  All subjects who receive a dose of 
abatacept will be evaluated for safety. 
Secondary efficacy outcomes in detail 
1. Percent hair regrowth from baseline determined by SALT measurements following 12, 24 
weeks of treatment and during the observational phase at weeks 36 and 48.   
2. Comparison of the proportion of responders in the experimental group with the 
historically known placebo response rate (<10%), with response defined as 50% change 
in SALT score (50% regrowth) from baseline, at weeks 12, 36 and 48. 
3. Comparison of the proportion of subjects in the experimental group and the proportion of 
subjects in the historical control group attaining global overall improvement SALT score 
of A5 (100% coverage) supported by </= SALT 25 at weeks 12, 24, 36 and 48.  
4. Change in PGA (Physician Global Assessment) based on evaluation of live evaluations 
and standardized photographs between baseline, week 12, 24, 36 and 48. 
5. Change in patient global assessment between baseline, Week 12, 24, 36 and 48. 
6. Change in patient quality of life assessment from baseline to weeks 12, 24, 36 and 48. 
7. Frequency of occurrence and timing of relapse (as defined above) in responders followed 
for 6 months off therapy.  
8. Safety will be evaluated as a secondary endpoint using descriptive statistics to summarize 
the cumulative incidence and types of AEs.  
9. The proportion of patients who discontinued treatment will be summarized. 
6.4.3 
Other Assessments 
Photography  
Photography will be performed using a high-resolution digital camera with Intelliflash system 
from Canfield Scientific, Inc., mounted on a stereotactic arm.  Patients will be positioned using a 
fixed guide, after which photographs of the entire scalp will be taken at standardized locations and 
at a fixed distance.  Close-up photographs may also be taken using an epiluminescent attachment 
in order to assess for the presence of early regrowth.  
 
Biopsy 


 
 
 
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All punch biopsies will be performed by the study 
doctor at a specific location and time point according 
to the schedule of study assessments. The biopsy site 
will be anesthetized with an injection of 1% lidocaine 
with epinephrine. After approximately 1 minute, the 
physician applies pressure to the biopsy site using a 4 
mm skin punch (a sterile cylindrical tube with a sharp 
edge).  The punch is twisted until the blade of the skin 
punch has pierced the epidermis and dermis of the skin 
and enters the subcutaneous fat. Depending on the 
thickness of the skin in the area being biopsied, the 
cylindrical blade may be buried to the hub 
(approximately 6mm).  After the blade has sufficiently 
cored or carved out a cylinder of skin, the skin punch is removed.  Nontraumatic forceps are used 
to gently grasp the cored skin, pulling upward to remove the core and reveal the subcutaneous fat. 
Scissors are used to cut the cored tissue free from the underlying subcutaneous fat.  The specimen 
is placed immediately into the appropriate media. Once the specimen has been removed, pressure 
is applied to the biopsy site with a sterile 2 x 2 gauze. The biopsy site is then closed with several 
simple interrupted sutures. Either an absorbable or nonabsorbable suture may be used at the 
investigators discretion.  Antibiotic ointment is applied and the area is covered with a standard 
BandAid or sterile gauze and paper tape. When necessary, a small pressure dressing may be 
applied.  Subjects will be instructed in wound care and will be advised to call the research unit if 
they have any concerning signs or symptoms during healing. 
 
Biosamples 
 
A recent histological/gene expression study of synovial biopsies from RA patients treated with 
abatacept noted only mild changes in cellular synovial infiltrates during treatment. However, 
marked changes in IFN-γ expression was identified, with significant reductions only seen in the 
clinically responding patients (Buch et al. 2009). The decrease in IFN-γ production in the 
responders implies that functional inhibition of T cell activity is important for therapeutic outcome. 
Our proposed studies will include longitudinal biopsies that could provide additional support for 
interferon-γ modulation and abatacept treatment outcome. 
 
Our procurement of serial biopsies, sera and PBMCs obtained at baseline and during treatment 
will provide the opportunity to correlate resolution of inflammatory biomarkers with treatment 
response in AA. 
 
Biosamples will be obtained upon entry and again after 4 weeks, 12 weeks and 24 weeks of 
treatment and optional blood collection timepoints. Biospecimens at each time point will include: 
1) a 4 mm skin biopsy; 2) 5 ml of blood for serum; 3) 60 ml of blood for PBMCs.  


 
 
 
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Blood volumes for research: 60 ml of blood is required to insure that sufficient viable cells are 
available after thawing of cryopreserved PBMC aliquots to enable functional T cell studies in 
triplicate. Our experience is that viable recovery of PBMC in freeze-thawed specimens is highly 
variable and range from 0.1-1.0 x 106 per ml of blood. Our blood volume obtained for research 
is 65 ml at one time, a maximum of 130 ml in a 4 week period and 260 ml in total over 6 months. 
 
Biomarker Assessment and Clinical Correlative Studies 
 
Our mechanistic studies are focused on correlating treatment and disease status with;  
1) histological improvement of T cell infiltrates;  
2) reduced IFN responses in the skin and blood;  
3) reduced HF NKG2DL expression; and  
4) declines in circulating and peribulbar CD4+ and CD8+NKG2D+ infiltration.  
5) AA GWAS risk haplotype susceptibility 
 
Previous studies in AA have reported elevated NKG2D expression in circulating CD8 T cells and 
NK cells (Ito et al. 2008), supporting the feasibility of our approach. Here we will be able to 
correlate the numbers of CD8+NKG2D+ cells in the blood with those infiltrating the target organ 
of patients with each other and as a function of disease status. The limited studies proposed here 
seeking an association of IFN-cells in
+NKG2D+ positive cells and clinical outcome will not, 
however, exhaust the “biobank” and all human materials [frozen biopsy tissue & RNA, serum and 
the remaining (90%) of PBMCs] will remain banked and available for future hypothesis driven 
questions.  
 
Flow Cytometry Studies. The presence of CD8+NKG2D+ cells will be tracked in the blood and in 
the skin during treatment with Abatacept. By assessing CD8+NKG2D+ involvement in 
longitudinally obtained skin biopsies at baseline and during treatment we can correlate disease 
severity and clinical response (progression or regression) with immunopathological evidence of 
resolution of total cellular infiltration (by H&E) or loss of specific CD8+NKG2D+ cells in the skin 
(by IF) or in the blood (flow studies).  CD8+NKG2D+ frequency in the peripheral circulation will 
be quantified using freshly isolated PBMCs obtained from 30 mls of blood obtained upon 
scheduled and optional blood collection timepoints. A portion of the PBMCs 2x106 cells will be 
stained with anti-CD4, anti-CD8, anti-CD25, anti-CD28 and anti-NKG2D antibodies, stimulated 
with PMA/ionomycin in the presence of brefeldin and stained with anti-FOXP3 and anti-IFN-γ 
Abs. The remaining PBMCs will be used for RNA analysis (see below) and viably frozen for future 
ancillary studies. We will seek evidence of a comparable pathogenic T cell subset in the human 
that we observed in C3H mice, namely an activate CD25+ IFN-γ-producing CD8+NKG2D+ T cell. 
 
Histology and Immunofluorescence Analysis. As shown in previous studies (Ito et al. 2008; 
Petukhova et al. 2010) in active AA NKG2D ligands are upregulated on hair follicles in association 
with peribulbar NKG2D-bearing CD8+ T-cells and natural killer cells. We will seek evidence of 
resolution of total cellular infiltration (by H & E) and loss of specific CD8+NKG2D+ cells (by IF) 
and NKG2D ligands by comparing baseline biopsies with biopsies obtained on treatment after 4, 


 
 
 
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12, 24 and 36 weeks.  Frozen sections will be stained with and anti-CD4, anti-CD8, anti-CD56, 
anti-NKG2D and anti-IFN-g antibodies to visualize the total number of leukocytes, cytotoxic T-
cells and NK cells present in the baseline and drug treated skin, respectively. Immunostaining with 
anti-ULBP3, anti-MICA antibodies and recombinant NKG2D soluble receptor (NKG2D-Ig, 
detects all NKG2D ligands, R & D systems) will determine whether NKG2DL “danger/stress” 
signals are down modulated. 
Punch biopsies from patient skin before and after treatment will be embedded in OCT and 7-8 
micron frozen sections will be cut. The sections will be fixed in 4% paraformaldehyde and stained 
overnight with primary antibodies for NKG2D ligands, receptor and immune markers. The 
following day, sections will be treated for 1 hr with fluorescence labeled antibody, counter-stained 
and mounted with DAPI containing media. Frozen sections will also be used to for H&E staining. 
The total number of immune cells, as well as NKG2D bearing cells, will be quantified by counting 
stained cells per magnification field using the NIH imaging software ImageJ and a student T-test 
will be carried out to determine significant changes in the number of infiltrating, NKG2D bearing 
immune cells to quantitatively correlate the simultaneous presence or absence of these cells in 
lesional skin and in circulation (by flow) during active disease or in remission.   
 
Haplotype Analysis for CTLA4 Modulation with Abatacept Therapy 
The costimulatory pathway has demonstrated perturbations in a number of autoimmune 
diseases.  We and others have identified haplotypes at the Costimulatory locus that confer risk 
for autoimmunity and alopecia areata, in particular 1,2. We hypothesize that variants carried on 
these haplotypes perturb the costimulatory axis and patients carrying such risk variants in 
particular will receive benefit from therapies specifically targeted to this pathway. Long range 
haplotype analysis using a small set of common SNPs across the costimulatory locus revealed 
two predominating haplotypes in European populations, termed 15-2-4 and 5-1-4 that are 
associated with autoimmune protection or risk respectively. We will analyze for the presence of 
haplotype susceptibility for each enrolled subject at baseline. We will utilize these results to 
explore whether treatment response with abatacept for AA is affected by haplotype 
susceptibility. 
Analysis of Gene Expression by Quantitative RT-PCR  
We will analyze the transcriptional expression signature of costimulatory and IFN-response 
genes in the skin and PMBC of drug-treated AA patients using qPCR as an indirect measure 
of the efficacy of Abatacept. Signature genes were selected based on their differential expression 
in affected vs. unaffected C3H mice (Carroll et al. 2002), and on published studies on human AA 
patients vs. controls (Subramanya et al. 2010) The genes in the list represent mediators and 
effectors of the IFN response, which we found to be instrumental in disease pathology. Briefly, 
biopsies and peripheral blood from baseline and Abatacept treated patients will be collected at 0, 
4, 12 and 24 week time points. RNA will be extracted from the tissues, and Sybr green-based 
qPCR assays will be performed. Differential gene expression resulting from inhibitor treatment 
will be normalized to the expression of a housekeeping gene. We expect many of the genes on this 
list to revert to a basal level of expression, as compared in unaffected skin of an AA patient, or 
skin from a healthy control.  


 
 
 
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Serum inflammatory biomarkers 
Serum will be obtained at baseline and during treatment and assessed for resolution of elevated 
levels of IFN-inducible chemokines.   
 
6.5 
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. 
6.5.1 
Serious Adverse Events 
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose:  
1) 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; 
2) it does not refer to an event which hypothetically might have caused death if it were more 
severe) 
3) requires inpatient hospitalization or causes prolongation of existing hospitalization (see 
note below for exceptions)  
4) results in persistent or significant disability/incapacity is a congenital anomaly/birth 
defect is an important medical event (defined as a medical event(s) that may not be 
immediately life-threatening or result in death or hospitalization but, based upon 
appropriate medical and scientific judgment, may jeopardize the subject or may require 
intervention [eg, medical, surgical] to prevent one of the other serious outcomes listed in 
the definition above.)  
Examples of such events include, but are not limited to, intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions 
that do not result in hospitalization.) Potential drug induced liver injury (DILI) is also 
considered an important medical event.  (See Section 6.6 for the definition of potential 
DILI.) 
Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the study drug 
is an SAE. 
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. 


 
 
 
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Although pregnancy, overdose, cancer, and potential drug induced liver injury (DILI) are not 
always serious by regulatory definition, these events must be handled as SAEs and should also be 
reported to BMS in an expedited manner, as described in Section 7.2. 
NOTE: The following hospitalizations are not considered SAEs in BMS clinical studies: 
1) 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)  
2) 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)  
3)medical/surgical admission for purpose other than remedying ill health state that was planned 
before study entry. Appropriate documentation is required in these cases. 
4) 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). 
 
6.5.2 
Nonserious Adverse Events 
Nonserious adverse events are all adverse events that are not classified as SAEs. 
 
6.6 
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. 


 
 
 
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6.7 
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. 
 
6.7.1 
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 


 
 
 
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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/ 
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. 
 
6.7.2 
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 


 
 
 
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Suspected Unexpected Serious Adverse Reaction (SUSAR). BMS will send investigators an 
expedited safety report (ESR) to notify them of such an event. 
Other important findings that BMS may report as ESRs include increased frequency of a clinically 
significant expected SAE, an SAE considered associated with study procedures that could modify 
the conduct of the study, lack of efficacy that poses significant hazard to study subjects, clinically 
significant safety findings from a nonclinical (eg, animal) study, important safety 
recommendations 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). 
 
6.7.3 
Nonserious Adverse Events 
The investigator will begin collecting nonserious adverse event (NSAE) information once 
administration of the investigational product is initiated.  
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. 
6.8 
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. 
6.9 
Overdose 
An overdose is defined as the accidental or intentional ingestion or infusion of any dose of a 
product that is considered both excessive and medically important. All occurrences of overdose 
must be reported as an SAE. 


 
 
 
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6.10 
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.  
 
6.10.1 
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. 
6.10.2 
Reporting of Pregnancy 
If, following initiation of the investigational product, it is subsequently discovered that a study 
subject is pregnant or may have been pregnant at the time of investigational product exposure, 
including during at least 6 half-lives after administration, the investigational product will be 
permanently discontinued in an appropriate manner (eg, dose tapering if necessary for subject 
safety). The investigator must immediately notify BMS of this event and record the pregnancy on 
the Pregnancy Surveillance Form (not on an SAE form). Initial information on a pregnancy must 
be reported immediately to BMS, and information on the outcome provided once it is available. 
Completed Pregnancy Surveillance Forms must be forwarded to BMS according to SAE reporting 
procedures.  
Note: Any pregnancy that occurs in a female partner of a male study subject must be reported to 
BMS using the Pregnancy Surveillance Form. 


 
 
 
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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.  
 
6.11 
Other Safety Considerations 
Any 
significant 
worsening 
noted 
during 
interim 
or 
final 
physical 
examinations, 
electrocardiograms, x-rays, and any other potential safety assessments, whether or not these 
procedures are required by the protocol, should also be recorded in the medical record. 
7 
STATISTICAL CONSIDERATIONS 
7.1 
Sample Size Determination 
Based on two recently completed randomized trials (Price et al, 2008; Strober et al, 2009) in 
similar patient populations (moderate to severe AA) we expect placebo response rates to be 
between 6% (>50% improvement in SALT score) and 12% (>25% improvement). We have 
chosen our primary endpoint conservatively (proportion of patients with >50% improvement in 
SALT index) as a relatively strict criteria that should minimize spontaneous remission rates to 
10% or less (0-2 of 15 subjects). This allows a higher degree of confidence that appreciable 
response rates are attributable to drug rather than spontaneous remission.  
Assuming a historically known placebo response rate of 10% and the usual 5% level of 
significance (alpha), the sample size of 15 would provide 80.7% power to detect a difference of 
30% in the response rate between the experimental treatment group and the historical placebo 
group. 
7.2 
Populations for Analyses 
The Dermatology clinic and private practice at CUMC currently sees 600 AA patients yearly, of 
which we anticipate 20-30% would be eligible (>30% hair loss). Accrual will be greatly 
facilitated by targeted recruitment through our existing NAAF registry, which includes 400 AA 
patients in the New York area, the majority of which have patchy type disease. Thus, complete 
accrual of 15 subjects should be feasible within 1 year from a pool of >100 eligible subjects 
yearly. 
7.3 
Endpoint Definitions 
1. Proportion of patients with >50% improvement in SALT index at 24 weeks  


 
 
 
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64
2. Percent hair regrowth from baseline determined by SALT measurements following 12, 24 
weeks of treatment and at weeks 36 and 48 following discontinuation of treatment.   
3. Comparison of the proportion of responders in the experimental group with the 
historically known placebo response rate (<10%), with response defined as 50% change 
in SALT score (50% regrowth) from baseline, at weeks 12, 36 and 48. 
4. Comparison of the proportion of subjects in the experimental group and the proportion of 
subjects in the historical control group attaining global overall improvement SALT score 
of A5 (100% coverage) supported by </= SALT 25 at weeks 12, 24, 36 and 48.  
5. Change in PGA (Physician Global Assessment) based on evaluation of live evaluations 
and standardized photographs between baseline, week 12, 24, 36 and 48. 
6. Change in patient global assessment between baseline, weeks 12, 24, 36, and 48. 
7. Change in patient quality of life assessment from baseline to weeks 12, 24, 36, and 48. 
8. Frequency of occurrence and timing of relapse (as defined above) in responders followed 
for 6 months off therapy. 
9. To assess safety, we will summarize the incidence of adverse events for the study group. 
7.4 
Analyses 
7.4.1 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will summarized via descriptive statistics. 
7.4.2 
Safety Analyses 
To assess safety, we will summarize the incidence of adverse events for the study group. 
Analysis of safety is included as a secondary endpoint.  All subjects who receive a dose of 
abatacept will be evaluated for safety. Safety outcomes include adverse events, clinically 
significant changes in vital signs, laboratory test abnormalities, and clinical tolerability of the 
drug. The investigator will determine the severity of each adverse event as mild, moderate, 
severe, or very severe. Laboratory findings that the investigator feels are clinically relevant 
should be recorded as adverse events. In addition, the investigator will determine the relationship 
of the adverse event to the administration of the study drug. Any occurrence of a SAE from time 
of consent forward, up to and including follow-up visits will be reported. See Section 6.5 for the 
SAE reporting procedures. 
7.4.3 
Efficacy Analyses 
Since this is a small open label proof of concept study, we recognize that it will likely lack 
adequate power to conclusively demonstrate small efficacy signals (particularly if the assumed 
detectable difference of 30% is not met).  Yet, descriptive summaries of all the primary and 
secondary efficacy outcomes (proportions for binary outcomes, means for continuous outcomes) 


 
 
 
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will provide a preliminary indication of the effect size (even if smaller than 30%) that will aid 
design of subsequent efficacy trials.  
8 
ADMINISTRATIVE SECTION 
8.1 
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 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 (e.g., if it 
contains new information regarding safety), and the revised consent must be used to obtain consent 
from new subjects before enrollment.  
 
8.2 
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 (e.g, 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 


 
 
 
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 amount transferred to another area/site for dispensing or storage 
 non-study disposition (e.g, lost, wasted, broken), and 
 amount destroyed at study site. 
 
8.3 
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. 
 
 
 
 
 
 
 
 
 
 
 
9 
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.  


 
 
 
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Term 
Definition 
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 
(e.g, Investigator Brochure for an unapproved 
investigational product) 
 
 
 
 
 
 
 
 
 
 
 
10 
LIST OF ABBREVIATIONS 
AA 
AB 
Alopecia areata 
Antibody  
ACR 
American College of Rheumatology  
AE 
Adverse event 
ALT 
Alanine Transaminase  
APC 
Antigen-Presenting Cell  
ARA 
American Rheumatology Association  
AST 
Aspartate Transaminase  
BCG 
Bacillus Calmette-Guérin  


 
 
 
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BMS 
Bristol-Myers Squibb  
BUN 
Blood Urea Nitrogen  
CBC 
Complete Blood Count  
CDC-ACID  
Centers for Disease Control and Prevention Advisory 
Committee on Immunization Practices  
CFR 
Code of Federal Regulations  
CI 
Confidence Interval  
CMV 
Cytomegalovirus  
CRF 
Case Report Forms  
CRP 
C-Reactive Protein  
CTLA 
Cytotoxic T-Lymphocyte Associated  
CXR 
Chest X-Ray  
DMARD 
Disease-Modifying Antirheumatic Drug  
DNA 
Deoxyribonucleic Acid  
D5W 
Dextrose (5%) in Water  
EC 
European Commission  
ESR 
Expedited Safety Report  
EULAR 
European League Against Rheumatism  
FDA 
Food and Drug Administration 
FSH 
Follicle-Stimulating Hormone  
GCP 
Good Clinical Practice  
GGT 
Gamma-Glutamyltransferase  
GM-CSF 
Granulocyte Macrophage Colony-Stimulating Factor  
HCG 
Human Chorionic Gonadotropin  
HIV 
Human Immunodeficiency Virus  
HLA 
Histocompatibility Leukocyte Antigen  
HRT 
Hormone Replacement Therapy 
IB 
Investigator Brochure 
ICH 
International Conference on Harmonisation  
IEC 
Independent Ethics Committee  
IL 
Interleukin  
IND 
Investigational New Drug (Application) 


 
 
 
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IRB 
Independent Review Board  
IST 
Investigator-Sponsored Trial 
IU 
International Unit  
IV 
Intravenous  
JRA 
Juvenile Rheumatoid Arthritis  
MHC 
Major Histocompatibility Complex  
MRI 
Magnetic Resonance Imaging  
NPV 
Negative Predictive Value  
NS 
Normal Saline  
NSAE 
Non-Serious Adverse Event 
NSAID 
Non-Steroidal Anti-inflammatory Drug  
OA 
Osteoarthritis  
PCR 
Polymerase Chain Reaction  
PPD 
Purified Protein Derivative  
PPV 
Positive Predictive Value  
PVC 
Polyvinylchloride  
RA 
Rheumatoid Arthritis  
RF 
Rheumatoid Factor  
SAE 
SALT 
Serious Adverse Event  
Severity of alopecia tool 
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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11 
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Footnotes 
(i) Abatacept (BMS-188667) Summary of Clinical Safety, 2005: BMS Document Control No. 
930013008. 
(ii) A study to assess the pharmacokinetics, safety, and immunogenicity of single doses of 
abatacept (BMS-188667) administered subcutaneously to healthy subjects (Study IM101013). 
Bristol-Myers Squibb; 2006. Document Control No. 930015830.  
(iii) A multi-center, randomized, double-blind, placebo-controlled study to evaluate the safety and 
clinical efficacy of intravenous infusions of abatacept (BMS-188667, 2 mg/kg) given monthly in 
combination with subcutaneous injections of etanercept (25 mg given twice weekly) to subjects 
with active rheumatoid arthritis (Study IM101101). Bristol-Myers Squibb; 2004. Document 
Control No. 930007559.  


 
 
 
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(iv) Clinical Study report for IM101063: A Study To Assess The Steady-State Trough Serum 
Concentrations, Safety, And Immunogenicity Of Abatacept (BMS-188667) Administered 
Subcutaneously In Subjects With Active Rheumatoid Arthritis Who Are Receiving Disease 
Modifying Anti-Rheumatic Drugs (DMARDs). Bristol-Myers Squibb; 2008. Document Control 
No. 930025069.  
(v) Clinical Study Report for IM101173: A Phase 3, Multicenter, Stratified, Open Label Study to 
Evaluate the Immunogenicity, Steady State Trough Level, and Safety of Subcutaneous Abatacept 
in Subjects with Rheumatoid Arthritis Administered with or Without Background Methotrexate. 
Bristol-Myers Squibb; 2009. Document Control No. 930038658.  
(vi) Clinical Study Report for IM101102: A Phase III, multi-center, randomized, double-blind, 
placebo controlled study to evaluate the efficacy and safety of BMS-188667 in combination 
therapy with methotrexate versus methotrexate alone in subjects with active rheumatoid arthritis 
and inadequate response to methotrexate. Bristol-Myers Squibb; 2004. Document Control No. 
930008345.  
(vii) Expedited Safety Report #21 to Abatacept IB version 12. Bristol-Myers Squibb; 29-Sep-2008. 
Document Control No.  930031057.  
(viii) Preliminary guidelines for diagnosing and treating tuberculosis in subjects with RA in 
immunosuppressive trials or being treated with biological agents. Ann Rheum Dis. 
2002;61(supp):ii62-ii63. 
 
(ix) Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit 
Care. 2000;161:221-247. 
 
89