Clinical trial NCT02594735
Conditions: Dermatomyositis
Keywords: Juvenile dermatomyositis inflammatory myopathies Orencia Abatacept
Sponsor: George Washington University
Start date: 2015-11-01; Completion date: 2021-10-22
Enrollment: 10 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to assess the safety and efficacy of subcutaneous abatacept in 10 patients seven years of age and older with refractory JDM.

Detailed description:
JDM is a chronic systemic autoimmune disease with a predominance of muscle and skin inflammation of unknown etiology and varying prognosis. Children with JDM unresponsive to corticosteroids or other immunosuppressive medications face poor clinical and functional outcome and suffer various sequelae of the disease. Abatacept is a fully human soluble recombinant protein consisting of the cytotoxic T cell Lymphocyte Antigen-4 (CTLA4) fused with Fc region of human IgG1 that has been modified to prevent complement fixation and antibody-dependent cellular cytotoxicity. Abatacept binds specifically to the CD80 (B7-1) and CD86 (B7-2) molecules, those expressed on antigen-presenting cells (APCs). Upon engagement of CTLA4 to CD80 or CD86, the resultant inhibition of signal transduction inhibits T cell activation.. The rationale for use of Abatacept in the therapy of JDM includes the expression of CTLA4, CD28, CD86, and CD40 on inflammatory cells of muscle biopsies of patients with DM, as well as CTLA4 and CD28 on muscle cells.

A patient's participation in this study will last approximately 24 weeks with possible extension to 48 weeks. At screening, participants will have a physical exam, muscle strength assessment, blood and urine collection, and chest x-ray; they will also be asked to complete several questionnaires. All participants will receive each week subcutaneous injection of Abatacept. Each injection will be given on an outpatient basis.

There will be a total of 6 study visits. All participants will visit the outpatient clinic at selected time points for muscle strength testing, a physical exam, disease activity measurements, blood and urine collection, and muscle MRI; they will also be asked to complete several questionnaires. During the study, participants will be monitored closely for improvement or worsening of their disease and for serious drug related side effects.

Eligibility Ages Eligible for Study: ≥ 7 years and older Genders Eligible for Study: Both Race/Ethnic Backgrounds Eligibility for Study: No restrictions

Arms: arm 1: A patient's participation in this study will last approximately 24 weeks ( screening visit and 5 intervention visits) with possible extension to 48 weeks. At screening, participants will have a physical exam, muscle strength assessment, blood and urine collection, and chest x-ray; they will also be asked to complete several questionnaires. All participants will receive each week subcutaneous injection of Abatacept. During intervention phase of the trial, muscle strength testing, physical exam, disease activity measurements, blood and urine collection, and muscle MRI will be performed. Participants will also be asked to complete several questionnaires. Participants will be also monitored closely for for serious drug related side effects.
Interventions: intervention 1: Abatacept
Intervention descriptions: intervention 1: Study participation will consist of a screening visit and 5 protocol visits over six months (week 0, week 6, week 12, week 18, and week 24) for each subject, and phone follow-up (week 2, week 4, week 8, week 10, week 14, week 16, week 20, and week 22). At Visit 1, which will be treatment initiation, eligible subjects will be instructed on the use and side effects of subcutaneous abatacept and will be started on the study drug (abatacept 125 mg SQ weekly for subjects with body weight ≥ 50 KG or abatacept 87.5mg SQ for subjects with body weight \< 50 KG).

Protocol documents:
Prot_SAP_000.pdf: 
Abatacept in the Treatment of Refractory Juvenile Dermatomyositis
Dr. Rodolfo Curiel, GWU
Version 10.5 22April2020                                                                       Page 1 of 84
                                        
Abatacept for the Treatment of 
Refractory Juvenile Dermatomyositis (JDM) 
AID (Abatacept in dermatomyositis) Trial                                   
BMS PROTOCOL NUMBER: Abatacept BMS study ID IM101-479
Rodolfo Curiel, MD, FACP, FACR
Associate Professor of Medicine
 Program Director, Rheumatology fellowship 
Director, GWU Myositis Clinic
Medical Faculty Associates
The George Washington University 2300 M Street, NW, Suite 3-313
Washington, DC 20037
Tel: (202) 741-2488
Fax: (202) 741-2490
Email: rcuriel@mfa.gwu.edu 
IRB NUMBER: 111418
IRB APPROVAL DATE: 05/02/2020


Abatacept in the Treatment of Refractory Juvenile Dermatomyositis
Dr. Rodolfo Curiel, GWU
Version 10.5 22April2020                                                                       Page 2 of 84
Associate Investigators
Lisa Rider, MD
Clinical Professor
The George Washington University 
 Medical Faculty Associates
The George Washington University
2150 Pennsylvania Ave, NW Suite G-400
Olcay Jones, MD, PhD
Chief of Pediatric Rheumatology
Walter Reed National Military Medical Center
4954 North Palmer Road, 
America Building 4th Floor, Room 4040
Bethesda, MD 20889
Tel: (301) 400-1619
  
Alison Ehrlich, MD
Professor of Dermatology
Director of Clinical Research
Chair, Department of Dermatology
Medical Faculty Associates
The George Washington University
2150 Pennsylvania Ave, NW 
Tel: (202) 741-2627
Kathleen Brindle, MD
Associate Professor of Radiology
Chief Musculoskelatal Radiology
Department of Radiology
Medical Faculty Associates
The George Washington University
900 23rd Street, NW 
Tel: (202) 715-4907
Gulnara Mamyrova, MD, PhD
Researcher/GWU Myositis Center Coordinator
Division of Rheumatology
Medical Faculty Associates
The George Washington University
IRB NUMBER: 111418
IRB APPROVAL DATE: 05/02/2020


Abatacept in the Treatment of Refractory Juvenile Dermatomyositis
Dr. Rodolfo Curiel, GWU
Version 10.5 22April2020                                                                       Page 3 of 84
2150 Pennsylvania Ave, NW Suite G-400
Washington, DC 20037
Tel: (202) 741-3069
Fax: (202) 741-2490
Victoria Shanmugam, MD 
Director, Division of Rheumatology
The George Washington University 
Medical Faculty Associates
2300 M Street, N.W.
Washington, DC 20037
Phone: 202-741-2488
Fax: 202-741-3490
Derek R. Jones, PhD
Post Doctoral Research Scientist
The Shanmugam Laboratory
701 Ross Hall, 2300 Eye St NW
Washington, DC 20037
Phone: 202-994-8567
Fax: 202-994-8188
http://smhs.gwu.edu/shanmugam-lab/
Hassan Awal, MD
Clinical Research Coordinator
The GW Medical Faculty Associates 
2300 M Street NW, Suite 7-740
Washington, DC 20037
Phone: 202 741 2389
Email: hawal@mfa.gwu.edu
Robert Sheets, MD
Associate Investigator
Rady Children’s Hospital 
San Diego, CA
Phone: 858735549
Email: rsheets@rchsd.org
IRB NUMBER: 111418
IRB APPROVAL DATE: 05/02/2020


Abatacept in the Treatment of Refractory Juvenile Dermatomyositis
Dr. Rodolfo Curiel, GWU
Version 10.5 22April2020                                                                       Page 4 of 84
ABBREVIATIONS
AE
adverse event
ACR
American College of Rheumatology
AIHA
autoimmune hemolytic anemia
ANA
antinuclear antibody
BSA
Body Surface Area
CHAQ
child health assessment questionnaire
CTD
connective tissue disease
DOI
definition of improvement
DM
dermatomyositis
FDA
Food and Drug Administration
FVC
forced vital capacity
HACA
human anti-chimeric antibody
HAQ
health assessment questionnaire
HIV
human immunodeficiency virus
IBM
inclusion body myositis
ICF
informed consent form
ID
identification
IIM
idiopathic inflammatory myopathy
IMACS Group
International Myositis Assessment & Clinical Studies Group
IND
Investigational New Drug
IRB
Institutional Review Board
IS
immunosuppressive
JDM
juvenile dermatomyositis
JRA
juvenile rheumatoid arthritis
MDI
Myositis Damage Index
MDAAT
Myositis Disease Activity Assessment Tool
MMT
manual muscle testing
MOOP
Manual of Operations
MSAs
myositis specific autoantibodies
PCP
primary care physician
PK
pharmacokinetics
PM
polymyositis
PRINTO
Pediatric Rheumatology International Trials Organization
RA
rheumatoid arthritis
SAE
serious adverse event
SLE
systemic lupus erythematosus
SQ
Subcutaneous
TNF
tumor necrosis factor
VAS
visual analog scale
IRB NUMBER: 111418
IRB APPROVAL DATE: 05/02/2020


Abatacept in the Treatment of Refractory Juvenile Dermatomyositis
Dr. Rodolfo Curiel, GWU
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TABLE OF CONTENTS
1.0 INTRODUCTION
    12
1.1 BACKGROUND
           13  
 
1.2 Abatacept Background
    15

1.3 Previous Clinical Studies overview
1.3.1 Clinical Experience with Abatacept in Adult and Pediatric Patients.       15
1.3.2 Abatacept in IIM: Pilot Data 
     23

1.4 Ethical considerations 
     24

1.5  Rationale 
     24  
         
2.0 OBJECTIVES
     25

2.1 Primary Objective
     26

2.2 Secondary Objective
         27
3.0 STUDY DESIGN
 
     27

3.1 Endpoints                                                                                             28

3.2 Safety Endpoints
     29
4.0 SUBJECT POPULATION
.     30

4.1 Inclusion Criteria
30

4.2 Exclusion Criteria
33

4.3 Risk/Benefit Ratio Study Medication
33
5.0 CONCOMITANT MEDICATIONS
35

5.1 Pre-Study Drug Restrictions
37 

5.2 Concomitant Medications Allowed for the Duration of the Study
37

5.3 Concomitant Medications Not Allowed for the Duration of the Study     38

5.4 Other Restrictions
      39
6.0 STUDY MEDICATIONS
 
Medication Description
40

6.2 Study Medication Schedule
       41
      6.3 Drug Ordering and Accountability 
       42 

6.4 Storage and Accountability
       42
7.0  TREATMENT PLAN                                                                                          42
8.0
DOSE MODIFICATION                                                                                     50
9.0
DISCONTINUATION OF SUBJECTS                                                            50
10.0
TREATMENT COMPLIANCE                                                                        52 
IRB NUMBER: 111418
IRB APPROVAL DATE: 05/02/2020


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Version 10.5 22April2020                                                                       Page 6 of 84
11.0   SAFETY ISSUES                                                                                            52
12.0 ADVERSE EVENT REPORTING                                                                      52

12.1 Adverse Event                                                                                        53

12.1.1 Study Drug Relationship                                                                      53 

12.2 Immediately Reportable Adverse Events                                               53

12.3 Physical Examination Observations                                                       54
13.0 DATA SAFETY MONITORING PLAN                                                               55 
14.0 ASSESSMENT TOOLS: description                                                                   56
15.0 STATISTICAL ANALYSIS                                                                                 59
16.0 COSTS AND PAYMENTS

16.1 Research Study Costs                                                                        60

16.2 Research Study Payments                                                                 61 
17.0 REFERENCES                                                                                                 61
Appendix A
Bohan and Peter Criteria for diagnosis of dermatomyositis
65
Appendix B
Proposed new classification criteria for IIM
67 
Appendix C      IMACS and PRINTO Core Set Activity Measures
68 
Appendix D      Definitions of Improvement, Moderate, Major Clinical Response 
and Clinically Inactive Disease  
70
Appendix E      Table 1: Study schedule of Events
73
Table 2: Laboratory Studies
Appendix F   
Action Plan for Treatment of Worsening of Disease 
78
Appendix G    Clinical Laboratory Evaluation
79
Appendix H       Study Personnel and Roles
81
 
IRB NUMBER: 111418
IRB APPROVAL DATE: 05/02/2020


Abatacept in the Treatment of Refractory Juvenile Dermatomyositis
Dr. Rodolfo Curiel, GWU
Version 10.5 22April2020                                                                       Page 7 of 84
PROTOCOL SYNOPSIS
Complete the Protocol Synopsis after you have finalized all content in the protocol. Make sure 
the information in the Synopsis matches the corresponding information in the body of the 
protocol.
Protocol Title:
Abatacept for the Treatment of Refractory 
Juvenile Dermatomyositis  (JDM) 
Site Numbers & Names:
The George Washington University (GWU), Medical 
Faculty Associates, GWU Myositis Center, The 
George Washing University Hospital. 
Research Hypothesis:
To assess the safety and efficacy of subcutaneous 
abatacept in 10 patients seven years of age and older 
with   refractory JDM. Our hypothesis is that abatacept 
will be well-tolerated and safe, and clinically efficacious 
with improvement in myositis disease activity following 
6 months of subcutaneous abatacept weekly
Study Schema:
Drugs / Doses /
Length of Treatment)
Study participation will consist of a screening visit and 
5 protocol visits over six months (week 0, week 6, week 
12, week 18, and week 24) for each subject, and phone 
follow-up (week 2, week 4, week 8, week 10, week 14, 
week 16, week 20, and week 22). At Visit 1, which will 
be treatment initiation, eligible subjects will be 
instructed on the use and side effects of subcutaneous 
abatacept and will be started on the study drug 
(abatacept 125 mg SQ weekly for subjects with  body 
weight ≥ 50 KG or abatacept 87.5mg SQ   for subjects 
with  body weight < 50 KG).
For patients not improving with therapy by at least 5% 
on at least 3 of 6 core set measures at week 12 and 
who are clinically unchanged or worse by physician 
assessment, they would be offered the opportunity to 
increase their dose of treatment to abatacept 212.5 mg 
(87.5 + 125 mg) for subjects with body weight ≥ 50 kg 
or to abatacept 137.5 mg (87.5 mg + 50 mg) once a 
week subcutaneously for subjects with body weight < 
50 kg, or to continue on their present dose.
An open label extension of 6 months will be offered to 
subjects who met improvement criteria and are rated 
as at least minimally improved by physician 
assessment. 
IRB NUMBER: 111418
IRB APPROVAL DATE: 05/02/2020


Abatacept in the Treatment of Refractory Juvenile Dermatomyositis
Dr. Rodolfo Curiel, GWU
Version 10.5 22April2020                                                                       Page 8 of 84
Study Objectives:

Primary:

Secondary:
Primary:   
a) To evaluate tolerance and safety of abatacept in 
treatment –refractory JDM patients.
b) To assess the improvement in myositis disease 
activity: the myositis definition of improvement will 
be achieved   in at least 6 of 10 patients at the end 
of the trial.
Secondary: 
a) Steroid-sparing benefit will be obtained. We 
hypothesize that we can reduce daily corticosteroid 
therapy by at least 20% in at least 6 of 10 
treatment-refractory JDM patients in this trial 
b) To examine response to treatment  in individual 
core set measures of disease activity as developed 
by IMACS and PRINTO 
c) To examine improvement in patient reported 
outcomes
d) To 
examine 
improvement 
in 
cutaneous 
dermatomyositis disease activity
e) To examine improvement in muscle inflammation 
by examining a thigh/pelvis STIR MRI
f)
To examine that disease damage does not 
increase while under treatment with abatacept
g) To examine improvement of biomarkers that may 
relate to disease pathogenesis and the mechanism 
of action of abatacept in JDM
h) To estimate the PK and immunogenicity of SC 
abatacept weekly in JDM
Study Design:
Open label, non-randomized trial 
Accrual Goal:
(Total number of subjects)
10 receiving abatacept therapy
Accrual Rate:
(Number of subjects 
expected per month)
  0-1
IRB NUMBER: 111418
IRB APPROVAL DATE: 05/02/2020


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Version 10.5 22April2020                                                                       Page 9 of 84
FPFV:
LPFV:
Follow Up:
(dd-mm-yy)
 6 months 
Correlative Studies:
(PK/PD, etc.)
Biomarkers (please see below)
Pharmacokinetics per BMS 
Inclusion Criteria:
Adults or  pediatric patients seven  years of age and 
older with definite or probable JDM
Body weight of at least 25 kg 
Refractory myositis 
At least moderately active disease 
Exclusion Criteria
Drug –induced myositis 
Juvenile myositis, cancer-induced myositis, inclusion 
body myositis
Myositis in overlap with another CTD
Concomitant illness
Pregnant or nursing mothers 
Life threatening non-myositis illness
Any history or evidence of severe illness 
IRB NUMBER: 111418
IRB APPROVAL DATE: 05/02/2020


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Version 10.5 22April2020                                                                       Page 10 of 84
Criteria for Evaluation:
(Efficacy, safety,
stopping rules, etc.)
SAFETY: To assess safety the NCI Common 
Terminology criteria version 4.0 June 2010 will be 
applied.   Particular attention to serious adverse events 
and infections will be given. Patient evaluations will 
include: vital sign measurement, physical examination, 
and laboratory parameters for hematology and routine 
chemistries.
EFFICACY: To assess efficacy, the primary endpoint 
will be the Definition of Improvement (DOI): 3 of any 
of the 6 core set measures improved by ≥ 20%, with 
no more than 2 of the core set measures worsening 
by ≥25% (worsening measure cannot include the 
muscle strength).
STOPPING RULES: Subjects in this study may be 
discontinued  for any of the following reasons:

Severe allergic reaction to the study medication

Participation in another investigational drug 
study

Any medical condition which, in the opinion of 
the investigator, warrants discontinuation from 
the study for the safety of the patient, either as 
a cause of the study drug or protocol violations, 
including non-compliance or inability to perform 
protocol-required procedures

Voluntary withdrawal (withdrawal of consent)

Pregnancy

If 3 or more patients develop a serious adverse 
event thought to be related to study drug, no 
new patients will be enrolled into the study until 
the adverse events have been reviewed by the 
Medical Safety Officer and/or Data Safety 
Monitoring Board.
IRB NUMBER: 111418
IRB APPROVAL DATE: 05/02/2020


Abatacept in the Treatment of Refractory Juvenile Dermatomyositis
Dr. Rodolfo Curiel, GWU
Version 10.5 22April2020                                                                       Page 11 of 84
Statistics:
n-randomized trial to assess the safety and efficacy of 
subcutaneous abatacept in 10 patients (children 
and 
adults) 
with 
juvenile-onset 
refractory 
dermatomyositis (JDM).  Summary statistics will be 
generated to describe the study data. Descriptive 
statistics, including measures of central tendency (e.g. 
means, medians) and estimates of spread (e.g. 
standard deviations) will be used for continuous 
variables, including reporting of adverse event 
frequencies, core set measure assessments, and 
demographic and clinical variables. Non-parametric 
Wilcoxon signed rank tests will be used to investigate 
changes in continuous variables. 95% confidence 
intervals will be calculated for all point estimates. 
APPENDICES
Appendix A
Bohan and Peter Criteria for diagnosis of dermatomyositis
Appendix B
Proposed new classification criteria for IIM 
Appendix C       IMACS and PRINTO Core Set Activity Measures 
       Appendix D
Definitions of Improvement, Moderate, Major Clinical Response and 
Clinically Inactive Disease  
 
Appendix E       Table 1: Study schedule of Events
Table 2: Laboratory Studies
      Appendix F   
Action Plan for Treatment of Worsening of Disease 
Appendix G    
Clinical Laboratory Evaluation
      Appendix H       Study Personnel and Roles
IRB NUMBER: 111418
IRB APPROVAL DATE: 05/02/2020


Abatacept in the Treatment of Refractory Juvenile Dermatomyositis
Dr. Rodolfo Curiel, GWU
Version 10.5 22April2020                                                                       Page 12 of 84
PROTOCOL TITLE:
Abatacept the Treatment of Refractory Juvenile Dermatomyositis
PRODUCT:
Abatacept 
BMS Protocol Number:  ID IM 101-479
1.0 INTRODUCTION
This is an open label interventional study to test the safety and efficacy of Abatacept for 
treatment of refractory juvenile dermatomyositis (JDM).  JDM is a rare autoimmune 
disease affecting 1 to 3 per million children per year at ages less than 18 years [1]
The clinical manifestations include inflammatory changes in the muscle and skin tissue.  
The disease often presents with progressive muscle weakness, which can lead to severe 
disability.(2)  In addition there are characteristic skin rashes (Gottron’s papules and 
heliotrope rash), but also a number of photosensitive rashes and other systemic features, 
including arthritis, joint contractures, calcinosis, dysphagia and other gastrointestinal 
manifestations, and involvement of other systems (2,3).  The diagnosis of JDM requires 
the presence of proximal muscle weakness, characteristic rashes, and often elevation of 
serum muscle enzymes. The diagnosis is often confirmed with muscle biopsy, which 
shows several pathognomonic changes, including perivascular inflammatory cells, 
immune complex deposition in the walls of the intramuscular arteries and veins, and 
perifascicular muscle fiber atrophy (4-6). JDM is a serious and potentially life threatening 
illness unless there is adequate treatment. With the advances in medicine, the current 
mortality is 3-6% in published series (4). There is significant morbidity associated with 
JDM, as 30-50% of patients demonstrate a chronic illness course, 15-30% have used 
wheelchairs, and 20-35% develop dystrophic calcification (4,7).  In addition, 
understanding of disease pathophysiology is incomplete, but clearly involves specific 
immunity by T and B cells.  The most striking histopathologic feature of affected muscle 
in JDM is vasculopathy that is believed to be secondary to endothelial changes due in 
part immune complex mediated inflammation.(8)  This vasculopathy is critical in the 
pathogenesis of JDM and extent of occlusive vasculopathy is predictive of prognosis 
(8,9). High dose corticosteroids have traditionally been and are still to date is the first line 
therapy, but are associated with significant drug-related toxicity.  Over 30% of JDM 
patients fail to respond adequately to corticosteroids and require additional 
immunosuppressive medications, none of which have been tested in controlled trials 
(10,11).  These include DMARDs such as methotrexate, cyclosporine and azathioprine, 
and intravenous gamma globulin (IVIG) (10, 11). There are efforts toward standardizing 
treatment for JDM (11), but the outcomes are variable for the existing treatment 
modalities. The response to treatment can be partial and children often need prolonged 
treatment with combination drugs. The treatment of a child with steroids and DMARDs 
can cause adverse effects,  including  growth arrest and other sequelae as a result of 
long-term steroid usage.(7,12,13)  Intolerance to other immunosuppressive medications 
also occurs, including frequent aseptic meningitis after IVIG, nausea and abdominal 
discomfort with certain DMARDs such as methotrexate, infusion reactions with biologics, 
IRB NUMBER: 111418
IRB APPROVAL DATE: 05/02/2020


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and increased risk of infections.(14)  Poorly treated JDM can lead to calcinosis and 
vasculitic damage in the mucosa of the gastrointestinal tract as well as other organs and 
may be fatal.  Agents for treatment-refractory patients have been studied primarily in 
small, retrospective case series. Etanercept was studied in treatment-refractory JDM 
patients and appeared to have little effect (15,16)   Rituximab has been studied in a large 
multi-center therapeutic trial and had a positive effect in treatment-refractory 
dermatomyositis (DM), polymyositis (PM) and JDM patients, but failed to meet the trial 
endpoint of a difference in time to response between the treatment arms (17).  
Documentation of benefit of additional agents, particularly biologic therapies, is important 
for treatment refractory patients, as there is a dearth of studied agents in this population. 
The rationale for use of abatacept in the therapy of JDM includes the expression of 
CTLA4, CD28, CD86, and CD40 on inflammatory cells of muscle biopsies of patients with  
DM, as well as CTLA4 and CD28 on muscle cells (18,19)  Abatacept also completely 
inhibits antigen presentation by cytokine-induced myoblasts to HLA-DR-matched antigen-
specific CD4+ T cell lines (19). Co-stimulatory molecules and their receptors are also 
seen on CD4+ T cells and BB-1-positive muscle fibers in cell-to-cell contact in patients 
with scleroderma-myositis overlap syndrome (20,21).   
The goal of this study is to examine the safety and efficacy of Abatacept for the treatment 
of refractory JDM as a novel biologic agent that is being increasingly utilized in adult and 
pediatric autoimmune diseases to modulate and down regulate lymphocytes(18)
1.2  ABATACEPT  BACKGROUND
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 co-
stimulation modulators.” Abatacept binds specifically to the CD80 (B7-1) and CD86 (B7-
2) molecules, those expressed on antigen-presenting cells (APCs). Activation of naive 
T cells during an immune response requires two stimuli from APCs. The first signal is 
antigen-specific upon binding of MHC restricted antigen on APC to T cell receptor; the 
second signal is antigen-nonspecific and is delivered through engagement of CD80 or 
CD86 co-stimulatory ligand on APC with CD28, a cognate receptor on the T cell. CD28 
is constitutively expressed on resting T cells (22-25). A co-stimulatory 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 (22,23). At 24 to 48 hours following T cell 
activation, the T cell expresses CTLA4 on its surface that has higher affinity for CD80 and 
CD86, thus limiting cell activation by interfering with CD28’s ability to bind CD80 and 
CD86. Upon engagement of CTLA4 to CD80 or CD86, the resultant inhibition of signal 
transduction inhibits T cell activation. Abatacept binds specifically to CD80 and CD86 and 
blocks binding of CD28, and the co-stimulation of T cells. The Fc region of abatacept was 
engineered with several point mutations preventing antibody-dependent cell cytotoxicity 
or activation of complement-cascade (22). 
IRB NUMBER: 111418
IRB APPROVAL DATE: 05/02/2020


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Version 10.5 22April2020                                                                       Page 14 of 84
Pathogenesis and significance: Role of CTLA-4 in idiopathic inflammatory 
myopathies
It is widely accepted that DM and JDM are autoimmune conditions derived from chronic 
activation of immune system following specific environmental exposures in genetically 
susceptible individuals (26,27).  The initial trigger and molecular pathogenesis is not fully 
understood.  Histologically these illnesses are characterized by early changes in the 
intramuscular capillaries, leading to vasculopathy and perivascular inflammation. Thus, 
the cumulative insults from the vascular damage lead to development of perifascicular 
atrophy or typical skin rashes. (8, 26,27) 
There has been convincing evidence that JDM immunopathogenesis predominantly 
involves heightened activation status of both the innate (macrophages and dendritic cells) 
as well as specific (B cells, CD4+ T cells) immune systems and is associated with chronic 
endothelial changes (26, 27). In fact, pro-inflammatory cytokines and cell adhesion 
molecules, including interleukin IL1-α, IL-β, ICAM-1, and TGF-β, are present in the 
inflamed muscle tissues of adult and juvenile myositis patients.  Several studies have 
noted a strong expression of TNF-alpha in macrophages, myofibers, regenerating 
myoblasts, and endothelial cells (28,29). Furthermore, immune complex-mediated 
complement activation is likely to have central importance as the terminal C5b-9 
membrane attack complex is often found deposited on muscular capillaries resulting in 
endothelial damage, capillary loss, and ischemic injury (26). The degree of such 
vasculopathy in the muscle correlates with the clinical disease course of JDM.  It has 
been suggested that the vasculopathy may result from the decreased ability to repair 
vascular damage observed at early stages of the disease secondary to impaired 
angiogenic mechanisms (8). .  Also, both mature and immature dendritic cells can be 
found in the perivascular infiltrates, along with implicated chemotactic chemokines, such 
as CCL19/21 and CCL20 (18), which can perpetuate the tissue damage. 
The pathogenesis also involves alterations in immune regulation; in this regard, CTLA-4, 
the negative modulator of T cell activation, has been found important for following 
reasons: CTLA-4 is expressed by antigen presenting cells (dendritic cells and B cells) as 
well as by the muscle fibers.  There is increased expression of CTLA-4 in the biopsy 
samples from inflammatory myopathies (18) and this is believed to be a natural 
mechanism of disease control. CTLA-4 gene knockout mice develop a massive 
lymphoproliferative disorder along with profound and spontaneous autoimmunity affecting 
skeletal and cardiac muscle (30,31)   It was suggested muscle CTLA-4 and CD28 may 
play a role in protecting muscle cells from apoptosis. Alternatively, or perhaps in addition, 
they may contribute to the repair of damaged muscle by influencing muscle cell cytokine 
production (18-20) or by acting on myoblast proliferation, differentiation, and fusion. 
Unlike T cells, unstimulated muscle cells express neither CTLA-4 nor CD28. In vitro 
experiments showed that CTLA-4 and CD28 are differentially expressed under the 
influence of different cytokines: IL-1-  and IFN-  induce both, IL-1-   and TNF- induce 
only CTLA-4, and IL-6 had no effect on the expression. These cytokines are present in 
varying amounts in myositis biopsies (32).   Of note, the expression of CTLA-4 has also 
been observed in the muscle biopsy of patients with scleroderma-PM syndrome. (21) 
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Thus, abatacept-based treatment is likely to deliver immune modulation that naturally 
blends in the physiologic pathways of down regulation of inflammation. Furthermore, 
because activated T cells undergo capping of CTLA-4 to reduce its surface expression, it 
is conceivable that disease control by abatacept in JDM is through the targeting of 
activated and autoreactive T cells in perivascular and perimysial regions through down 
regulation of dendritic cells and B cells.  
1.3 PREVIOUS CLINICAL STUDIES OVERVIEW
Current knowledge about the safety profile of abatacept is derived from clinical trials   and 
post marketing experience. Detailed information can be found in the Investigator’s 
brochure. 
1.3.1 Clinical Experience with Abatacept in Adult & Pediatric Patients
         
Abatacept is approved for the treatment of adult rheumatoid arthritis (RA) and juvenile 
idiopathic arthritis (JIA). 
The efficacy and safety of intravenous abatacept were assessed in randomized, double-
blind, placebo-controlled clinical trials in adult patients with active RA diagnosed 
according to American College of Rheumatology (ACR) criteria. Studies I, II, III, V, and VI 
required patients to have at least 12 tender and 10 swollen joints at randomization. Study 
IV did not require any specific number of tender or swollen joints. The accumulated long-
term experience with abatacept shows that efficacy is maintained in subjects treated for 
up to 8 years with abatacept. Hence, these data confirm that the consistent efficacy profile 
of abatacept observed in the pivotal studies is maintained over an extended duration of 
exposure. 
The key efficacy results are the following:

Abatacept provided a clinically meaningful long-term  efficacy benefit in a highly 
consistent manner for subjects with moderate to severe RA across 3 populations, 
(methotrexate (MTX) -naïve, MTX-inadequate responder [IR], and TNF-IR, in 
multiple measures of disease (Signs and Symptoms, Physical Function, and 
Health-related Outcomes).

MTX-naive and MTX-IR subjects maintained inhibition of structural damage for 
up to 2 years and 5 years of long-term treatment with abatacept, respectively 
(radiographic assessments were not performed in the TNF-IR population).
Clinical Efficacy - IV Formulation in Pediatric JIA Population
The IM101033 study evaluated response using the ACR Pediatric 30 definition of 
improvement. Subjects who met the criteria for improvement at the end of Period A were 
randomized 1:1 to either abatacept or placebo into the double-blind phase (Period B). 
The primary efficacy endpoint evaluated in the double-blind phase (Period B) was the 
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time to polyarticular JIA disease flare and was compared between the treatment groups 
using a log-rank test.
The efficacy of abatacept was assessed by additional prospectively defined measures as 
secondary objectives, including comparison of the rate of disease flare and an 
assessment of the changes from baseline during Periods B and C for each of the 6 
individual ACR Pediatric core response variables. Additionally, subjects were assessed 
for ACR Pediatric 30, 50, 70, and 90 definitions of improvement and inactive disease 
during Periods A and C.

The time to disease flare was statistically significantly shorter for the placebo-treated 
group than the abatacept-treated group based on the log-rank test (p = 0.0002). The risk 
of disease flare among subjects continuing on abatacept was less than one-third that for 
the subjects who had been randomly withdrawn from the abatacept treatment (hazard 
ratio = 0.31, 95%CI [0.16, 0.59]).

A higher proportion of subjects in the placebo group (53.2%, 33/62) than in the abatacept 
group (20.0%, 12/60) experienced a flare of polyarticular JIA (p < 0.001).
Clinical Efficacy - Subcutaneous abatacept  
The subcutaneous and intravenous formulations of abatacept demonstrate comparable 
efficacy, safety and immunogenicity in adult rheumatoid arthritis. (33) 
1.3.2 Risk/Benefit Ratio:
Study Medications
Abatacept is FDA-approved since 2005 in the United States for the treatment of adult RA 
and JIA patients with an inadequate response to anti-TNF agents. Current knowledge 
about the safety profile of abatacept is derived from clinical trials and post marketing 
experience. Detailed information can be found in the Investigator’s brochure. 
Clinical Studies Experience in Adult RA Patients Treated with Intravenous
Abatacept 
Because clinical trials are conducted under widely varying and controlled conditions,
adverse reaction rates observed in clinical trials of a drug cannot be directly compared to 
rates in the clinical trials of another drug and may not predict the rates observed in a 
broader patient population in clinical practice.
The data described herein reflect exposure to abatacept administered intravenously in 
patients with active RA in placebo-controlled studies (1955 patients with abatacept, 989 
with placebo). The studies had either a double-blind, placebo-controlled period of 6 
months (258 patients with abatacept, 133 with placebo) or 1 year (1697 patients with 
abatacept , 856 with placebo). A subset of these patients received concomitant biologic 
DMARD therapy, such as a TNF blocking agent (204 patients with abatacept , 134 with 
placebo).
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The majority of patients in RA clinical studies received one or more of the following
concomitant medications with abatacept: methotrexate, non-steroidal anti-inflammatory 
drugs (NSAIDs), corticosteroids, TNF blocking agents, azathioprine,
chloroquine, gold, hydroxychloroquine, leflunomide, sulfasalazine, and anakinra.
The most serious adverse reactions were serious infections and malignancies.
The most commonly reported adverse events (occurring in ≥10% of patients treated with 
abatacept) were headache, upper respiratory tract infection, nasopharyngitis, and 
nausea.
The adverse events most frequently resulting in clinical intervention (interruption or
discontinuation of abatacept ) were due to infection. The most frequently reported
infections resulting in dose interruption were upper respiratory tract infection (1.0%),
bronchitis (0.7%), and herpes zoster (0.7%). The most frequent infections resulting in 
discontinuation were pneumonia (0.2%), localized infection (0.2%), and bronchitis (0.1%).
Infections
In the placebo-controlled trials, infections were reported in 54% of abatacept -treated 
patients and 48% of placebo-treated patients. The most commonly reported
infections (reported in 5%-13% of patients) were upper respiratory tract infection,
nasopharyngitis, sinusitis, urinary tract infection, influenza, and bronchitis. Other
infections reported in fewer than 5% of patients at a higher frequency (>0.5%) with
ABATACEPT compared to placebo, were rhinitis, herpes simplex, and pneumonia.
Serious infections were reported in 3.0% of patients treated with abatacept and 1.9% of 
patients treated with placebo. The most common (0.2%-0.5%) serious infections reported 
with abatacept were pneumonia, cellulitis, urinary tract infection, bronchitis, diverticulitis, 
and acute pyelonephritis.
Malignancies
In the placebo-controlled portions of the clinical trials (1955 patients treated with
Abatacept for a median of 12 months), the overall frequencies of malignancies were
similar in the abatacept - and placebo-treated patients (1.3% and 1.1%, respectively). 
However, more cases of lung cancer were observed in abatacept -treated patients (4, 
0.2%) than placebo-treated patients (0). In the cumulative abatacept clinical trials 
(placebo-controlled and uncontrolled, open-label) a total of 8 cases of lung cancer (0.21 
cases per 100 patient-years) and 4 lymphomas (0.10 cases per 100 patient years) were 
observed in 2688 patients (3827 patient-years). The rate observed for lymphoma is 
approximately 3.5-fold higher than expected in an age- and gender-matched general 
population based on the National Cancer Institute’s Surveillance, Epidemiology, and End 
Results (SEER) Database. Patients with RA, particularly those with highly active disease, 
are at a higher risk for the development of lymphoma. Other malignancies included skin, 
breast, bile duct, bladder, cervical, endometrial, lymphoma, melanoma, myelodysplastic 
syndrome, ovarian, prostate, renal, thyroid and uterine cancers. The potential role of 
abatacept in the development of malignancies in humans is unknown.
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Infusion-Related Reactions and Hypersensitivity Reactions
Acute infusion-related events (adverse reactions occurring within 1 hour of the start of the 
infusion) in were more common in the abatacept -treated patients than the placebo 
patients (9% for abatacept , 6% for placebo). The most frequently reported events (1%-
2%) were dizziness, headache, and hypertension.
Acute infusion-related events that were reported in >0.1% and ≤1% of patients treated 
with abatacept included cardiopulmonary symptoms, such as hypotension,
increased blood pressure, and dyspnea; other symptoms included nausea, flushing,
urticaria, cough, hypersensitivity, pruritus, rash, and wheezing. Most of these
reactions were mild (68%) to moderate (28%). Fewer than 1% of abatacept -treated
patients discontinued due to an acute infusion-related event. In controlled trials, 6
abatacept -treated patients compared to 2 placebo-treated patients discontinued study 
treatment due to acute infusion-related events. Anaphylaxis was observed in patients 
dosed with abatacept administered intravenously in controlled and open-label clinical 
trials, and the occurrence was rare (<0.1%). Other reactions potentially associated with 
drug hypersensitivity, such as hypotension, urticaria, and dyspnea that occurred within 
24 hours of abatacept infusion, were uncommon (<1%). Appropriate medical support 
measures for the treatment of hypersensitivity reactions should be available for immediate 
use in the event of a reaction.
Other Adverse Reactions
Adverse events occurring in 3% or more of patients and at least 1% more frequently
in abatacept -treated patients during placebo-controlled RA studies are summarized in 
Table 
Adverse Events Occurring in 3% or More of Patients and at Least 1% more 
Frequently in abatacept -Treated Patients During Placebo- Controlled RA Studies
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   Immunogenicity
Antibodies directed against the entire abatacept molecule or to the CTLA-4 portion of 
abatacept were assessed by ELISA assays in RA patients for up to 2 years following 
repeated treatment with Abatacept. Thirty-four of 1993 (1.7%) patients developed 
binding antibodies to the entire abatacept molecule or to the CTLA-4 portion of 
abatacept. Because trough levels of abatacept can interfere with assay results, a subset 
analysis was performed. In this analysis it was observed that 9 of 154 (5.8%) patients 
that had discontinued treatment with abatacept for over 56 days developed antibodies. 
Samples with confirmed binding activity to CTLA-4 were assessed for the presence of 
neutralizing antibodies in a cell-based luciferase reporter assay. Six of 9 (67%) 
evaluable patients were shown to possess neutralizing antibodies. However, the 
development of neutralizing antibodies may be underreported due to lack of assay 
sensitivity. No correlation of antibody development to clinical response or adverse 
events was observed.
The data reflect the percentage of patients whose test results were positive for
antibodies to abatacept in specific assays. The observed incidence of antibody
(including neutralizing antibody) positivity in an assay is highly dependent on several 
factors, including assay sensitivity and specificity, assay methodology, sample 
handling, timing of sample collection, concomitant medication, and underlying disease. 
For these reasons, comparison of the incidence of antibodies to abatacept with the 
incidence of antibodies to other products may be misleading.
   Clinical Experience in Adult RA Patients Treated with Subcutaneous Abatacept
Because clinical trials are conducted under widely varying and controlled conditions, 
adverse reaction rates observed in clinical trials of a drug cannot be directly compared 
to rates in the clinical trials of another drug and may not predict the rates observed in a 
broader patient population in clinical practice.
Study SC-1 was a randomized, double-blind, double-dummy, non-inferiority study that 
compared the efficacy and safety of abatacept administered subcutaneously (SC) and 
intravenously (IV) in 1457 subjects with RA, receiving background methotrexate, and 
experiencing an inadequate response to methotrexate (MTX-IR). The safety experience 
and immunogenicity for abatacept administered subcutaneously was consistent with 
intravenous Studies I-VI. Due to the route of administration, injection site reactions and 
immunogenicity were evaluated in Study SC-1 and two other smaller studies discussed 
in the sections below. The highest dose tested in adults is 200 mg weekly.
Injection Site Reactions in Adult RA Patients Treated with Subcutaneous
ABATACEPT
Study SC-1 compared the safety of abatacept including injection site reactions
following subcutaneous or intravenous administration. The overall frequency of
injection site reactions was 2.6% (19/736) and 2.5% (18/721) for the subcutaneous
abatacept group and the intravenous abatacept group (subcutaneous placebo),
respectively. All these injection site reactions (including hematoma, pruritus, and 
erythema) were mild (83%) to moderate (17%) in severity, and none necessitated drug 
discontinuation.
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Immunogenicity in Adult RA Patients Treated with Subcutaneous abatacept : 
Study SC-1 compared the immunogenicity to abatacept following subcutaneous or 
intravenous administration. The overall immunogenicity frequency to abatacept was 
1.1% (8/725) and 2.3% (16/710) for the subcutaneous and intravenous groups, 
respectively. The rate is consistent with previous experience, and there was no 
correlation of immunogenicity with effects on pharmacokinetics, safety, or efficacy.
Immunogenicity and Safety of Subcutaneous abatacept Administration as
Monotherapy without an Intravenous Loading Dose: 
Study SC-2 was conducted to determine the effect of monotherapy use of abatacept  
on immunogenicity following subcutaneous administration without an intravenous load 
in 100 RA patients, who had not previously received abatacept or other CTLA4Ig, who 
received either subcutaneous abatacept  plus methotrexate (n=51) or subcutaneous 
abatacept  monotherapy (n=49). No patients in either group developed anti-product 
antibodies after 4 months of treatment. The safety observed in this study was consistent 
with that observed in the other subcutaneous studies.
Immunogenicity and Safety of Subcutaneous abatacept upon Withdrawal (Three 
Months) and Restart of Treatment: 
Study SC-3 in the subcutaneous program was conducted to investigate the effect of 
withdrawal (three months) and restart of abatacept subcutaneous treatment on 
immunogenicity in RA patients treated concomitantly with methotrexate. One hundred
sixty-seven patients were enrolled in the first 3-month treatment period and
responders (n=120) were randomized to either subcutaneous abatacept  or placebo for 
the second 3-month period (withdrawal period). Patients from this period then received 
open-label abatacept treatment in the final 3-month period of the study (period 3). At 
the end of the withdrawal period, 0/38 patients who continued to receive subcutaneous 
Abatacept developed anti-product antibodies compared to 7/73 (9.6%) of patients who 
had subcutaneous abatacept  withdrawn during this period. Half of the patients 
receiving subcutaneous placebo during the withdrawal period received a single 
intravenous infusion of abatacept  at the start of period 3 and half received intravenous 
placebo. At the end of period 3, when all patients again received subcutaneous 
Abatacept, the immunogenicity rates were 1/38 (2.6%) in the group receiving 
subcutaneous Abatacept throughout, and 2/73 (2.7%) in the group that had received 
placebo during the withdrawal period. Upon reinitiating therapy, there were no injection 
reactions and no differences in response to therapy in patients who were withdrawn 
from subcutaneous therapy for up to 3 months relative to those who remained on 
subcutaneous therapy, whether therapy was reintroduced with or without an 
intravenous loading dose. The safety observed in this study was consistent with that 
observed in the other studies.
Clinical Studies Experience in Juvenile Idiopathic Arthritis: Because clinical trials 
are conducted under widely varying conditions, adverse reaction rates observed in the 
clinical trials of a drug cannot be directly compared to rates in the clinical trials of 
another drug and may not reflect the rates observed in practice. In general, the adverse 
events in pediatric patients were similar in frequency and type to those seen in adult 
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patients. Abatacept has been studied in 190 pediatric patients, 6 to 17 years of age, 
with polyarticular juvenile idiopathic arthritis. Overall frequency of adverse events in the 
4-month, lead-in, open-label period of the study was 70%; infections occurred at a 
frequency of 36%. The most common infections were upper respiratory tract infection 
and nasopharyngitis. The infections resolved without sequelae, and the types of 
infections were consistent with those commonly seen in outpatient pediatric 
populations. Other events that occurred at a prevalence of at least 5% were headache, 
nausea, diarrhea, cough, pyrexia, and abdominal pain. A total of 6 serious adverse 
events (acute lymphocytic leukemia, ovarian cyst, varicella infection, disease flare [2], 
and joint wear) were reported during the initial 4 months of treatment with Abatacept. 
Of the 190 patients with juvenile idiopathic arthritis treated with abatacept in clinical 
trials, there was one case of a hypersensitivity reaction (0.5%). During Periods A, B, 
and C, acute infusion-related reactions occurred at a frequency of 4%, 2%, and 3% 
respectively, and were consistent with the types of events reported in adults. Upon 
continued treatment in the open-label extension period, the types of adverse events 
were similar in frequency and type to those seen in adult patients, except for a single 
patient diagnosed with multiple sclerosis while on open-label treatment.
Immunogenicity
Antibodies directed against the entire Abatacept molecule or to the CTLA-4 portion of 
Abatacept were assessed by ELISA assays in patients with juvenile idiopathic arthritis 
following repeated treatment with Abatacept throughout the open-label period. For 
patients who were withdrawn from therapy for up to 6 months during the double-blind 
period, the rate of antibody formation to the CTLA-4 portion of the molecule was 41% 
(22/54), while for those who remained on therapy the rate was 13% (7/54). Twenty of 
these patients had samples that could be tested for antibodies with neutralizing activity; 
of these, 8 (40%) patients were shown to possess neutralizing antibodies. The 
presence of antibodies was generally transient and titers were low. The presence of 
antibodies was not associated with adverse events, changes in efficacy, or an
effect on serum concentrations of Abatacept. For patients who were withdrawn from 
Abatacept  during the double-blind period for up to 6 months, no serious acute infusion-
related events were observed upon re-initiation of Abatacept  therapy.
Laboratory monitoring: Complete blood counts (CBC) and platelet counts will be 
obtained at regular intervals during the study Blood Drawing: Subjects may experience 
pain, bruising and/or bleeding at the site of the needle insertion for blood drawing.  Very 
rarely an infection may occur at the site.  Subjects may also experience dizziness 
and/or fainting.
Hepatitis B and C and HIV blood testing:  The hepatitis testing requires the drawing 
of blood.  Being tested for hepatitis may cause anxiety regardless of the test results. If 
a subject has a positive test results, they may have trouble obtaining insurance or 
employment.  There is always the possibility the test result is wrong and therefore a 
repeat test would be done. 
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Magnetic resonance imaging (MRI): MRI involves no x-rays and there are no known 
risks from the test, although some people may feel claustrophobic about being in a 
small space. No contrast agent will be administered for the MRI examination.
Photography: Photographs of skin rashes and the periungual capillaries (Optional) are 
taken throughout the study.  The possibility exists that patients may be identifiable in 
some of the photographs when unique birthmarks or other identifiable skin changes 
are present.
Loss of privacy:  Every effort will be made to protect the subject’s privacy and 
information will be handled in a confidential manner.  The only information that will be 
provided with the subject’s stored blood and urine samples is a study code.  Files that 
link the subjects name to the code number will be kept in a locked cabinet and only the 
study staff will have access to them.  The samples will be provided to the researchers 
in such a manner whereby it will not be possible for them to connect the subject’s 
identity with the sample or medical information.  Information about race, ethnicity, sex 
and medical history may be made available to the investigators studying the blood, 
muscle tissue and urine samples.  Such information might be important for research. 
Although no one can absolutely guarantee confidentiality, using a code number greatly 
reduces the chance that someone will ever be able to link the subjects name to their 
sample or to their results.  
Confidentiality:  All records pertaining to the subject’s involvement in this research 
study will be stored in locked file cabinets. Only a subject number in these records will 
identify him or her. Any information about the subject or his or her treatment will be 
handled in a confidential manner consistent with other identifiable health information. 
The subject will not be specifically identified in any publication of research results.
Potential benefits: There may be no direct benefit to participate in this study. There is 
no guarantee that participants will receive any personal benefit from participating. It is 
hoped that the information gained from the study will be beneficial to patients in the 
future. 
Alternative Treatments: Other treatments available to patients include other 
immunosuppressive medications known to be considered as possibly effective in 
patients with immunological diseases. These drugs may be effective in managing the 
symptoms associated with JDM.  The Principal Investigator or Associate Investigators 
will discuss all of the treatment options with potential participants.      
Evaluation of Risk/Benefit Ratio: If abatacept proves to be effective, many such 
patients with JDM may ultimately benefit from this therapy.  Such benefits may include 
improved symptoms and health.  Practitioners may gain increased knowledge and 
treatment of myositis in clinical practice.  Subjects participating in this study may 
experience some benefit during the period of study medication therapy. Evaluation is 
performed as per the statistical information provided in the protocol.   The risks for 
those subjects involved in this study are reasonable when compared to the potential 
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disease damage and catastrophic sequelae that occurs in adult and pediatric patients 
with inflammatory myopathy. 
Reproductive Risks: Animal studies to determine the effects of the study drug on the 
fetus have not been done. To avoid risk to the fetus, it is important that female 
participants or female partners of male participants take care to avoid becoming 
pregnant during this study.  Avoiding sexual activity is the only certain method to 
prevent pregnancy.  However, females of child-bearing potential must be willing to use 
an appropriate method of birth control (such as female use of a diaphragm, intrauterine 
device (IUD), or contraceptive sponge, in addition to male use of a condom) or the 
female should be using prescribed “birth control” pills, injections, or implants throughout 
the study.  Even with use of these birth control measures, pregnancy could still result.  
The risks of receiving the study drug while pregnant include potential loss of pregnancy 
or possible birth defects.  Females of child-bearing potential will undergo a urine 
pregnancy test prior to exposure to the study drug. In the pediatric group the parent 
signing the consent will be informed of the result of the pregnancy test.
1.3.3 Abatacept in IIM: Pilot Data 
The efficacy of Abatacept has been established in adult RA and JIA. However, there have 
been only a few reports on the use of abatacept to treat inflammatory myopathies.  These 
few case reports suggest a beneficial effect. We have had direct experience at the George 
Washington University (GWU) Myositis Center in the treatment of two patients with severe 
treatment-refractory JDM who responded very well to Abatacept SC therapy and tolerated 
this with no side effects. From our published report (34), our first patient at GWU 
responded with a significant improvement in muscle strength and function, skin rashes 
and ulceration, ability to reduce daily prednisone therapy over a 6 month period and also 
in the extent of calcinosis, after initiation of Abatacept and failure so suppress disease 
activity with a number of other agents, including prednisone, IVIG, methotrexate, 
tacrolimus and cyclophosphamide (34).  A second patient under our guidance, after 
failure to suppress JDM disease activity with corticosteroids, IVIG, cyclosporine, 
methotrexate, rituximab, etanercept, and other agents, had a dramatic response to 
Abatacept within 6 months of beginning infusions, including clearing of her refractory skin 
disease, normalization of her muscle strength and function, and ability to reduce daily 
prednisone down to 10 mg daily; she achieved clinical remission with abatacept. A third 
patient that Dr. Rider was involved with at the NIH was a teenager who failed multiple 
medications 
(steroids, 
methotrexate, 
cyclosporine, 
cyclophosphamide, 
IVIG, 
mycophenolate mofetil, azathioprine, tacrolimus and had a hypersensitivity reaction to 
rituximab).  Only after the addition of intravenous infusions with abatacept, she achieved 
marked clinical and laboratory parameters, with near normalization of her muscle 
strength, function and serum levels of muscle enzymes.  An adult patient at an academic 
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center in France (35) with severe treatment- refractory myositis who had failed to the 
combination of methotrexate and azathioprine, responded  to the addition of abatacept 
with a significant improvement in muscle strength and function  and was able to reduce 
daily prednisone. A Japanese patient with refractory anti-signal recognition particle 
myopathy achieved remission following treatment with abatacept (36).  Dr. Rider is aware 
of at least 10 other refractory JDM patients under treatment with abatacept who have 
experienced an excellent response.  All patients have received the dosing regimen used 
in JIA patients (37).
    1.4 ETHICAL CONSIDERATIONS
          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 will 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). 
 
    1.5  RATIONALE 
JDM is an autoimmune disease involving specific immunity, including plasmacytoid 
dendritic cells, B and CD4+ T lymphocytes.  We postulate that the immunomodulatory 
action of abatacept in JDM will inhibit the co-stimulatory signal from CD80 and CD86, by 
inhibiting dendritic-cell mediated T cell activation.  Our hypothesis is that treatment 
refractory patients with JDM will respond to abatacept and that abatacept will also be 
safe for use in this population.
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2.0
OBJECTIVES
This open label non-randomized trial will assess the safety and efficacy of 
subcutaneous abatacept in 10 patients ≥ 7 years of age with refractory JDM.
    2.1  PRIMARY OBJECTIVE
AIM: To assess the safety and efficacy of subcutaneous abatacept in an open-label trial 
of refractory JDM in 10 adults and children.  

Hypothesis A:  Abatacept will be well-tolerated and safe in treatment–refractory 
JDM patients.  For this, the NCI Common Terminology criteria version 4.0 June 2010 
will be applied.  Medical records will be reviewed for the 6 months prior to enrollment to 
obtain adverse events prior to beginning abatacept, which will be compared to any 
adverse events that develop after abatacept was initiated. Particular attention will be 
given to serious adverse events and infections.  Patient evaluations will include:  vital 
sign measurement, physical examination, and laboratory parameters for hematology 
and routine chemistries.

Hypothesis B: Patients will clinically improve after treatment with abatacept.  We 
hypothesize that at least 6 of 10 patients will meet the myositis preliminary definition of 
improvement after receiving 24 weeks of therapy with abatacept.  
  
Definitions of improvement (DOIs) for clinical trials in IIM have recently been proposed 
by the IMACS Group (International Myositis Assessment and Clinical Studies) for adult 
and pediatric myositis utilizing six core set measures among five domains of myositis 
disease activity (38)  (see Appendix C).  They are: 
a) Physician global disease activity; 
b) Parent/patient global disease activity; 
c) Muscle strength, utilizing manual muscle strength testing (MMT8); 
d) Physical function assessment using the (Childhood) Health Assessment 
Questionnaire (CHAQ); 
e) Laboratory assessment using the most abnormal serum muscle enzyme level; and 
f)
Extra-muscular disease activity using the Myositis Disease Activity Assessment 
Tool (MDAAT). (see section 14.0: assessment tools: description) (39)   
For this clinical trial, the primary endpoint will be the published Definition of 
Improvement (DOI): 3 of any of the 6 core set measures improved by ≥ 20%, with 
no more than 2 of the core set measures worsening by ≥25% (worsening 
measures cannot include the muscle strength). (Appendix D1) (38)  
The PRINTO Group (Pediatric Rheumatology International Trials Organization) has 
developed and validated a core set of outcome variables for the evaluation of response 
to therapy in JDM. (40)  (Appendix C) 
The additional PRINTO core set activity measures are:  
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1) Childhood Myositis Assessment Scale is used as a measure of strength; 
2) A health related quality of life measure, CHQ-PF50, is used and 
3) Disease Activity Score  (DAS) is used as a measure of global activity (42)
PRINTO also has a definition of minimal clinical improvement (20%), moderate (50%) 
and major (70%) improvement (41) (Appendix D).
 
PRINTO has also defined clinically inactive disease (41) as creatine kinase ≤150 (within 
normal limits), CMAS ≥48, MMT ≥78 and Physician Global Activity VAS ≤0.2. (41) 
(Appendix D) 
The frequency of minimal, moderate and major improvement by the DOIs, with 
20%, 50% and 70% change, as well as clinically inactive disease by the PRINTO 
criteria will also be examined in this trial.
 
Finally, the DOIs are currently undergoing revision in an ACR-EULAR project that is 
combining the efforts of IMACS and PRINTO.  New definitions of minimal, moderate 
and major improvement have been developed and are expected to be finalized within 
the coming year. These newly-developed definitions will be added to the criteria as a 
secondary efficacy outcome measures for this trial (Appendix D2).  Other criteria found 
to perform very highly in the ACR-EULAR project will be used as secondary endpoints 
in this trial (Appendix D2).
       2.2 
SECONDARY OBJECTIVES
Steroid-sparing benefit will be obtained. We hypothesize that we can reduce daily 
corticosteroid therapy by at least 20% in this population of treatment-refractory 
patients. 
To this end, a standardized corticosteroid tapering regimen will be utilized (Section 5). 
All subjects will remain on their initial prednisone dose until at least the first follow-up 
visit (week 6) and until they meet the definition of improvement and are rated as ‘much 
improved’ by both the physician and the patient or parent. The prednisone dose may 
then be reduced according to the standardized steroid tapering schedule in Section 5.     
a) To examine response to treatment  in individual core set measures of disease activity 
as developed by IMACS, including Physician and Patient/Parent global activity, Muscle 
strength (by manual muscle testing, MMT-8), Physical function (by HAQ/CHAQ), Muscle 
enzymes, and Extra-muscular activity (by the Myositis Disease Activity Assessment 
Tool, MDAAT).
b) To examine other core set activity measures as developed by PRINTO, including the 
Childhood Myositis Assessment Scale (CMAS), the Disease Activity Score (DAS) and 
Health Related Quality of Life Questionnaire (Childhood Health Questionnaire (CHQ-
PF50) for children or SF-36 for adults.
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c) To examine improvement in patient reported outcomes, including health-related quality 
of life and fatigue measures, including the PROMIS fatigue questionnaire and PedsQL 
fatigue questionnaire.  Both patient and parent questionnaires will be obtained, for 
patients < 18 years of age.
d) (optional Assessment by Dermatology) To examine improvement in cutaneous activity, 
using the Cutaneous Dermatomyositis Area and Severity Index (CDASI) and the 
Dermatology Life Quality Index (DLQI), as well as periungual nailfold capillary density. 
To document changes in cutaneous findings by standardized photography.
e) To examine improvement in muscle inflammation by examining a thigh/pelvis STIR MRI 
at baseline and 6 month follow-up.
f)
To examine that disease damage does not increase while under treatment with 
abatacept, by examining the Myositis Damage Index (MDI) at baseline and 6 month 
follow-up.
g)  To examine improvement of biomarkers that may relate to disease pathogenesis and 
the mechanism of action of abatacept in JDM, including:   
i.
Immunophenotyping for CD4, CXCR3, IFNγ (TH1), CD4, CCR4, CRTH2, IL4 
(TH2), CD4, CCR6, IL17a (TH17), CD4, CD25, Foxp3 (T regulatory cells), B cell 
markers and macrophage markers along with B71, B72, CTLA4, CT28 on fresh 
lymphocytes
ii.
Isolation of T cells, B cells, dendritic cells, monocyte and macrophages, and freeze 
the isolated cells for subsequent molecular and functional analysis, including gene 
expression profiling
iii.
Cytokine 30-plex panel on serum samples
iv.
Peripheral blood mononuclear cells for RNA gene expression using a gene bead 
chip panel.
h)   To evaluate immunogenicity and the pharmacokinetics of SC abatacept by the trough 
concentrations at steady state. 
 
3.0
STUDY DESIGN
TREATMENT PHASE 
This study will employ an open label nonrandomized design in the treatment of subjects 
with JDM.  Study participation will consist of a screening visit and 5 protocol visits over 
six months (week 0, week 6, week 12, week 18, and week 24) for each subject, and phone 
follow-up in between in-person visits (week 2, week 4, week 8, week 10, week 14, week 
16, week 20, and week 22). Some patients will undergo some of the screening tests at 
home, and present results at a screening visit. This will enable them to move to the week 
0 visit simultaneously and begin treatment.
At Visit 1, which will be treatment initiation, eligible subjects will be instructed on the use 
and side effects of subcutaneous abatacept. Patients will be started on the study  drug 
(abatacept) 125 mg SQ weekly for subjects with body weight ≥ 50KG and 87.5 mg SQ for 
subjects with weight  <50 KG. For patients not improving with therapy by at least 5% on 
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at least 3 of 6 core set measures (IMACS or PRINTO measures) at week 12, they would 
be offered the opportunity to increase their dose of treatment to abatacept 212.5 mg SQ 
weekly (125 mg prefilled syringe plus 87.5 mg prefilled syringe) for subjects with weight 
≥ 50KG and 137.5 mg SQ weekly (87.5 mg prefilled syringe plus 50 mg prefilled syringe) 
for subjects with weight <50KG, or to continue on their present dose.
At each study visit, patients will undergo assessment and questionnaires to include the 
core set myositis activity measures (both IMACS and PRINTO core set measures), 
patient questionnaires (including patient/parent global activity, [Childhood] Health 
Assessment Questionnaire ([C]HAQ), Health Related Quality of Life Questionnaire 
(Childhood Health Questionnaire (CHQ-PF50) for children or SF-36 for adults) and 
PROMIS and PedsQL fatigue questionnaires;    at Visit 1 (week 0) and Visit 5 (week 24),  
the Myositis Damage Index- performed by a pediatric or adult rheumatologist; at visit 1 
(week 0) and visit 5 (week 24);  Cutaneous Dermatomyositis Activity and Severity 
Index and  Dermatology Life Quality Index,  by our affiliated dermatologist Dr. Allison 
Ehrlich or Dr. Rider on interim visits. (The dermatologic assessments will be optional)     
(Section 14). An open label extension of 6 months will be offered to subjects who met the 
primary study endpoint and are rated by the study physician as at least minimally 
improved from baseline visit. During this period, patients will be evaluated twice a year.
      3.1 
ENDPOINTS     
Primary
The primary endpoint of this trial is to establish safety and efficacy of Abatacept in 
patients with refractory Juvenile Dermatomyositis 
a) Safety: Abatacept will be well-tolerated and safe. 
b) Improvement in myositis disease activity:  the published IMACS myositis definition of 
improvement will be achieved in at least 6 of 10 patients at the end of the trial (38).
Secondary
a) To evaluate the response rate to Abatacept in JDM using the PRINTO definition of 
improvement, including criteria for minimal, moderate and major clinical response (40, 
41).
b) To evaluate the response rate to Abatacept using newly developed criteria for myositis 
clinical response, which are pending ACR-EULAR approval (Appendix D2), as well as 
other top performing criteria considered at the International Myositis Response Criteria 
Consensus Conference.
c) To examine response to treatment  in individual core set measures of disease activity 
as developed by IMACS, including physician and patient/parent global activity, muscle 
strength (by manual muscle testing), physical function (by HAQ/CHAQ), muscle 
enzymes, and extra-muscular activity (by the Myositis Disease Activity Assessment 
Tool)
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d) To examine other core set activity measures as developed by PRINTO, including the 
Childhood Myositis Assessment Scale, the Disease Activity Score and CHQ-PF50 
e) Steroid-sparing benefit: 20% reduction of the corticosteroid therapy  will be achieved 
in 6 of 10 patients at the end of the trial 
f)
To examine improvement in patient reported outcomes, including health-related 
quality of life and fatigue measures, including the PROMIS and PedsQL fatigue 
questionnaires.  Both patient and parent questionnaires will be obtained, for patients 
< 18 years of age.
g) To examine improvement in cutaneous activity, using the Cutaneous Dermatomyositis 
Area and Severity Index (CDASI) and the Dermatology Life Quality Index, as well as 
periungual nail fold capillary density. To document changes in cutaneous findings by 
standardized photography.
h) To examine improvement in muscle inflammation by examining a thigh/pelvis STIR 
MRI at baseline and 6 month follow-up.  MRI readings will be blinded to the clinical 
assessment information, including, if possible, date of assessment, and study drug 
dose.
i)
To examine that disease damage does not increase while under treatment with 
abatacept, by examining the Myositis Damage Index at baseline and 6 month follow-
up.
h) To examine at baseline, 3  and 6 months biomarkers of disease  including:   
i.
Immunophenotyping for CD4, CXCR3, IFNγ (TH1), CD4, CCR4, CRTH2, IL4 
(TH2), CD4, CCR6, IL17a (TH17), CD4, CD25, Foxp3 (T regulatory cells), B 
cell markers and macrophage markers along with B71, B72, CTLA4, CT28 on 
fresh lymphocytes
ii.
Isolation of T cells, B cells, dendritic cells, monocyte and macrophages, and 
freeze the isolated cells for subsequent molecular and functional analysis, 
including gene expression profiling
iii.
Cytokine 30-plex panel on serum samples
iv.
Peripheral blood mononuclear cells for RNA gene expression using a gene 
bead chip panel.
     Biomarker studies will be blinded to the clinical assessment information and drug   
dose.
To evaluate immunogenicity and the pharmacokinetics of SC abatacept  by the 
steady-state trough concentrations of abatacept  at week 0, week 12 and week 24  
3.2
 SAFETY ENDPOINTS
Safety assessment will include adverse events, vital signs, physical examination 
findings, laboratory parameters and NCI common terminology safety assessment, 
including focus on serious adverse events and the infection module.  This will be 
collected in person during study visits, but in between study visits, a phone call will be 
made at weeks 2, 4,8,10,14,16, 20 and 22  to review adverse events. 
 Patient evaluations include:
1. Vital sign measurement, physical examination 
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2. Laboratory parameters for hematology, routine chemistry, muscle enzymes and 
urinalysis
3. NCI Common Toxicity assessment (version 4.0 June 2010) including focus on serious 
adverse events and the infection module.
4. Adverse event monitoring 
5. Assessment of primary and secondary efficacy endpoints
4.0
SUBJECT POPULATION
Enrolled patients will include male and female, adults with a definite or probable 
diagnosis of  JDM  and pediatric patients ≥ seven   years of age and older with definite 
or probable JDM (using the criteria of Bohan and Peter-Appendix A) [33]  with greater 
than four  months of disease duration. Patient body weight will be at least 25 kg. Patient 
enrolment will occur at the GWU Myositis Center of the Medical Faculty Associates.   
The total number of subjects will be 10.  A diagnosis of DM prior to age 18 is considered 
JDM; patients with JDM enrolled after age 18 will continue to be classified as JDM.
A log will be kept of all patients screened for study enrollment and will document the 
reasons for exclusion for each subject not entered. Every effort will be made to keep 
patients in the study until they complete all study procedures. We plan to screen up to 
30 patients in clinic to enroll 10 patients.  Additional patients may be screened by phone 
and not seen in clinic if not qualified for the protocol.
4.1Inclusion Criteria: 
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 In order to qualify for participation, a subject must meet all of the following 
criteria:
1
Considering 1A-1F below, does the subject have documented criteria for probable 
(2 + rash) or definite (3-4 + rash) juvenile DM by the criteria of Bohan and Peter? 
a. Does the subject have documented symmetric proximal muscle weakness on 
exam?   
                 
b. Does the subject have documented Gottron’s papules or Heliotrope rash on exam?  
                 
c. Does the subject have documented elevations of any of the following muscle 
enzymes (CK, LD, AST, ALT or aldolase)?
d. Was the age at diagnosis < 18 years? 
                
e. Has the subject had an EMG and if so, if so, does the subject have documented 
EMG evidence for myopathy  
                 
f.
Does the subject have documented muscle biopsy evidence of dermatomyositis?  
2
Is the body weight at least 25 kg or over?
3
Is the subject at least 7 years or older? 
4
Does the patient reside within the United States or Canada?
5
Considering 5A-5J below, Does the patient have refractory myositis? 
(As defined by the intolerance to or an inadequate response to corticosteroids plus 
at least one other IS agent?)
a. Has the patient had intolerance or an inadequate response to prednisone for at least 
one month?
b. Has the patient had intolerance at any time, or an inadequate response for at least 
3 months to azathioprine at least 2 mg/kg/d or 150 mg/day?
c. Has the patient had intolerance or an inadequate response to methotrexate at least 
15 mg/week or 0.3 mg/kg or 15 mg/m2/ week for at least 3 months?
d. Has the patient had intolerance or an inadequate response to   mycophenolate 
mofetil at least 30 mg/kg/d or 1000 mg bid for at least 3 months?
e. Has the patient had intolerance or an inadequate  response to   cyclophosphamide  
at  least 1.0 mg/kg/d poor
             500 mg/m2/month IV   for at least 3 months?
f.
Has the patient had intolerance or an inadequate response to   oral tacrolimus for 
at least 3 months?
g. Has the patient had intolerance or an inadequate response to   cyclosporine at least 
2.5 mg/kg/d for at least 3 months?
h. Has the patient had intolerance or an inadequate response to   IVIG   at least 1.0 
g/kg/month for at least 3 months?
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i.
Has the patient had intolerance or an inadequate response to   an anti-TNF agent 
(including Etanercept, Infliximab, Humira, etc) for at least 3 months?
j.
Has the patient had intolerance or an inadequate response to 2 infusions of 
Rituximab (375mg/m2 (for 4 doses), or 500 mg/m2 or 1000 mg for 2 doses)? 
6
Considering 6a-6f, Does the patient have a moderately active disease (MD global VAS 
with a minimum value of 2,5 cm on a 10 cm scale  plus another  2 other abnormal 
Core set Measures as listed above (7b-7f)
a. Does the MD global VAS have a minimum value of 2.5 cm on a 10 cm scale 
b. Is the MMT-8 score no greater than 125/150  
c. Does the Patient/parent Global VAS have a minimum value of 2.0 cm on a 10 cm 
scale 
d. Does the CHAQ/HAQ disability index have  minimum value of 0.25
e. Is at least one of the muscles enzymes (including CK, aldolase, LDH, AST and ALT) 
elevated at a minimum level of 1.3 times the upper limit of normal. If more than one 
muscle enzyme is identified as being elevated and meeting the above guidelines, 
then the most abnormal will be selected and this enzyme will be the target enzyme 
followed to evaluate disease improvement or worsening. 
f.
Does the Global extra-muscular disease have a score with a minimum value of 2 cm 
on a 10 cm VAS scale.  
7
Is the prednisone dose stable for 4 weeks prior to the screening visit? (recommended 
dose ≤ 1.0 mg/kg/day)
8
Background therapy with at least 1 non-corticosteroid immunosuppressive agent is required 
at a stable dose (timeframe mentioned below) prior to the screening visit with the following 
exception: 

There is written documentation in the medical record that the patient is intolerant 
of an IS agent which is defined as side effects that require discontinuation of the 
medication(s) or an underlying condition that precludes the further use of the IS 
medication.  
Stable dose for 4 weeks: Prednisone, IVIG, IV Methylprednisolone
Stable dose for 6 weeks: Methotrexate, Azathioprine, mycophenolate mofetil, leflunomide, 
cyclophosphamide, tacrolimus or cyclosporine
9
Did an immunosuppressive agent, discontinued prior to the screening visit, have the 
required washout period: 
4 weeks for prednisone, IV methylprednisolone and methotrexate 
8 weeks for other IS agents including IVIG, Azathioprine, mycophenolate, mofetil, 
leflunomide, cyclophosphamide, tacrolimus or cyclosporine. 
For discontinuation of biologic therapies-with the required washout period
 
IRB NUMBER: 111418
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**Age and Reproductive Status Reproductive Status: Definition of Women of 
Child-Bearing Potential (WOCBP). WOCBP comprises women who have 
experienced menarche and who have not undergone successful surgical sterilization 
(hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or who are not post-
menopausal.
The following women are WOCBP:

Women using the following methods to prevent pregnancy: Oral contraceptives, 
other hormonal contraceptives (vaginal products, skin patches, or implanted or 
injectable products), or mechanical products such as intrauterine devices or barrier 
methods (diaphragm, condoms, spermicides).

Women who are practicing abstinence.

Women who have a partner who is sterile (e.g., due to vasectomy).
washout period for Rituximab is 3 month+ and CD19 has to be detectable and IgG level is within 
normal limits (normal serum levels of IgG per reference lab: 7-9 years ≥572 mg/dl, 10-11 yrs ≥698 
mg/dl, 12-13 yrs ≥759 mg/dl, 14-15 yrs ≥716 mg/dl,16-19 yrs ≥549 mg/dl, >19 yrs ≥700 mg/dl). 
10
If on hydroxychloroquine or colchicine, the dose should be stable for 6 weeks prior to Visit 
1
11
Is the statin or fibric acid derivative drug dose stable for 6 weeks prior to the screening 
visit?
12
Ability of patient or parent to complete self-report questionnaires.
13
If of reproductive potential**, does the patient agree to use a reliable method of birth 
control during the 24 week duration of the trial and for 100 days after the last dose of 
study drug was administrated?
14
Does patient agree to forgo immunization with a live vaccine during the course of the study 
and for at least 3 months after discontinuation of study drug?
15
Patients must have a letter from the referring rheumatologist or specialist supervising the 
care of the JDM, agreeing to the patient’s participation in the study and to continuing to 
provide care for the patient, including emergency care during the trial.
16
Has the patient or parent provided informed consent, and assent when applicable for 
patients ages 8-17 or younger, for participation in study?
17
For children of divorced or separated parents:
A copy of the parental custody papers will be received.
One parent has sole custody and will sign the consent, OR There is joint custody and 
1 parent gives permission for the other parent to sign consent/be in charge of medical 
decisions, OR Both parents sign the consent
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WOCBP must be using an acceptable method of contraception to avoid pregnancy 
throughout the study and for up to 10 weeks after the last dose of study drug in such 
a manner that the risk of pregnancy is minimized. 
WOCBP must have a negative urine pregnancy test result (minimum sensitivity 
25 IU/L or equivalent units of HCG) within 0 to 48 hours before the first dose of study 
drug. 
Women must not be breast-feeding.
Sexually active fertile men must use effective birth control if their partners are 
WOCBP. 
4.2 
Exclusion Criteria
In order to qualify for participation, subjects must not meet any of the following criteria:
1
Drug-induced myositis (myositis in patients taking medications known to induce myositis-
like syndromes, including, but not limited to, statin agents, fibric acid derivatives, and 
colchicine).
2
Juvenile polymyositis; inclusion body myositis; cancer-associated myositis, defined as the 
diagnosis of myositis within 2 years of the diagnosis of cancer except basal or squamous 
cell skin cancer or carcinoma in situ of the cervix if at least 5 years since excision
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3
Myositis in overlap with another connective tissue disease (CTD) that precludes the 
accurate assessment of a treatment response (for example, difficulty in assessing 
muscle strength in a scleroderma patient with associated myositis)
4
History of receiving a live vaccine 4 weeks prior to initiation of study treatment
5
Does the patient have any of the following concomitant illnesses that would prevent adequate 
assessments or in the opinion of the investigator pose an added risk to patient:
a. Joint disease, severe calcinosis, or other musculoskeletal condition which precludes the 
ability to quantitate muscle strength
b. Wheelchair bound
c.
Recurrent or chronic infections, including HIV, hepatitis B or C, TB (incl contact with 
household contact with active TB and no prophylaxis), or recurrent or active infections with 
calcinosis
d. Symptomatic herpes zoster or herpes simplex (not including just simple oral HSV lesions) 
within past 12 weeks
e. Disseminated/complicated herpes zoster (multi-dermatomal involvement, ophthalmic 
zoster, CNS involvement, post-herpetic neuralgia
f.
Known liver disease (i.e. cirrhosis or other conditions compromising the synthetic function 
of the liver)
g. Disorder that would preclude accurate assessment of neuromuscular function?
h. Cardiomyopathy or arrhythmias that in the investigators opinion poses an additional risk for 
study participants.
i.
New York Heart Association Classification III or IV for congestive heart failure.
j.
Psychiatric illness that precludes compliance or neuromuscular assessment 
k. Life threatening non-myositis illness that would interfere with the patient’s ability to 
complete the study
l.
History of cancer within the last 5 years 
6
Known hypersensitivity to abatacept or prior receipt of abatacept
7
Serum creatinine > 2.0mg/dl
8
Pregnant females or nursing mothers 
9
Known or suspected history of drug or alcohol abuse within the past 6 months as 
determined by the medical record or patient interview 
10
Anticipated poor compliance 
11
Participation in another clinical experimental therapeutic study within 30 days of screening 
visit.
12
Any history or evidence of severe illness or any other condition that would make the 
patient, in the opinion of the investigator unsuitable for the study.
13
Low total WBC <2.000, platelets < 100,000/mm3; hemoglobin <10 gm/dl
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14
History of recurrent infection including active skin infections with calcinosis
15
Is the patient receiving and concomitant treatment with anti-TNF therapies, rituximab or anakinra 
or other biologic therapies? 
  
Washout period for etanercept is 1 month and anakinra is  1 week
Washout period for  adalimamub and infliximab  is 2 months 
Washout period for Rituximab is 3 and CD19 has to be detectable and IgG level is within normal 
limits (normal serum levels of IgG per reference lab: 7-9 years ≥572 mg/dl, 10-11 yrs ≥698 mg/dl, 
12-13 yrs ≥759 mg/dl, 14-15 yrs ≥716 mg/dl,16-19 yrs ≥549 mg/dl, >19 yrs ≥700 mg/dl). 
 
16
Initiation of colchicine and hydroxychloroquine as new drugs during study participation is 
not allowed.
17
Initiation of statins or fibric acid derivatives during study participation is not allowed.
18
Initiation of an exercise program within 4 weeks of the screening visit. Only a stretching 
program may be initiated during the study
19
Prisoners or subjects who are involuntarily incarcerated. 
20
Subjects who are compulsorily detained for treatment of either a psychiatric or physical 
(e.g., infectious disease) illness
5.0
     CONCOMITANT MEDICATIONS
One of the important issues of trial design involves the use of concomitant 
medications. IMACS has addressed this by survey and consensus conference format 
and both adult and pediatric specialists agreed that concomitant corticosteroids 
should be allowed in a clinical trial, but tapering should follow a standardized 
reduction regimen. If the patient has achieved the Definition of Improvement (DOI)   
at week 6 (visit 2) or at any point thereafter rated moderate improvement 
compared to the baseline visit and/or mild improvement compared to the last 
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visit, tapering of corticosteroids may commence using a dose reduction schedule as 
follows:

For patients taking 36 to 60 mg daily, prednisone will be tapered by 10 mg , if they 
meet the DOI and are rated as at least “at least “mild improvement” compared to 
the last visit and/or “Moderate improvement” compared to the baseline visit ” by 
both the physician  and the patient or parent (if patient is less than 18 years of 
age). 

For patients taking 16  to 35  mg daily, prednisone will be tapered by 5 mg , if they 
meet the DOI and are rated as at least “at least “mild improvement” compared to 
the last visit and/or “Moderate improvement” compared to the baseline visit ” by 
both the MD and the patient or parent (if patient is less than 18 years of age).

For patients taking 6 to 15  mg daily, prednisone will be tapered by 2.5  mg , if they 
meet the DOI and are rated as at least “at least “mild improvement” compared to 
the last visit and/or “Moderate improvement” compared to the baseline visit ” by 
both the MD and the patient or parent (if patient is less than 18 years of age).

For patients taking 1 to 5  mg daily, prednisone will be tapered by 1 mg if they 
meet the DOI and are rated as at least “at least “mild improvement” compared to 
the last visit and/or “Moderate improvement” compared to the baseline visit ” by 
both the MD and the patient or parent (if patient is less than 18 years of age).

For patients receiving intravenous pulse methylprednisolone therapy, they may 
alternatively reduce the dose of IV therapy, instead of oral by a decrease of 25% if 
they meet the DOI and are rated as at least “at least “mild improvement” compared 
to the last visit and/or “Moderate improvement” compared to the baseline visit ” by 
both the MD and the patient or (parent if patient is less than 18 years of age).

Corticosteroid tapering using the aforementioned guidelines can be commenced at 
any time on or after week 6 if (a) the patient achieves the DOI and is rated as at 
least “mild improvement” compared to the last visit and/or “Moderate 
improvement” compared to the baseline visit by both the MD and the patient or 
parent (for patients less than 18 years of age) or (b) there are complications or 
circumstances that, in the investigator’s opinion, necessitate the tapering of 
corticosteroids. The taper schedule is at each visit and the corticosteroid dose will 
remain stable between study visits.  As noted above under Inclusion Criteria #6, it 
is recommended that patients be on less than 1 mg/kg/day of prednisone at study 
entry. 
Corticosteroid dosing in disease flare: 
If in the clinical investigator’s opinion, there are complications or worsening of disease 
that necessitate an increase in the corticosteroid dose, then the smallest reasonable 
increase should be considered.
IRB NUMBER: 111418
IRB APPROVAL DATE: 05/02/2020


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A stable dose of an immunosuppressive (IS) agent must be maintained for a period of 
4-6 weeks prior to Visit 1.  The dose(s) should be held constant without tapering (unless 
there is a serious adverse event). 
Medications known to induce myositis-like syndromes, including but not limited to, statin 
agents, fibric acid derivatives, colchicine, and hydroxychloroquine will be subject to the 
following restrictions. See Tables 1, 2 & 3 below.
5.1
Pre-study drug restrictions 
Table 1
Drug
Restrictions
Biologic Agents 
See Table Below for washout period. 
Prednisone
Stable dose for 4 weeks prior to Visit 1
If discontinued, a washout of 4 weeks is 
required
IVIG (JDM)
Stable regimen 4 weeks prior to Visit 1. If 
discontinued a washout period of 8 weeks is 
required.
IV methylprednisolone (pulse therapy) 
Stable regimen 4 weeks prior to Visit 1
If discontinued, a washout of 4 weeks is 
required
Methotrexate
Stable dose for 6 weeks prior to Visit 1
If discontinued, a washout of 4 weeks is 
required
Other immunosuppressive agents including:  
azathioprine, mycophenolate mofetil, leflunomide, 
cyclophosphamide, tacrolimus or cyclosporine
Stable dose for 6 weeks prior to Visit 1
If discontinued, a washout of 8 weeks is 
required
Statin agents: Lovastatin, Simvastatin, Pravastatin, 
Fluvastatin, Atorvastatin and
Fibric acid derivatives: Fenofibrate (Lipidil TM, Lipidil 
micro TM, Tricor), Gemfibrozil (Lopid TM), Benafibrate 
(Bezalip TM), Clofibrate (Atromid-S)   
Stable dose for 6 weeks prior to Visit 1
Colchicine
Stable dose for 6 weeks prior to Visit 1
Hydroxychloroquine
Stable dose for 6 weeks prior to Visit 1
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IRB APPROVAL DATE: 05/02/2020


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Version 10.5 22April2020                                                                       Page 39 of 84
*For rituximab, CD19 has to be detectable and IgG level is within normal limits 
(normal serum levels of IgG per reference lab: 7-9 years ≥572 mg/dl, 10-11 yrs 
≥698 mg/dl, 12-13 yrs ≥759 mg/dl, 14-15 yrs ≥716 mg/dl,16-19 yrs ≥549 mg/dl, >19 
yrs ≥700 mg/dl).
5.2
Concomitant Medications Allowed for the Duration of the Study
   
Table 2
Drug
Restrictions
Prednisone
Stable dose for 4 weeks prior to Visit 1
(see tapering/escalation guidelines above 
under section 5.0)
IVIG 
Stable regimen for 4 weeks prior to Visit 1
IV methylprednisolone (pulse therapy) 
Stable regimen for 4 weeks prior to Visit 1
Methotrexate and other IS agents including 
azathioprine, mycophenolate mofetil, leflunomide, 
cyclophosphamide, tacrolimus or cyclosporine
Stable dose for 6 weeks prior to Visit 1  
Statin agents: Lovastatin, Simvastatin, Pravastatin, 
Fluvastatin, Atorvastatin and
Fibric acid derivatives: Fenofibrate (Lipidil TM, Lipidil 
micro TM, Tricor), Gemfibrozil (Lopid TM), Benafibrate 
(Bezalip TM), Clofibrate (Atromid-S)   
Stable dose for 6 weeks prior to Visit 1
Colchicine
Stable dose for 6 weeks prior to Visit 1 
Hydroxychloroquine
Stable dose for 6 weeks prior to Visit 1
*When possible, patients will take no more than 2 immunosuppressive agents, not including 
prednisone, IVIG, colchicine, hydroxychlorloquine
5.3
Concomitant Medications Not Allowed for the Duration of the Study
Table 3
Drug
Restrictions
Biologic agents 
Not allowed throughout study
Colchicine 
Initiation of new therapy is not allowed after 
Visit 1 or throughout enrollment.
IRB NUMBER: 111418
IRB APPROVAL DATE: 05/02/2020


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Fibric acid derivatives: Fenofibrate (Lipidil TM, Lipidil 
micro TM, Tricor), Gemfibrozil (Lopid TM), Benafibrate 
(Bezalip TM), Clofibrate (Atromid-S)   
Initiation of new therapy is not allowed after 
Visit 1 or throughout enrollment
Statin agents: Lovastatin, Simvastatin, Pravastatin, 
Fluvastatin, Atorvastatin
Initiation of new therapy is not allowed after 
Visit 1 or throughout enrollment
Hydroxychloroquine
Initiation of new therapy is not allowed after 
Visit 1 or throughout enrollment.
IVIG and IV methylprednisolone use throughout the trial:
 
These medications will be allowed during the trial.

Patients must be on a stable regimen of 4 weeks prior to Visit 1.

Dose of IVIG and dosing interval of both agents must remain stable. 

Suggested guidelines for IVIG:  one (1) - two (2)  grams / kg monthly  
Suggested guidelines for IV methylprednisolone or equivalent 10 - 30 mg/kg: IV once 
weekly to IV once per month.
  5.4
Other Restrictions 

A patient may continue with an exercise program that was initiated before the 4 
week period prior to the screening visit, regardless of the components of the 
program (stretching, muscle building, etc.) 

A stretching program may be initiated during the 4 week period prior to the 
screening visit or during the study period as long as there is no muscle building 
component to the program.
6.0   
STUDY MEDICATION
           
Study Treatment: Abatacept
 
Definition of Investigational Product: A pharmaceutical form of an active substance or    
placebo being tested or used as a reference in a clinical study, including products already 
with a marketing authorization but used or assembled (formulated or packaged) in a way 
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Version 10.5 22April2020                                                                       Page 41 of 84
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. Abatacept will be provided by 
BMS in 50 mg pre-filled syringes, 87.5 mg pre-filled syringes and 125 mg prefilled 
syringes. 
       6.1
Study Medication Description
Abatacept Injection, 125 mg/Syringe (125 mg/mL), is a sterile solution for SC 
administration, which contains approximately 125 mg abatacept, 171 mg sucrose, 8 mg 
Poloxamer 188, 0.29 mg monobasic sodium phosphate, monohydrate, and 0.84 mg 
dibasic sodium phosphate, anhydrous, in Water for Injection. 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. 
Two presentations of Abatacept Injection 125 mg/Syringe are currently commercialized:

Abatacept injection prefilled syringe with UltraSafe Passive Needle Guard (SSI 
NeedleGuard) and flange extenders

Abatacept injection prefilled syringe with flange bags have been observed.
Abatacept injection, 50 mg/syringe (50 mg/ml) and Abatacept injection, 87.5 mg/syringe 
(87.5 mg/ml) will also be available for subjects with body weight <50 kg 
      6.2  
Study Medication Schedule
At Visit 1 (week 0), eligible subjects will be instructed on the use and potential side 
effects of subcutaneous abatacept and will be started on the study drug (abatacept 125 
mg SQ weekly for subjects with body weight ≥ 50, or abatacept 87.5 mg SQ weekly  for 
subjects with body weight < 50 kg) ). Subjects will be on weekly Abatacept for the 
duration of the study (from week 0 through week 24). For patients not improving with 
therapy by at least 5% on at least 3 of 6 core set measures at week 12 (visit 3), and 
rated as unchanged or worsened from visit 1 by the study physician, they would be 
offered the opportunity to increase their dose of treatment to abatacept 212.5 mg (125 
mg prefilled syringe plus 87.5 mg prefilled syringe) weekly subcutaneously for subjects 
with body weight ≥ 50 kg  or to abatacept 137.5 mg (87.5 mg prefilled syringe plus 50 
mg prefilled syringe) for subjects withy body weight < 50 kg, or to continue on their 
present dose.
IRB NUMBER: 111418
IRB APPROVAL DATE: 05/02/2020


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Version 10.5 22April2020                                                                       Page 42 of 84
STUDY SCHEMATIC 
          
W0                        W6                               W12                           W18                      W24
                      
   w2       w4                           w8          w10                       w14      w16                   w20      w22
                  
                         V1                           V2                               V3                                V4                         V5
  (Screening)      Treat                                                          Potential
Dose                                                       Treat.
                           starts                                                          increase                                                    ends  
                               
The short lines indicate phone follow-ups, which will occur at weeks 2, 4, 8, 10, 14, 16, 20 and 
22
An open label extension phase will be offered for up to 6 months (visit could be in time 
less than that) for patients meeting the definition of improvement and who are 
rated by their study physician as at least minimally improved.
  6.3 
Drug Ordering and Accountability
Initial Orders:  The BMS project manager will be contacted for study drug     
requirements. 
Re-Supply:  The BMS project manager will be contacted for study drug requirements. 
Packaging and Labeling:  Abatacept SC is supplied in a box of 4 syringes.   
Handling and Dispensing: 
Administration of Study Medication
The investigational product will 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 by authorized personnel, as dictated by local regulations.
The investigator is responsible for ensuring that the investigational product is stored under 
the appropriate environmental conditions (temperature, light, and humidity), as described 
below:
Abatacept SC formulations (prefilled syringes) will be stored under refrigeration 
(approximately 2 to 8°C) and protected from long-term (more than 24 hours) exposure to 
light. 
Abatacept injection, 125 mg/syringe (125 mg/mL) is ready to use solutions provided in 
pre-filled siliconized syringes with a 29 gauge needle. 
IRB NUMBER: 111418
IRB APPROVAL DATE: 05/02/2020


Abatacept in the Treatment of Refractory Juvenile Dermatomyositis
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Version 10.5 22April2020                                                                       Page 43 of 84
Abatacept injection, 50 mg/syringe (50 mg/ml) and Abatacept injection, 87.5 mg/syringe 
(87.5 mg/ml) will also be available for subjects with body weight <50 kg 
Care will be taken when handling the injectable drug products that are used in this 
protocol. Proper aseptic techniques will be used 
Patients will be instructed to inject the full amount in the syringe (1 mL), which provides 
either 125 mg of Abatacept or 87.5 mg. At week 12 and weekly until the end of the study, 
some patients (those without improvement by at least 5% who are rated as unchanged 
or worsened by the study physician and those who agreed to this dose change) will be 
instructed to inject the full amount of a second syringe (1 ML) containing 87.5 mg of 
abatacept for subjects with body weight ≥ 50 kg or a second syringe containing 50 mg of 
abatacept for subjects with body weight < 50 kg. 
Abatacept injection should be inspected visually for particulate matter and discoloration 
prior to administration, whenever solution and container permit.  ABATACEPT prefilled 
syringes should not be used if exhibiting particulate matter or discoloration. ABATACEPT 
should be clear and colorless to pale yellow, according to the directions provided in the 
Instructions for Use.
Injection sites (abdomen, thigh, upper arms) should be rotated and injections should 
never be given into areas where the skin is tender, bruised, red, or hard.
6.4 Storage and Accountability
All study drugs must be kept in a secure location under appropriate storage conditions 
(see investigator brochure).   The medication provided for this study is for use only as 
directed in the protocol.  GWU Medical Faculty Associates will be responsible for the 
storage, handling, and dispensing of study drug.  GWU Medical Faculty Associates will 
monitor all documentation related to drug handling activities to ensure adherence to 
proper procedures.  At each study visit, GWU Medical Faculty Associates will dispense 
the required study medication needed until the next study visit.
All used and unused study drugs must be retained at the clinic for reconciliation and 
accountability and should be destroyed at the study site by authorized personnel 
according to approved procedures or collected by the monitor for disposal.
7.0  
TREATMENT PLAN
All subjects must sign the informed consent form (ICF) and if applicable privacy 
authorization for release of health information prior to initiating any screening 
procedures including: discontinuing/changing or withholding (washout) of any 
medication.  It is expected that after being consented, if any subject is using a 
IRB NUMBER: 111418
IRB APPROVAL DATE: 05/02/2020


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Version 10.5 22April2020                                                                       Page 44 of 84
concomitant medication where his/her dosage has not met the stable dose time frame 
outlined in Section 5.0 the subject will be asked to return to the site after the 
appropriate timeframe to complete the Visit 1 procedures.  This return to the site would 
be considered a continuation of screening visit.  At no time should a subject withhold 
medication prior to signing the ICF. The visit schedule is outlined in “Treatment 
Protocol Schedule.”  
The original signed patient consent form will be kept in the patient’s source document 
study folder and maintained at the clinical site.  A copy of the signed patient consent 
form will be given to the study participant.
 7.1. Details on Treatment Schedule and Procedures
A schedule of all study visits and assessments is provided in Appendix E, table 1.  
Appendix E, Table 2 provides all laboratory studies being performed on screening and 
throughout the trial.  Patient should be encouraged to adhere to the study visit 
schedule unless an emergency occurs preventing compliance.
Screening/enrollment
Subjects will be screened at the screening visit to determine their eligibility for enrollment. 
The following data are to be collected at Screening Visit for every patient and recorded 
in the CRF.

Obtain written informed consent for screening and treatment phase of study, and 
privacy authorization for release of medical information to include muscle biopsy 
results and tissue if done previously. 

Demographics: date of birth, sex, race

Diagnosis of definite or probable JDM by Bohan and Peter criteria (or JDM by 
newly-developed myositis classification criteria after approval by American College 
of Rheumatology), and date of diagnosis

Review inclusion and exclusion criteria for eligibility for study and verify that 
inclusion/exclusion criteria have been met

Obtain and record medication history 

Obtain referring physician’s contact information,  patient release to share 
information, and agreement with patient’s potential entry into trial

Medical and surgical history: past and current medical and surgical history relevant 
for purpose of the study.

Vital signs: height (m), weight (kg), pulse (beats/min), blood pressure (mmHg), and 
pulse oximetry 

History and physical examination

Core set measures: CMAS, MMT-8, MDAAT (Extra-muscular Global activity), MD 
global activity (VAS), MD global damage (VAS), Patient-parent global activity 
(VAS), CHAQ/HAQ 
IRB NUMBER: 111418
IRB APPROVAL DATE: 05/02/2020


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Version 10.5 22April2020                                                                       Page 45 of 84

Obtain laboratory samples for clinical chemistry  (Chem-20, GGT), complete blood 
count (CBC) with differential, urinalysis, muscle enzymes (CK, LDH, aldolase, 
AST, ALT), GGT;  serologies: HIV antibody,  Hepatitis B surface antigen, Hepatitis 
B core antigen, and hepatitis C antibody , CD19 (for those who received rituximab 
before) Quantiferon will be completed at the screening visit. If the Quantiferon is 
indeterminate, then a T spot or PPD will be done.

Urinalysis

Collect urine sample for  pregnancy for females of child bearing potential (where 
applicable) Post-menopausal females defined as > age 60 and twelve (12) 
consecutive months of amenorrhea (lack of menstruation) will not be required to 
undergo pregnancy testing

Perform radiographic  examination of chest 
Some patients may wish to obtain screening labs at home and present the results 
at the screening visit. This would enable them to enter the intervention phase at 
the same visit as the screening visit. Results dated within 6 weeks prior to 
screening 
visit 
will 
be 
accepted 
to 
satisfy 
eligibility 
criteria. 
All safety labs during the regular study visit may be completed at the home 
institution up to 10 days prior to the visit and reports sent to GW. 
A re-screen protocol will be followed if a period of greater than 45 days elapses between 
the screening visit and start of treatment.
Visit 1/Week 0 (Intervention phase)
Visit 1(week 0)  will occur 0- 45 days after  all initial screening evaluations are concluded 
and the results of screening testing procedures are completed. The subject must remain 
in the clinic for 15 minutes following administration of study drug.  The following 
evaluations/procedures will be performed at this visit.  

Review of inclusion/exclusion criteria

NCI Common Toxicity Assessment

Obtain  vital signs (HR,BP,RR, oral temperature and weight, and if indicated , by 
history of shortness of breath or lung disease, pulse oximetry)

Medical history and  perform a full physical examination 

Collect urine sample for pregnancy test for females of child bearing potential prior 
to administration of study medication (where applicable)  

Core set activity measures: physician global activity, patient/parent global activity, 
manual muscle testing (MMT-8), CMAS, HAQ/CHAQ, MDAAT, muscle enzymes, 
CHQ PF-50/SF- 36, and Disease Activity Score (DAS) 

Myositis Damage Index (MDI): assessment of disease damage completed by the 
physician during physical examination.  

Physician  global damage (VAS)

Dermatology assessment: CDASI, MD Global Skin Activity + Damage (Optional)

CDASI, photographs of skin rashes, periungual nailfold capillary assessment. 
IRB NUMBER: 111418
IRB APPROVAL DATE: 05/02/2020


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Version 10.5 22April2020                                                                       Page 46 of 84

Quality of life questionnaires: CHQ PF-50/SF- 36,Dermatology Life Quality Index 
(DLQI), PROMIS/fatigue, Peds QL fatigue

Muscle MRI: bilateral thighs and pelvis, axial STIR and T1 images

Plain radiographs for calcinosis for patients with calcinosis

Obtain blood samples for Chem-20,GGT,  CK, aldolase, LDH, CBC with diff., TSH, 
anti-thyroid antibodies, von Willebrand Factor antigen level, quantitative 
immunoglobulins (IgG, IgM, IgA), ANA, ENA, dsDNA, Lymphocyte flow cytometry 
(TBNK cells) 

Urinalysis

Collect pre -treatment  research blood samples for Immunophenotyping (T, B cells 
and macrophages), gene expression,  and cytokine/chemokine analysis    (see 
Section 3.1.h) 

Myositis specific and associated autoantibody testing 

Collect pre -treatment  blood samples for immunogenicity

Pregnancy test for females of child bearing potential (where applicable)

Administer first dose of study medication and observe after the injection for at least 
15 minutes 

Schedule and instruct the subject to return for the next visit, teaching injection 
technique, review medication administration log. 
Phone follow-up #1 (14 days (+/- 7 days after visit 1)

Adverse events will be reviewed and recorded (NCI Common Toxicity criteria 
version 4.0). 
Phone follow-up #2 (will occur 28 days (+/- 7 days) after visit 1. 

Adverse events will be reviewed and recorded. 
 
Visit 2 (week 6) will occur 42 days (+/-10 days) after visit 1 

Review concomitant medication and query for adverse events and document in 
CRF

NCI Common Toxicity Assessment

Obtain  vital signs (HR,BP,RR, oral temperature and weight) and if indicated , by 
history of shortness of breath or lung disease, pulse oximetry)

Medical history and  perform a full physical examination 

Collect urine sample for pregnancy  test for females of child bearing potential prior 
to administration of study medication (where applicable)  

Core set activity measures: physician global activity, patient/parent global activity, 
manual muscle testing (MMT-8), CMAS, HAQ/CHAQ, MDAAT, muscle enzymes, 
CHQ PF-50/SF- 36, and Disease activity score (DAS), physician global damage 
(VAS) 

Dermatology assessment: CDASI, photographs of skin rashes

Quality of life questionnaires: CHQ PF-50/SF- 36,DLQI, PROMIS/fatigue, and 
Peds QL fatigue

Physician and patient/parent assessment of study outcome
IRB NUMBER: 111418
IRB APPROVAL DATE: 05/02/2020


Abatacept in the Treatment of Refractory Juvenile Dermatomyositis
Dr. Rodolfo Curiel, GWU
Version 10.5 22April2020                                                                       Page 47 of 84

Obtain blood samples for Chem-20, GGT,  CK, aldolase, LDH, CBC with diff., von 
Willebrand Factor antigen level [ may be performed at home institution, up to 
10 days before the visit date]

Urinalysis

Collect urine sample for  pregnancy  test for females of child bearing potential 
(where applicable)  

 Prednisone taper may commence using a predetermined schedule (section 5) If 
the patient has achieved the Definition of Improvement (DOI) and is rated by the 
study physician as at least minimally improved. 

Review log of medication self-administration and pharmacy to dispense study 
medication needed before next visit

Administer dose of study medication and observe after the injection for at least 15 
minutes 

Schedule and instruct the subject to return for the next visit  
Phone follow-up #3 (14 days (+/- 7 days after visit 2)

Adverse events will be reviewed and recorded (NCI Common Toxicity criteria 
version 4.0). 
Phone follow-up #4 (will occur 28 days (+/- 7 days) after visit 2. 

Adverse event will be reviewed and recorded. 
Visit 3 (week 12) will occur 42 days (+/- 10) days after Visit 2


Review concomitant medication and query for adverse events and document in 
CRF. 

NCI Common Toxicity Assessment

Obtain  vital signs (HR,BP,RR, oral temperature and weight) and if indicated , by 
history of shortness of breath or lung disease, pulse oximetry)

Medical history and  perform a full physical examination 

Collect urine sample for pregnancy  test for females of child bearing potential prior 
to administration of study medication (where applicable)  

Core set activity measures: physician global activity, patient/parent global activity, 
manual muscle testing (MMT-8), CMAS, HAQ/CHAQ, MDAAT, muscle enzymes, 
CHQ PF-50/SF- 36, and Disease activity score (DAS), physician global damage 
(VAS) 

Quality of life questionnaires: CHQ PF-50/SF- 36,DLQI , PROMIS/fatigue and 
Peds QL fatigue

Physician and patient/parent assessment of study outcome

Dermatology assessment performed by Rheumatologist : CDASI, photographs of 
skin rashes, periungual nailfold capillary assessment Dermatology Assessment 
Performed by Derm: CDASI, MD Global Skin Activity + Damage (Optional)
IRB NUMBER: 111418
IRB APPROVAL DATE: 05/02/2020


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Version 10.5 22April2020                                                                       Page 48 of 84

Obtain blood samples for Chem-20,GGT, CK, aldolase, LDH, CBC with diff.,  von 
Willebrand Factor antigen level, Lymphocyte flow cytometry (TBNK cells) [ may 
be performed at home institution, up to 10 days before the visit date]

Urinalysis

Collect research  blood samples for Immunophenotyping (T, B cells and 
macrophages), gene expression  and cytokine/chemokine analysis  (see Section 
3.1.h) 

Review if patient improved by ≥ 5% in at least 3 of 6 core set measures (by IMACS 
or PRINTO measures). If patient did not meet this criterion and was rated by the 
study physician as unchanged or worsened since visit 1, an option to increase the 
dose to 212 mg (87.5 + 125 mg) SQ weekly for subjects with body weight ≥ 50 kg 
or to increase the dose to 137.5 mg (87.5 mg + 50 mg) for subjects with body 
weight < 50 kg will be presented.

Prednisone taper may commence using a predetermined schedule (section 5) If 
the patient has achieved the Definition of Improvement (DOI) and is rated by the 
study physician as at least minimally improved. 
. 

Collect blood samples prior to the injection at Week 12 for PK and immunogenicity 
assessment 

Review log of medication self-administration and pharmacy to dispense study 
medication needed before next visit

Administer dose of study medication and observe after the injection for at least 15 
minutes 

Schedule and instruct the subject to return for the next visit 
Phone follow-up #5 (14 days (+/- 7 days after visit 3)

Adverse events will be reviewed and recorded (NCI Common Toxicity criteria 
version 4.0). 
Phone follow-up #6 (will occur 28 days (+/- 7 days) after visit 3. 

Adverse event will be reviewed and recorded. 
 
Visit 4 (week 18) will occur 42 days (+/-10 days) after visit 3 

Review concomitant medication and query for adverse events and document in 
CRF.

NCI Common Toxicity Assessment

Obtain  vital signs (HR,BP,RR, oral temperature and weight) and if indicated , by 
history of shortness of breath or lung disease, pulse oximetry)IRB NUMBER: 111418
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Version 10.5 22April2020                                                                       Page 49 of 84

Medical history and  perform a full physical examination 

Collect urine sample for pregnancy  test for females of child bearing potential prior 
to administration of study medication (where applicable)  

Core set activity measures: physician global activity, patient/parent global activity, 
manual muscle testing (MMT-8), CMAS, HAQ/CHAQ,MDAAT, muscle enzymes, 
CHQ PF-50/SF- 36, and Disease activity score (DAS), physician global damage 
(VAS)  

Quality of life questionnaires: CHQ PF-50/SF- 36,DLQI, PROMIS/fatigue and 
Peds QL fatigue

Physician and patient/parent assessment of study outcome

Obtain blood samples for Chem-20, GGT, CK, aldolase, LDH, CBC with diff., von 
Willebrand Factor antigen level [ may be performed at home institution, up to 
10 days before the visit date]

Urinalysis

Prednisone taper may commence using a predetermined schedule (section 5) If 
the patient has achieved the Definition of Improvement (DOI) and is rated by the 
study physician as at least minimally improved. 

Review log of medication self-administration and pharmacy to dispense study 
medication needed before next visit

Administer dose of study medication and observe after the injection for at least 15 
minutes 

Schedule and instruct the subject to return for the next visit  
Phone follow-up #7 (14 days (+/- 7 days after visit 4)

Adverse events will be reviewed and recorded (NCI Common Toxicity criteria 
version 4.0). 
Phone follow-up #8 (will occur 28 days (+/- 7 days) after visit 4. 

Adverse event will be reviewed and recorded. 
 Visit 5 (week 24) will occur 42 days (+/- 10) days after Visit 4 (End of Study 
Treatment or Early Termination)

Review concomitant medication and query for adverse events and document in 
CRF. 
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
NCI Common Toxicity Assessment

Obtain  vital signs (HR,BP,RR, oral temperature and weight) and if indicated , by 
history of shortness of breath or lung disease, pulse oximetry)

Medical history and  perform a full physical examination 

Collect urine sample for pregnancy  test for females of child bearing potential prior 
to administration of study medication (where applicable)  

Core set activity measures: physician global activity, patient/parent global activity, 
manual muscle testing (MMT-8), CMAS, HAQ/CHAQ, MDAAT, muscle enzymes, 
CHQ PF-50/SF- 36, and Disease activity score (DAS) 

Quality of life questionnaires: CHQ PF-50/SF- 36, DLQI , PROMIS/fatigue and 
Peds QL fatigue

Myositis Damage Index (MDI): assessment of disease damage completed by the 
physician during physical examination.  Physician global damage (VAS)

Physician and patient/parent assessment of study outcome

Dermatology assessment performed by Rheumatologist: CDASI, photographs of 
skin rashes, periungual nailfold capillary assessment

Dermatology Assessment performed by Dermatologist: CDASI, MD Global Skin 
Activity + Damange (Optional)

Prednisone taper may commence using a predetermined schedule (section 5) If 
the patient has achieved the Definition of Improvement (DOI) and is rated by the 
study physician as at least minimally improved.. 

Muscle MRI: bilateral thighs and pelvis, axial STIR and T1 images

Plain radiographs for calcinosis for patients with calcinosis

Obtain blood samples for Chem-20,GGT,  CK, aldolase, LDH, CBC with diff., TSH, 
anti-thyroid antibodies, von Willebrand Factor antigen level, quantitative 
immunoglobulins (IgG, IgM, IgA), ANA, ENA, dsDNA, Lymphocyte flow cytometry 
(TBNK cells) [ may be performed at home institution, up to 10 days before the 
visit date]

Collect research  blood samples for Immunophenotyping (T, B cells and 
macrophages), gene expression  and cytokine/chemokine analysis  (see Section 
3.1.h) 

Urinalysis

Review log of medication self-administration

Collect blood samples prior to the injection at Week 24 for PK and immunogenicity 
assessment

Prednisone taper may commence using a predetermined schedule (section 5) if 
the patient has achieved the Definition of Improvement (DOI) and is rated by the 
study physician as at least minimally improved. 

Administer dose of study medication (abatacept) and observe after the injection 
for at least 15 minutes

Patient terminates study enrollment and all study supplies are returned, or patient 
will continue on open-label extension: schedule and instruct the subject to return 
for the next visit  
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
An open label extension phase will be offered for up to 6 months for patients 
meeting the definition of improvement and who are rated by their study physician 
as at least minimally improved.

If the subject chooses not to continue to be in the open label extension phase of 
the trial, the subject will be referred back to his/her local rheumatologist for further 
care. Subject terminates study enrollment and all study supplies are returned

Subjects will receive their last injection of abatacept at week 24 even if they do not    
want to continue in the open label extension phase of the trial 
Open label extension Visit (will occur within 6 months of visit 5)
An open label extension phase of up to 6 months duration will be offered to all 
patients meeting the definition of improvement and who are also rated as at least 
minimally improved from the baseline visit (visit 1). Patients must commit to at least 
one follow-up visit within 6 months of visit 5, which will be at their own expense for 
travel and testing costs.  At each follow-up visit, the following will be performed:

Review concomitant medication and query for adverse events and document in 
CRF.

NCI Common Toxicity Assessment

Obtain  vital signs (HR,BP,RR, oral temperature and weight) and if indicated , by 
history of shortness of breath or lung disease, pulse oximetry)

Medical history and  perform a full physical examination 

Collect urine sample for pregnancy  test for females of child bearing potential prior 
to administration of study medication (where applicable)  

Core set activity measures: physician global activity, patient/parent global activity, 
manual muscle testing (MMT-8), CMAS, HAQ/CHAQ,MDAAT, muscle enzymes, 
CHQ PF-50/SF- 36, and Disease activity score (DAS), physician global damage 
(VAS) 

Physician and patient/parent assessment of study outcome

Obtain blood samples for Chem-20, GGT, CK, aldolase, LDH, CBC with diff.,

Urinalysis

Review log of medication self-administration

Prednisone taper may commence using a predetermined schedule (section 5) If 
the patient has achieved the Definition of Improvement (DOI) and is rated by the 
study physician as at least minimally improved. 

Administer dose of study medication and observe after the injection for at least 15 
minutes

Patient terminates open-label extension. Patient is referred back to referring 
rheumatologist.  
7.2 Laboratory Sample Collection 
In case staff at the GW-MFA unable to get a reliable venous access for blood sample, 
the subject will be taken to the George Washington University Hospital to undergo 
ultrasound guided phlebotomy. The sample will then be carried to 2300 M Street 
location and processed there as per protocol. 
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8.0
DOSE MODIFICATION 
The dose of abatacept will remain constant until week 12. For patients not improving 
with therapy by at least 5% on at least 3 of 6 core set measures at week 12, they would 
be offered the opportunity to increase their dose of treatment to abatacept 212 mg (87.5 
+ 125 mg) for subjects with body weight ≥ 50 kg or to abatacept 137.5 mg (87.5 mg+ 50 
mg for subjects with body weight of < 50 kg) weekly subcutaneously, or to continue on 
their present dose.
9.0
DISCONTINUATION OF SUBJECTS
Subjects in this study may be discontinued for any of the following reasons:

Severe allergic reaction to the study medication

Participation in another investigational drug study

Any medical condition which, in the opinion of the investigator, warrants 
discontinuation from the study for the safety of the patient, either as a cause of the 
study drug or Protocol violations, including non-compliance or inability to perform 
protocol-required procedures

Voluntary withdrawal (withdrawal of consent)

Pregnancy

Instruct WOCBP to contact the investigator or study staff immediately if they 
suspect they might be pregnant (e.g., 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 will notify BMS if a study subject becomes pregnant.

Loss of ability to freely provide consent through imprisonment or involuntary 
incarceration for treatment of either a psychiatric or physical (e.g., infectious 
disease) illness.

If 3 or more patients develop a serious adverse event thought to be related to 
study drug, no new patients will be enrolled into the study until the adverse events 
have been reviewed by the Medical Safety Officer and/or Data Safety Monitoring 
Board.
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Criteria for Disease Worsening (Appendix F):
Criteria for disease worsening in a clinical trial, by which patients could be termed 
treatment failures and offered alternative therapies, were preliminarily defined by  
IMACS. They will be incorporated into this trial and include: 

Physician global worsening of ≥ 2 cm on the 10 cm visual analog scale 
(VAS) and a worsening of the manual muscle testing by ≥ 20%, or 

Global extra muscular organ disease activity (a composite of constitutional, 
cutaneous, skeletal, gastrointestinal, pulmonary and cardiac activity) 
worsening by ≥ 2 cm on a 10 cm VAS, or 

3 of any 6 IMACS core set activity measures worse by ≥ 30%. 
In order to be classified as “worsening” in this trial, subjects will have to meet the 
above criteria and be classified by the physician as at least moderately worse (on 
the Assessment of Study Outcome form). It was also noted by IMACS that 
significant worsening in cardiac, pulmonary (interstitial   lung disease) or GI organs 
(dysphagia or vasculitis), which, based on the opinion of the treating protocol 
physician, requires alternate therapy, should be considered as alternate  
worsening criteria, potentially leading to patients being removed from a trial or 
considered treatment failures.
All subjects who leave the trial after receiving study drug, regardless of cause, are 
recommended to obtain a termination evaluation prior to study termination.  All 
patients receiving at least one dose of abatacept will be encouraged to remain in 
the trial and complete all study visits and phone follow-up evaluations to continue 
to assess safety.
Continuation of subjects after a serious adverse-event will be based on 
discussions between the Principal Investigator and Medical Safety Officer and/or 
Data Safety Monitoring Board.  If 3 or more patients develop a serious adverse 
event thought to be related to study drug, no new patients will be enrolled into the 
study until the adverse events have been reviewed by the Medical Safety Officer 
and/or Data Safety Monitoring Board.
10.0 Treatment Compliance
All study drugs must be kept in a secure location under appropriate storage 
conditions. Access must be restricted to authorized personnel. The intake of all 
study drugs will be recorded in the Case Report Form (CRF) in a medication 
administration log. Patients will take home the medication needed until next 
protocol visit in a safe container box. Used vials must be returned for 
accountability.  The medication provided for this study is for use only as directed 
in the protocol. GWU Medical Faculty Associates will be responsible for the 
storage, handling, and dispensing of study drug.  The GWU Medical Faculty 
Associates will monitor all documentation related to drug handling activities to 
ensure adherence to proper procedures.
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All unused study drugs must be returned to GWU Medical Faculty Associates for 
reconciliation and accountability and should be destroyed at the study site by 
authorized personnel according to approved procedures or collected by the 
monitor for disposal.
Study drugs are to be prescribed only by a physician named in the study form.  
Under no circumstances will the investigator allow the study drug to be used other 
than as directed by the protocol.
11.0 SAFETY ISSUES
SAFETY ASSESSMENTS
            General
Safety assessments will include adverse events, vital signs, physical examination 
findings, laboratory parameters (hematology, serum chemistry, including BUN, 
creatinine, urinalysis) and NCI common toxicity safety assessment. 
.
12.0
ADVERSE EVENT REPORTING
12.1
 Adverse Events
An adverse event (AE) is any reaction, side effect, or other undesirable or 
unexpected experience that occurs in conjunction with the use of the study drug, 
whether or not the experience is considered drug-related.  New or worsening 
signs and symptoms of underlying or emerging disease are also considered 
adverse events. Adverse events will be tracked through routine communication 
with the subjects and the family. 
12.1.1 Study Drug Relationship
The clinical site investigator will determine which events are associated with the 
use of study drug. For reporting purposes, an AE should be regarded as possibly 
related to the use of the investigational product if the investigator believes:

There is a clinically plausible time sequence between onset of the AE and 
abatacept administration; and/or

There is a biologically plausible mechanism for causing or contributing to the 
AE; and

The AE cannot be attributed solely to concurrent/underlying illness, other 
drugs, or procedures.
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An AE is deemed associated with the use of the study drug “if there is a 
reasonable possibility that the AE may have been caused by the drug” (21 CFR 
312.32)
12.2 Immediately Reportable Events
There are 2 categories of medical events that could occur during participation in 
this clinical trial that must immediately be reported to Dr. Curiel. The categories 
are as follows:

Death or other serious adverse experience (SAE) 

Pregnancy 
A serious adverse event is any experience that results in one of the following:  
hospitalization or prolonged hospitalization, a life threatening event resulting in: 
death, significant or permanent disability, congenital anomaly/birth defect (in the 
case of unanticipated birth to a study participant), or requires intervention to 
prevent permanent damage.  
Dr. Curiel will distribute reports of SAEs, which are both unexpected and related 
to the study medication, to the DSMB, the FDA, BMS Drug Safety, and to the  
Institutional Review Board. Reporting of adverse events will follow all applicable 
regulatory laws, guidelines and timeframes. Procedures for reporting adverse 
events are detailed in the Manual of Operations for this study.  
  
12.3 Physical Examination Observations
Baseline observations from the Screening physical examination that worsen during 
the study will be recorded on the Adverse Event CRF page. Every effort should be 
made for the same physician to conduct all physical examination assessments on 
each subject.  Care will be taken to avoid reporting worsening of initial physical 
examination observations which may result only from differing medical opinions 
when the same physician is not available to conduct pre-study, interim and end of 
study physical examinations.
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose:

Results in death

Is life-threatening (defined as an event in which the subject was at risk of death 
at the time of the event; it does not refer to an event which hypothetically might 
have caused death if it were more severe)

Requires inpatient hospitalization or causes prolongation of existing 
hospitalization (see note below for exceptions)

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect
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
Is an important medical event, defined as a medical event that may not be 
immediately life-threatening or result in death or hospitalization but, based on 
appropriate medical and scientific judgment, may jeopardize the subject or may 
require intervention (e.g., medical, surgical) to prevent one of the other serious 
outcomes listed above. Examples of such events include but are not limited to 
intensive treatment in an emergency department or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization. Potential drug induced liver injury (DILI) us also considered an 
important medical event (see Section 7.6 for the definition of potential DILI). 

Suspected transmission of an infectious agent (e.g., any organism, virus or 
infectious particle, pathogenic or non-pathogenic) via the study drug is a SAE.

Although pregnancy, overdose and cancer are not always serious by regulatory 
definition, these events must be handled as SAEs. Following the subject’s written 
consent to participate in the study, all SAEs, whether related or not related to 
study drug, must be collected, including those thought to be associated with 
protocol-specified procedures. All SAEs must be collected that occur within 30 
days of discontinuation of dosing.  The investigator should report any SAE 
occurring after these time periods that is believed to be related to study drug or 
protocol-specified procedure. An SAE report should be completed for any event 
where doubt exists regarding its status of seriousness. If the investigator believes 
that an SAE is not related to study drug, but is potentially related to the 
conditions of the study (such as withdrawal of previous therapy, or a complication 
of a study procedure), the relationship should be specified in the narrative section 
of the SAE Report Form. 
All SAEs, whether related or unrelated to abatacept, and all pregnancies must be 
reported to BMS and the Data Safety Monitoring Board (by the investigator or 
designee) within 24 hours. 
All SAEs should be reported via confirmed facsimile (fax) transmission, or scanned 
and reported via electronic mail to:  
SAE Email Address: Worldwide.Safety@BMS.com
SAE Fax Number: 609-818-3804
For studies conducted under an Investigator IND, any event that is both serious and 
unexpected must be reported to the Food and Drug Administration (FDA) as soon as 
possible and no later than 7 days (for a death or life-threatening event) or 15 days (for all 
other SAEs) after the investigator’s or institution’s initial receipt of the information. BMS 
will be provided with a simultaneous copy of all adverse events filed with the FDA. 
SAEs should be reported on MedWatch Form 3500A, which can be accessed at: 
http://www.accessdata.fda.gov/scripts/medwatch/.
MedWatch SAE forms should be sent to the FDA at:
MEDWATCH
5600 Fishers Lane
Rockville, MD 20852-9787
Fax: 1-800-FDA-0178 (1-800-332-0178)
http://www.accessdata.fda.gov/scripts/medwatch/
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All SAEs should simultaneously be faxed or e-mailed to BMS at:
Global Pharmacovigilance & Epidemiology
Bristol-Myers Squibb Company
Fax Number: 609-818-3804
Email: Worldwide.safety@bms.com
If an ongoing SAE changes in its intensity or relationship to study drug or if new 
information becomes available, a follow-up SAE report should be sent within 24 hours to 
the BMS using the same procedure used for transmitting the initial SAE report. All SAEs 
should be followed to resolution or stabilization.
13.0
DATA SAFETY MONITORING PLAN
The Data Safety and Monitoring Board (DSMB) will be appointed under the direction of 
(to be named). DSMB members have no potential financial conflicts of interest.  Written 
documentation attesting to the absence of conflict of interest will be required of all DSMB 
members on an annual basis.  The ongoing review of data by this independent committee 
assures the investigators that the trial can continue without jeopardizing patient safety.  
The DSMB will review the study protocol, recommend recruitment initiation, monitor all 
aspects of study (e.g., recruitment, protocol deviations, adverse events, data quality, 
descriptive characteristics, efficacy) and recommend protocol modifications, including 
early study termination.  
Meetings of the DSMB will occur on an annual basis to review all aspects of the study 
(e.g., recruitment, adverse events, and efficacy).  In addition, reports will be produced to 
show study progress according to a set schedule dictated by the DSMB.  The DSMB will 
also receive reports of any serious adverse events within 24 hours and review together if 
3 or more patients develop SAEs thought likely to be related to study drug.
14.0
ASSESSMENT TOOLS:  description
 The core assessment tools are available on the International Myositis Assessment and 
Clinical Studies (IMACS) Group website at:  
            
1.          IMACS website:
http://www.niehs.nih.gov/research/resources/imacs/imacsforms/
2. Disease activity core set measures:
http://www.niehs.nih.gov/research/resources/imacs/diseaseactivity/index.cfm
3. Disease damage core set measures:
http://www.niehs.nih.gov/research/resources/imacs/diseasedamage/index.cfm
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Manual Muscle Testing. (MMT):  MMT has been widely used in myositis therapeutic trials 
and clinical studies, previously as a primary end point (17) and more recently as part of a 
composite end point of core set measures (38). MMT has been modified to a shorter 
version called MMT-8, in which quantitative testing of eight  proximal, distal and axial 
muscle groups tested unilaterally (using a 0-10 point scale) closely approximate a total 
MMT score of 26 groups tested  bilaterally(42).  
MMT- 8 is a set of 8 designated muscles tested unilaterally (potential score 0-80) or 
bilaterally (potential score 0-150) 
Muscle Groups
Right (0 – 10)
Left (0 – 10)
Axial (0 – 10)
Axial Muscles (0 – 10)
Neck Flexors
X
X
0-10
Proximal Muscles (0 – 100)
Deltoid 
0-10
0-10
X
Biceps brachii
0-10
0-10
X
Gluteus maximus
0-10
0-10
X
Gluteus medius
0-10
0-10
X
Quadriceps
0-10
0-10
X
Distal Muscles (0 – 40)
Wrist Extensors
0-10
0-10
X
Ankle dorsiflexors
0-10
0-10
X
MMT-8 score (0 – 150)
0-70
0-70
0-10
Myositis Disease Activity Assessment Tool (MDAAT). This tool has been developed 
by IMACS.  This is a comprehensive tool that captures the physician’s assessment 
of disease activity of muscle, skin, joints, gastrointestinal tract, lung, and other organ 
systems. The MDAAT is a combined tool that includes the Myositis Disease Activity 
Assessment Visual Analog Scale (MYOTAC) and the Myositis Intention to Treat 
activities Index (MITAX).
 
The MYOACT is a series of physician’s assessments of disease activity in various 
organ systems using a VAS to assess severity of activity that has been modified from 
the Vasculitis Activity Index (42) The MYOACT consists of a 10-cm VAS for each 
organ system to score the overall severity of activity in each and a global extra-
muscular VAS. For the MYOTAC, each organ system has a single VAS; a global 
extra-muscular activity VAS is also scored.  
The MITAX assesses specific manifestations in 7 organs/systems, including 
constitutional, cutaneous, skeletal, gastrointestinal, pulmonary, cardiac, and muscle. 
For the MITAX each question is answered as 0= not present; 1= improving, 2= the 
same, 2= worse, 4=new. 
The key issue in relation to the MDAAT is to ensure that the items recorded are, in 
view of the physician, actually due to the active myositis and not due to disease 
damage, another unrelated process, or a side effect of medication. 
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Disease Activity Score (DAS): this tool assesses muscle and cutaneous manifestations, 
including vasculopathic features, based on bedside clinical assessment. The DAS 
consists of 19 items, resulting in a score of 0-20: 1) the presence or absence of weakness 
is assessed via 8 variables: neck flexors muscles, abdominal muscles, upper extremity 
proximal muscles, lower extremity proximal muscles, Gower’s sign, abdominal gait, 
difficulty swallowing, and nasal speech. 2) Functional status consists of a 4-point scale, 
ranging from normal function to severe limitations in daily life functions. 3) The presence 
or absence of vasculitis is assessed by determining the presence of any one of the 
following: eyelid erythema, eyelid vessel dilatation, eyelid thrombosis, nailfold erythema, 
nailbed telangiectasia, dilatation of blood vessels on the palate, and “other vasculitis”. 3) 
The presence of rashes is rated using polychotomous scales: the distribution of the 
involved skin is rated on a 4-point scale ranging from none to generalized, while the 
severity of skin involvement is rated on a 5-point scale, ranging from absent to severe. 
Gottron’s papules are rated on a 4-point scale,(42) 
                                          
Muscle Enzymes:  Activity of at least one serum muscle enzyme from the following: 
creatine 
kinase 
(CK), 
aldolase, 
lactate 
dehydrogenase 
(LDH), 
alanine 
aminotransferase (ALT) and aspartate aminotransferase (AST).  The most abnormal 
muscle enzyme will be chosen as the core measure to be followed.
MDI: Myositis Damage Index:  The MDI scores damage, which is defined as 
persistent or permanent change in anatomy, physiology, and function that develops 
from previously active disease, complications of therapy, or older events.(42). The 
MDI measures specific manifestations in 11 organ systems. The MDI also includes a 
series of visual analog scales (VAS) to quantify damage severity in a given organ 
system. 
Stanford HAQ/CHAQ: Health Assessment Questionnaire: The Stanford HAQ is a 
brief self-report questionnaire assessing physical function pertaining to activities of 
daily living in a variety of domains (42). Originally developed for use in rheumatoid 
arthritis, it has been successfully applied inflammatory myopathies. The C-HAQ was 
adapted directly from the HAQ and it has also been successfully applied to patient 
with juvenile myositis. (42). 
Physician Global Assessment (MD Global Activity): It is a tool that  measures the 
global evaluation by the treating physician of the overall disease activity of the patient 
at the time of assessment using a 10 cm. visual analogue scale and a 5 point Likert 
scale, validated by JDM study group.(43) 
Patient/Parent Global Assessment Patient/Parent Global Activity, 0- 10 cm VAS. 
It is a tool that measures the global evaluation by the patient, or by the parent if the 
patient is a minor, of the patient's overall disease activity at the time of assessment 
using a 10 cm. visual analogue scale. (Validated by JDM study group (43) 
Childhood Myositis Assessment Score (CMAS) is validated tool to assess muscle 
strength, physical function, and endurance. Items of the CMAS include upper and 
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lower extremity muscle groups, simple and compound movements, and timed items 
to evaluate endurance. The tool is weighted toward lower extremity proximal and axial 
muscle groups more than upper extremity and distal muscle groups. The CMAS 
consists of 14 items. The CMAS has been included as a core set activity measure by 
both the IMACS and PRINTO   (42)
Assessment to be performed by the Dermatologist is Optional: Cutaneous 
Dermatomyositis Disease Area and Severity Index (CDASI) It measures activity and 
damage in the skin. The modified CDASI (version 2) is the one in current use. It has 
3 activity scales (erythema, scale, erosion/ulceration) and 2 damage measures 
(poikiloderma and calcinosis). In addition, Gottron’s papules on the hands are 
evaluated in terms of activity (erythema/ulceration) and damage (dyspigmentation or 
scarring). Activity in terms of periungal changes and alopecia is also measured. Each 
of the 3 activity scales and 2 damage measures is assessed over 15 body areas; the 
worst level of activity is scored, whereas the damage measures is scored for their 
presence or absence. It will be performed by both Rheumatology and Dermatology. 
(42)
Childhood Health Questionnaire (CHQ) is validated tool to assess health related 
quality of life, physical and psychosocial well-being of children at least 5 years of age. 
The CHQ consists of 14 health concepts: global health, physical functioning, 
role/social limitations-emotional/behavioral, role/social limitations-physical, bodily 
pain/discomfort, behavior, general behavior, mental health, self-esteem, general 
health perception, parent impact-emotional. Parent impact-time, family activities, and 
family cohesion. In addition, there are 2 summary measures, the Physical summary 
score (PhS) and the Psychosocial summary score (PsS). The CHQ- PhS has been 
selected by PRINTO as a core set of measures to be used to evaluate response to 
therapy in JDM. (42)
SF-36 is a widely used tool that assesses the global medical quality of life, 
functional health and well-being. It has been used in several small natural history 
studies of PM and DM (44) 
Dermatology Life Quality Index (DLQI). It is a simple questionnaire to assess quality 
of life in skin disease. The measure consists of 10 questions related to skin symptoms 
and feelings, daily activities, leisure, work or school, personal relationships, and the 
side effects of treatment. Each item is scored on a Likert scale, where 0= not at all/not 
relevant, 1= a little, 2= a lot, 3=very much. (42) 
PROMIS and Peds QL Fatigue Questionnaires: The PROMIS Fatigue instruments 
evaluate a range of self-reported symptoms, from mild subjective feelings of 
tiredness to an overwhelming, debilitating, and sustained sense of exhaustion that 
likely decreases one’s ability to execute daily activities and function normally in 
family or social roles. Fatigue is divided into the experience of fatigue (frequency, 
duration, and intensity) and the impact of fatigue on physical, mental, and social 
activities. The fatigue short form is generic rather than disease-specific. It assesses 
fatigue over the past seven days. 
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Abatacept in the Treatment of Refractory Juvenile Dermatomyositis
Dr. Rodolfo Curiel, GWU
Version 10.5 22April2020                                                                       Page 61 of 84
The PedsQL Multidimensional Fatigue Scale was designed to measure fatigue in 
pediatric patients, but can also be used in adults.  It is comprised of the General 
Fatigue Scale (6 items), Sleep/Rest Fatigue Scale (6 items), and Cognitive Fatigue 
Scale (6 items).
Fatigue instruments are available for adults (ages 18+), pediatric self-report (ages 
8-17) and for parents serving as proxy reporters for their child (youth ages 5-17). 
Assessment of Study Outcomes: A physician assessment of whether the patient 
has improved or worsened from baseline, and by how much (mild, moderate, great 
degree of change) will be made at each follow-up visit, using the IMACS 
assessment tool available for this outcome.
15.0
STATISTICS/DATA ANALYSIS
  
Statistical Plan: 
This is an open label nonrandomized trial to assess the safety and efficacy of
     subcutaneous abatacept in 10 patients (children and adults) with juvenile onset 
refractory dermatomyositis (JDM).  
We postulate that at least 6 of 10 patients with JDM will meet the myositis preliminary 
definition of improvement (DOI) after receiving 24 weeks of therapy with abatacept. 
Data will be entered and stored in the RedCap database,licensed to George 
Washington University.  Primary analyses will be performed using intention to treat 
regardless of compliance with therapy or trial protocol. We will also perform analyses 
that include only those participants with known outcome data. 
Summary statistics will be generated to describe the study samples. Descriptive 
statistics, including measures of central tendency (e.g. means, medians) and 
estimates of spread (e.g. standard deviations) will be used for continuous variables, 
including reporting of adverse event frequencies, core set measure assessments, and 
demographic and clinical variables. Non-parametric Wilcoxon signed rank tests will be 
used to investigate changes in continuous variables. 95% confidence intervals will be 
calculated for all point estimates. 
We will examine the percentage of subjects meeting the DOI (20%),as well as 
moderate (DOI 50%) or major improvement criteria (DOI 70%), as well as frequency 
of patients achieving clinically inactive disease.  
Due to the small number of subjects, it is unlikely that any statistical test would have 
the power to detect significant differences in any of the measured variables.  We will 
therefore look not only at the percentage of subjects meeting improvement criteria by 
the DOIs, but also look for an improvement in individual core set myositis disease 
activity measurements of muscular and extra-muscular disease activity, as well as the 
in the patient- reported outcome measures, cutaneous assessments and MRI. We will 
also examine responsiveness after treatment using standardized response means 
and correlation degree of change between the measures. Differences between initial 
IRB NUMBER: 111418
IRB APPROVAL DATE: 05/02/2020


Abatacept in the Treatment of Refractory Juvenile Dermatomyositis
Dr. Rodolfo Curiel, GWU
Version 10.5 22April2020                                                                       Page 62 of 84
and 24 weeks values will be analyzed by Student t distribution and Wilcoxon matched 
pair tests. 
Statistical analyses will be performed by using GraphPad InStat version 3.00 for 
Windows 95 (GraphPad, San Diego, CA) and/or SAS System for Windows, version 
9.1.3 (SAS Institute, Cary, NC). For all statistical tests, a P-value of < 0.05 will be 
utilized to indicate statistical significance.
Results of this project may lead to the development of larger study that will have the 
statistical power to detect significant differences in the measured variables after 
treatment of JDM with abatacept.   
16.0
COSTS AND PAYMENTS
 
16.1 
Research Study Costs 
The study drug, abatacept will be provided at no cost to participants or their insurance 
companies.  The study will cover the costs of the study drugs laboratory testing, 
examinations and clinic visits and the patients insurance will not be billed for these.  
However, patients participating in the open-label extension phase of the study will be 
responsible for these costs, and their insurance companies will be billed.  Routine care 
not associated with research will be billed to the subject or third party payer and the 
subject will be responsible for costs not covered, including any applicable copays, 
coinsurances and deductibles. 
Emergent care will be billed to the subject or third party payer and the subject will be 
responsible for costs not covered, including any applicable copays, coinsurances and 
deductibles.
Patients and their families will be paid a participation fee for time and inconvenience 
associated with participation in the trial. They will receive $150 upon completion of 
visit 1   and visit 5 $100 upon completion of  visit 3, and $50 upon completion of visit 
2 and visit 4,  for a total of $500 per patient.
17.0  REFERENCES:
1)
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diagnosed cases in Allegheny County, PA 1963-1982. J. Rheumatol., 1990. 17: p. 1329-1334.
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Rider, LG, Shah M.  et al. The myositis autoantibody phenotypes of the juvenile idiopathic 
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(Baltimore). 2013 Jul;92(4):223-43
3)
Feldman BM, Rider LG, Reed AM, Pachman LM. Juvenile dermatomyositis and other idiopathic 
inflammatory myopathies of childhood. Lancet 2008: 371(9631): 2201-2212.
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Abatacept in the Treatment of Refractory Juvenile Dermatomyositis
Dr. Rodolfo Curiel, GWU
Version 10.5 22April2020                                                                       Page 63 of 84
4)
Shah M, Mamyrova G  et al. The clinical phenotypes of the juvenile idiopathic inflammatory 
myopathies.Childhood Myositis Heterogeneity Collaborative Study Group. Medicine (Baltimore). 
2013 Jan;92(1):25-41
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Lundberg IE, Dastmalchi M, Possible pathogenic mechanisms in inflammatory myopathies.  Rheum 
Dis Clin N Am.  2002; 28: 799-822.
6)
Bohan A. Peter JB. Polymyositis and dermatomyositis (first of two parts). N Engl J Med 
1975;292:344-347
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Ravelli A, Trail L, et al. Long-term outcome and prognostic factors of juvenile dermatomyositis: a 
multinational, multicenter study of 490 patients. Arthritis Care Res (Hoboken). 2010 Jan 15;62(1):63-
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Crowe W, Bove K, Levinson J, Hilton P.  Clinical and pathogenic implications of histopathology in 
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Nagaraju K, Rider LG, Fan C et al. Endothelial cell activation and neovascularization are prominent 
in dermatomyositis. J Autoimmune Dis 2006; 3:2
10) Wedderburn LR, Rider LG. Juvenile dermatomyositis: new developments in pathogenesis and 
treatment. Best Practice and Research: Clinical Rheum 2009:23 (5): 665-678.
11) Huber AM, Robinson AB, Reed AM, et al. Consensus treatments for moderate juvenile 
dermatomyositis: beyond the first two months. Results of the second Childhood Arthritis and 
Rheumatology Research Alliance consensus conference. Arthritis care Res (Hoboken) 2012: 64 (4): 
546-53.
12) Sanner H, Gran JT, Sjaastad I, Flatø B.  Cumulative organ damage and prognostic factors in juvenile 
dermatomyositis: a cross-sectional study median 16.8 years after symptom onset. Rheumatology 
(Oxford). 2009 Dec;48(12):1541-7.
13) Huang JL.  Long-term prognosis of patients with juvenile dermatomyositis initially treated with 
intravenous methylprednisolone pulse therapy. Clin Exp Rheumatol 1999; 17:621-4.
14) Kampylafka EI, Kosmidis ML et al. The effect of intravenous immunoglobulin (IVIG) treatment on 
patients with dermatomyositis: a 4-year follow-up study. Clin Exp Rheumatol. 2012 May-
Jun;30(3):397-401
15) Pachman LM, Niewold T et al. . TNF-[alpha] levels and IFN-[alpha] activity in children with juvenile 
dermatomyositis (JDM) are associated and modified by etanercept. Clin Immunol. 2009; 
131(suppl):S158.
16) Rouster-Stevens KA, Ferguson L et al.  Pilot study of etanercept in patients with refractory juvenile 
dermatomyositis. Arthritis Care Res (Hoboken). 2013 Oct 14
17) Oddis CV, Reed AM et al. Rituximab in the treatment of refractory adult and juvenile 
dermatomyositis and adult polymyositis: a randomized, placebo-phase trial.  RIM Study Group. 
Arthritis Rheum. 2013 Feb;65(2):314-24
18) Nagaraju K, Raben, N, et al. Costimulatory markers in muscle of patients with idiopathic 
inflammatory myopathies and cultured muscle cells. Clin Immun 92 92): 161-169.
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Abatacept in the Treatment of Refractory Juvenile Dermatomyositis
Dr. Rodolfo Curiel, GWU
Version 10.5 22April2020                                                                       Page 64 of 84
19) Murata KY, Dalakas MC. Expression of the costimulatory molecule BB-1, the ligands CTLA-4 and 
CD-28, and their mRNA in inflammatory myopathies. Am Journal of Pathology 1999; 155 (2): 453-
460.   
20) Behrens L, Kerschensteiner M, et al. Human muscle cells express a functional costimulatory 
molecule distinct from B7.1 (CD 80) and B7.2 (CD86) in vitro and inflammatory lesions. Journal of 
Immunol 161 (11): 5943-5951.
21) Murata KY, Sugie K, Takamura M, Ueno S. Expression of the costimulatory molecule BB-1 and its 
receptors in patients with scleroderma-polymyositis overlap syndrome. J Neurol Science 2002: 15: 
205 91): 65-70.
22) Azuma M, Ito D, et al. B70 antigen is a second ligand for CTLA-4 and CD28, Nature (London). 1993; 
366: 76-79. 
23) Freeman GJ, Gribben JG, et al. Cloning of B7-2: a CTLA-4 counter receptor that costimulates human 
T cell proliferation. Science. 1993; 262:909-911. 
24) Peach RJ, Bajorath J,  et al. Complementarity determining region 1 (CDR) and CDR3-analogous 
regions in CTLA-‘ and CD28 determine the binding to B7-1. J Exp Med. 1994;180:2049-2058.
25) Linsley PS, Greene JL, Brady W, et al. Human B7-1 (CD80) and B7-2 (CD86) bind with similar 
avidities but distinct kinetics to CD28 and CTLA-4 receptors. Immunity. 1994;1:793-801
26)
Rider LG, Miller FW. Deciphering the clinical presentations,pathogenesis, and treatment of the 
idiopathic inflammatory myopathies. JAMA 2011; 305:183–90.
27) Chiu YE Juvenile dermatomyositis: immunopathogenesis, role of myositis-specific autoantibodies, 
and review of rituximab use.Pediatr Dermatol. 2011 Jul-Aug; 28(4):357-67.
28) Kuru S, Inukai A, et al.  Expression of tumor necrosis factor-alpha in regenerating muscle fibers in 
inflammatory and non-inflammatory myopathies. Acta Neuropathol. 2003 Mar;105(3):217-24
29) Fedczyna TO, Lutz J, Pachman LM.Expression of TNFalpha by muscle fibers in biopsies from 
children with untreated juvenile dermatomyositis: association with the TNFalpha-308A allele. Clin 
Immunol. 2001 Aug;100(2):236-9.
30) Singh N, Chandler PR, et al. Role of CD28 in fatal autoimmune disorder in scurfy mice.
Blood. 2007 Aug 15;110(4):1199-206
31) Hwang KW, Sweatt WB, et al.  Transgenic expression of CTLA-4 controls lymphoproliferation in IL-
2-deficient mice. J Immunol. 2004 Nov 1;173(9):5415-24
32) Preuße C, Goebel HH et al. Immune-mediated necrotizing myopathy is characterized by a specific 
Th1-M1 polarized immune profile. Am J Pathol. 2012 Dec;181(6):2161-71
33) Schiff M. Subcutaneous abatacept for the treatment of rheumatoid arthritis.
Rheumatology (Oxford). 2013 Jun; 52(6):986-97.
34) Arabshahi B, Silverman RA, Jones OY, Rider LG. Abatacept and sodium thiosulfate for treatment of 
recalcitrant juvenile dermatomyositis complicated by ulceration and calcinosis. Journal of Pediatrics 
2012; 160: 520-22.
35) Musuruana JL, Cavallasca JA. Abatacept for treatment of refractory polymyositis Joint Bone Spine. 
2011 Jul;78(4):431-2.
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Abatacept in the Treatment of Refractory Juvenile Dermatomyositis
Dr. Rodolfo Curiel, GWU
Version 10.5 22April2020                                                                       Page 65 of 84
36) Maeshima K, Kiyonaga Y,  et al.   Successful treatment of refractory anti-signal recognition particle 
myopathy using abatacept. Rheumatology (Oxford). 2014 Feb;53(2):379-80
37) Ruperto N, Lovell DJ, Li T, et al. Abatacept improves health-related quality of life, pain, sleep quality, 
and daily participation in subjects with Juvenile idiopathic arthritis. Arthritis Care Res 2000 (62): 
1542-1551. 
38) Rider LG, Giannini EH et al. International consensus on preliminary definitions of improvement in 
adult and juvenile myositis.  International Myositis Assessment and Clinical Studies Group. Arthritis 
Rheum. 2004 Jul; 50(7):2281-90. Review.
39) Sultan SM, Allen E, et. al.  Reliability and validity of the myositis disease activity assessment tool.  
Arthritis Rheum. 2008 Nov; 58(11):3593-9. 
40) Ruperto N, Pistorio A et al. The Paediatric Rheumatology International Trials Organisation 
provisional criteria for the evaluation of response to therapy in juvenile dermatomyositis. Arthritis 
Care Res (Hoboken). 2010 Nov;62(11):1533-41
41) Lazarevic D, Pistorio A, Palmisani E et al. The PRINTO criteria for clinically inactive disease in 
juvenile dermatomyositis. Paediatric Rheumatology International Trials Organisation (PRINTO). Ann 
Rheum Dis. 2013 May;72(5):686-93
42) Rider LG, Werth V, et al. Measures of Adult and Juvenile dermatomyositis, Polymyositis and 
Inclusion Body Myositis. Arthritis Care Res (Hoboken). 2011 Nov;63 Suppl 11:S118-57
43) Rider LG, Feldman BM, et al. Development of validated disease activity and damage indices for the 
juvenile idiopathic inflammatory myopathies: I. Physician, parent, and patient global assessments. 
Juvenile Dermatomyositis Disease Activity Collaborative Study Group.
Arthritis Rheum. 1997 Nov; 40(11):1976-83.
44) Ponyi A, Borgulya G Functional outcome and quality of life in adult patients with idiopathic 
inflammatory myositis.Rheumatology (Oxford). 2005 Jan;44(1):83-8
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Version 10.5 22April2020                                                                       
APPENDIX A. 
BOHAN AND PETER CLASSIFICATION CRITERIA for Diagnosis of Dermatomyositis   
Criterion 
Definition
1. Symmetric weakness
Weakness of proximal limb-girdle muscles, progressing over weeks to months
2. Muscle Biopsy evidence  
Evidence of necrosis of Type I and II fibers, phagocytosis, regeneration with 
basophilia, large vesicular sarcolemmal nuclei and prominent nucleoli, atrophy in a
perifascicular distribution, variation in fiber size, and an inflammatory exudate, ofte
perivascular
3. Elevation of Serum Muscle Enzymes 
level 
Elevation in serum of any skeletal muscle enzyme, particularly creatine 
phosphokinase , aldolase, lactate dehydrogenase, aspartate aminotransferase 
and alanine amintransferase
4. EMG
Electromyographic triad of short, small, polyphasic motor units,
Evidence fibrillations, positive sharp waves, and insertional irritability, and bizarre, 
high frequency repetitive discharges
5. Dermatologic Changes   
A lilac discoloration of the eyelids (heliotrope rash) with periorbital edema 
(heliotrope rash), or a scaly, erythematous dermatitis over the dorsum of the 
hands, especially the metacarpophalangeal and proximal inter phalangeal joints, 
knees, elbows, and medial malleoli  (Gottron’s papules or sign)
a Confidence limits can be defined as follows.  For a definite diagnosis of dermatomyositis, three of four criteria plus the rash must be present.  For a 
probable diagnosis of dermatomyositis, two criteria plus the rash must be present.  Patients must be < 18 years of age at time of diagnosis to meet 
criteria for juvenile dermatomyositis.
 
The following findings exclude a diagnosis of dermatomyositis:

Evidence of central or peripheral neurologic disease, including motor-neuron disorders with fasiculations or long-tract signs, sensory 
changes, decreased nerve conduction times, and fiber-type atrophy and grouping on muscle biopsy.
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Version 10.5 22April2020                                                                       

Muscle weakness with a slowly progressive, unremitting course and a positive family history or calf enlargement to suggest 
muscular dystrophy

Biopsy evidence of granulomatous myositis such as with sarcoidosis.

Infection, including trichinosis, schistosomiasis, trypanosomiasis, staphylococcosis, and toxoplasmosis

Recent use of various drugs and toxins, such as clofibrate and alcohol

Rhabdomyolysis as manifested by gross myoglobinuria related to strenuous exercise, infections, crush injuries, occlusions of major 
limb arteries, prolonged coma or convulsions, high-voltage accidents, heat stroke, the malignant-hyperpyrexia syndrome, and 
envenomation by certain sea snakes.

Metabolic disorders such as McArdle’s syndrome.

Endocrinopathies such as thyrotoxicosis, myxedema, hyperparathyroidism, hypoparathyroidism, diabetes mellitus, or Cushing’s 
syndrome.

Myasthenia gravis with response to cholinergics, sensitivity to d-tubocurarine, and decremental response to repetitive nerve 
stimulation.
Data from Bohan A. Peter JB. Polymyositis and dermatomyositis (first of two parts). N Engl J Med 1975;292:344-347, 
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Version 10.5 22April2020                                                                       
   APPENDIX B: Proposed New classification criteria for IIM *
 
Variable
Score
Without 
muscle 
biopsy 
data
With 
muscle 
biopsy 
data
18 ≤ Age of onset of first symptom assumed to be related to the disease < 40
1.3
1.5
Age of onset of first symptom assumed to be related to the disease ≥ 40
2.1
2.2
Muscle weakness
Objective symmetric weakness, usually progressive, of the proximal upper extremities
0.7
0.7
Objective symmetric weakness, usually progressive, of the proximal lower extremities
0.8
0.5
Neck flexors are relatively weaker than neck extensors
1.9
1.6
In the legs proximal  muscles are relatively weaker than distal muscles
0.9
1.2
Skin manifestations
Heliotrope rash
3.1
3.2
Gottron´s papules
2.1
2.7
Gottron’s sign
3.3
3.7
Other clinical manifestations
Dysphagia or esophageal dysmotility
0.7
0.6
Laboratory measurements
Anti-Jo-1 (anti-Histidyl-tRNA synthetase) autoantibody positivity 
3.9
3.8
Serum creatine kinase activity (CK) activity or 
Serum lactate dehydrogenase (LDH) activity or
Serum aspartate aminotransferase (ASAT/AST/SGOT) activity or
Serum alanine aminotransferase (ALAT/ALT/SGPT) activity
1.3
1.4
Muscle biopsy features
Endomysial infiltration of mononuclear cells surrounding, but not invading, myofibers
1.7
Perimysial and/or  perivascular infiltration of mononuclear cells
1.2
Perifascicular atrophy
1.9
Rimmed vacuoles
3.1
Risk score ≥ 5 (without biopsy) or ≥ 6 (with muscle biopsy) classified as myositis.
*A Tjärnlund, M Bottai, LG Rider et al. The International Myositis Classification Criteria Project Progress Report on Development of 
Classification Criteria for Adult and Juvenile Idiopathic Inflammatory Myopathies.  Arthritis and Rheumatism. 2012. 64(suppl). 23-324.
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Version 10.5 22April2020                                                                       
APPENDIX C :               IMACS AND PRINTO CORE SET ACTIVITY MEASURES 
IMACS Core Set Disease Activity Measures for Juvenile Dermatomyositis*
Core Set 
Variables     
 Core Set Measures  
MD Global Activity  
Patient/parent 
global activity
Physician global disease activity assessment by Likert or VAS
Parent/patient global disease activity assessment by Likert or 
VAS
Muscle strength
MMT(manual muscle test) by a 0-10 point or expanded 0-5 point 
scale to include proximal , distal, and axial muscles
Physical Function 
Validated patient/parent questionnaire of activities of daily living 
(HAQ/CHAQ)
Laboratory 
Assessment 
At least 1 serum muscle enzyme activity level  from the 
following: CK, creatine kinase, aldolase, LDH, lactate 
dehydrogenase, AST, aspartate aminotransferase, ALT, alanine 
aminotransferase 
Extra skeletal 
Muscle Disease 
Activity 
Assessment   
MDAAT, Myositis Disease Activity Assessment Tool, extra 
muscular global activity assessment (constitutional, cutaneous, 
skeletal, gastrointestinal, pulmonary, cardiac) assessment score   
*IMACS, International Myositis Assessment and Clinical Studies Group
**Rider LG, Giannini EH, Harris-Love et al. Defining clinical improvement in adult and juvenile myositis. J of Rheumatol 2003; 30(3): 
603-617 
PRINTO Core Set Disease Activity Measures for Juvenile Dermatomyositis *
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Version 10.5 22April2020                                                                       
Core Set Variables    Core Set Measures  
MD Global Activity  
Physician global disease activity assessment by Likert or VAS
Patient/parent 
assessment of 
overall well being  
Parent/patient global disease activity assessment by Likert or 
VAS
Muscle strength
MMT(manual muscle test) by a 0-10 point or expanded 0-5 
point scale to include proximal, distal, and axial muscles, or
Validated observational tool of function, strength, and 
endurance, Childhood Myositis Assessment Scale (CMAS)
Physical Function 
Validated patient/parent questionnaire of activities of daily living 
(HAQ/CHAQ) 
Global Disease 
Activity  
Disease Activity Score (DAS) or Myositis Disease Activity 
Assessment Tool (MDAAT) 
Health Related 
Quality of Life     
Childhood Health Questionnaire (CHQ)  or SF-36 in adult 
patients 
*PRINTO, Pediatric Rheumatology International Trials
***Ruperto A, Pistorio A, Ravelli et al. The Paediatric Rheumatology International Trials Organization provisional criteria for the 
evaluation of response to therapy in juvenile dermatomyositis. Arthritis Care & Res 2010; 62 (11): 1533-41.  
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Version 10.5 22April2020                                                                       
APPENDIX D1. 
IMACS definition of minimal clinical improvement, PRINTO** definition of minimal, moderate, and major improvement and 
PRINTO criteria of inactive disease 
IMACS 
definition of  minimal 
improvement 
PRINTO definition of  
minimal improvement 
PRINTO definition of  
moderate clinical  
improvement
PRINTO definition of  
major clinical  
improvement
PRINTO definition of 
inactive disease
 ≥ 20% of improvement 
in at least 3 of 6 core set 
measures, 
with ≤  2 of the remaining  
worsening by > 25% 
(muscle strength cannot 
worsen)
≥ 20% of improvement 
in at least 3 of 6 core 
set measures, 
with ≤ 1 of the 
remaining  worsening 
by ≥ 30% (muscle 
strength cannot 
worsen).
 ≥ 50% of improvement 
in at least 3 of 6 core 
set measures, 
with ≤ 1 of the 
remaining  worsening 
by ≥ 30% (muscle 
strength cannot 
worsen).
≥ 70  of improvement in 
at least 3 of 6 core set 
measures, 
with ≤ 1 of the remaining  
worsening by ≥ 30% 
(muscle strength cannot 
worsen).
At least 3 of 4 criteria: 
CMAS≥ 48;
MD global Activity VAS ≤ 
0.5 cm;
CK ≤ 150;
MMT ≥ 78. 
*IMACS, International Myositis Assessment and Clinical Studies Group
**PRINTO, Pediatric Rheumatology International Trials
References: 
**Rider LG, Giannini EH et al. International consensus on preliminary definitions of improvement in adult and juvenile myositis.  International 
Myositis Assessment and Clinical Studies Group. Arthritis Rheum. 2004 Jul;50(7):2281-90. Review.
**Ruperto N, Pistorio A et al. The Paediatric Rheumatology International Trials Organisation provisional criteria for the evaluation of response to 
therapy in juvenile dermatomyositis. Arthritis Care Res (Hoboken). 2010 Nov;62(11):1533-41
**Lazarevic D, Pistorio A, Palmisani E et al. The PRINTO criteria for clinically inactive disease in juvenile dermatomyositis. Paediatric Rheumatology 
International Trials Organisation (PRINTO). Ann Rheum Dis. 2013 May;72(5):686-93
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Version 10.5 22April2020                                                                       
Appendix D2.  Newly Developed Criteria for Myositis Clinical Response (pending ACR-
EULAR approval). 
Definition 20: 1000 Minds Model 3 (absolute % change)
Core Set Measure
Improvement 
score for each 
level
 
MD Global Absolute % Change
 
 
Up to <=5%
0
 
>5% up to <=15%
7.5
 
>15% up to <=25%
15
 
>25% up to <=40%
17.5
 
>40%
20
 
Pt Global/Par Global Absolute 
% Change
 
 
Up to <=5%
0
 
>5% up to <=15%
2.5
 
>15% up to <=25%
5
 
>25% up to <=40%
7.5
 
>40%
10
 
MMT/CMAS Absolute % Change
 
 
Up to <=2%
0
 
>2% up to <=10%
10
 
>10% up to <=20%
20
 
>20% up to <=30%
27.5
 
>30%
32.5
 
HAQ/CHAQ Absolute % Change
 
 
Up to <=5%
0
 
>5% up to <=15%
5
 
>15% up to <=25%
7.5
 
>25% up to <=40%
7.5
 
>40%
10
 
Enzyme/CHQ-PF50 Absolute % 
Change
 
 
Up to <=5%
0
 
>5% up to <=15%
2.5
 
>15% up to <=25%
5
 
>25% up to <=40%
7.5
 
>40%
7.5
 
ExtraMusc/DAS Absolute % 
Change
 
 
Up to <=5%
0
 
>5% up to <=15%
7.5
 
>15% up to <=25%
12.5
 
>25% up to <=40%
15
 
>40%
20
 
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Version 10.5 22April2020                                                                       
Improvement Score (sum of all CSM)
 
Profile
Improvement 
Category
Cutpoint
Minimal
20
Moderate
40
Adult
Major
60
Minimal
30
Moderate
45
Pediatric (IMACS/PRINTO)
Major
70
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Version 10.5 22April2020                                                                       
APPENDIX E   TABLE 1 AND TABLE 2 /2a:   STUDY SCHEDULE OF EVENTS 
Table 1. 
Treatment Week
Study Events
Screening
W0
W2
W4
W6
W8
W10
W12
W14
W16
W18
W20
W22
W24
W25-W48
Visit
V1
V2
V3
V4
V5
V6 
(extension)
Phone f/up* 
X
X
X
X
X
X
X
X
Informed Consent/Assent   
X
Inclusion/Exclusion Criteria 
X
Vital signs, Weight, (pulse oximetry) is 
changed to screening evaluation
X
X
X
X
X
X
X
Brief  physical evaluation  
X
X
X
X
X
X
CMAS
X
X
X
X
X
X
X
MMT8
X
X
X
X
X
X
X
MDAAT (EM Global only at Screening)
X
X
X
X
X
X
X
Disease Activity Score
X
X
X
X
X
X
MD Global Activity (VAS)
X
X
X
X
X
X
X
Patient/Parent Global Activity (VAS)
X
X
X
X
X
X
X
CHAQ/HAQ
X
X
X
X
X
X
X
CHQ-PF50/SF36
X
X
X
X
X
Myositis Damage Index
X
X
Urine Pregnancy , UA, 
X
X
X
X
X
X
X
Screening Blood Tests 
X
Research Blood Tests form is changed 
to blood sample tracking form (regular 
and research blood test)
X
X
X
Chest X-ray
X
Plain radiograph for calcinosis 
(calcinosis pts only)
X
X
Muscle MRI (bilateral, Axial and T1)
X
X
MD Global Disease Damage (VAS)
X
X
X
X
X
X
 Physician Assessment of Study 
Outcome
X
X
X
X
X
IRB NUMBER: 111418
IRB APPROVAL DATE: 05/02/2020


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Version 10.5 22April2020                                                                       
Dermatology assessment (Includes 
CDASI, MD Global Skin 
Activity/Damage performed by 
Dermatologist) Optional
X
X
X
CDASI (performed by Rheumatologist)
X
X
X
X
X
X
DLQI, skin itch, Patient and MD skin 
global activity/damage (performed by 
Rheumatologist )
X
X
X
X
X
X
Photograph Documentation (if 
applicable)
X
X
X
X
X
X
Nailfold capillaries photograph 
(Optional)
X
X
X
X
PROMIS and PedsQL fatigue 
X
X
X
X
X
X
Review medication log and self-
administration log
X
X
X
X
X
X
NCI CTC Assessment 
X
X
X
X
X
X
Adverse Events assessments
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Prednisone taper if meet DOI and rated 
at least minimally improved
X
X
X
X
X
Increase Abatacept dose if ≤ 5% 
improved by DOI and rated as 
unchanged or worsened
X
Administer Abatacept medication
X
X
X
X
X
X
Visit
V1
V2
V3
V4
V5
V6
Week
Screening
W0
W2
W4
W6
W8
W10
W12
W14
W16
W18
W20
W22
W24
W25-W48
*Phone f/up at W2, 4, 8, 10, 14, 16, 20, and 22 will consist of evaluation of Adverse Events.
Abbreviations: CMAS, Childhood Myositis Assessment Scale; MMT8, manual muscle testing 8 muscle groups; MDAAT, Myositis Disease Activity 
Assessment Tool; EM Global, Extra muscular Global; CHAQ/HAQ, Childhood Health Assessment Questionnaire/Health Assessment Questionnaire; 
CHQ-PF50, Childhood Health Questionnaire, parent form 50; SF36, Short Form 36; CDASI, Cutaneous Dermatomyositis Assessment and Severity 
Index; DLQI, Dermatology Life Quality Index
IRB NUMBER: 111418
IRB APPROVAL DATE: 05/02/2020


Page 76 of 84
Version 10.5 22April2020                                                                       
Table 2 (*)
Test
Collection Date 
Collection Tube
Matrix
Required volume (ml) for
Children         Adults
Comprehensive Metabolic Panel (Chem 14)  
Screen, W0, 6,12,18,24, 25-48 
Gold SST top tube 
Serum 
2.5
4.0
Complete blood count (CBC) with diff 
Screen, W0, 6,12,18,24, 25-48 
Lavender top tube 
Whole Blood 
1.5
3.0
Von Willebrand Factor Antigen 
W0,6,12,18,24
Blue top tube 
Plasma 
1.0
1.0
Thyroid function test, TSH, Thyroid Abs   
W0, 24
Red top tube 
Serum
4.0
4.0
Glutamyl Transferase (GGT)
Screen, W0,6,12,18,24, 25-48
Green or Red top tube 
Serum 
0.6 
0.6
Creatine Kinase (CK) 
Screen, W0,6,12,18,24, 25-48 
Gold SST tube/Red top  
Serum 
5.0
5.0
Aldolase 
Screen, W0,6,12,18,24, 25-48
Red top tube 
Serum 
3.0
3.0
Lactate Dehydrogenase (LDH)
Screen, W0,6,12,18,24, 25-48
Red top tube 
Serum 
1.0
1.0
HIV Ab    
Screen 
Lavender top tube 
Serum
2.0
2.0
Hepatitis panel (HBsAg, Anti-HBc, Anti-
HepC) ,CD19 (for those who received 
rituximab before) 
Screen
Red /black SST tube 
Serum
8.0
12.0
Quantiferon-gold TB test
Screen 
Test Special kit
Whole blood 
3.0
3.0
Lymphocyte Phenotyping-TBNK/Flow 
cytometry  
W0,12,24
Lavender top tube
Whole blood 
2.0
2.0
Antinuclear Abs (ANA) and ENA (extractable 
nuclear Abs) comprehensive  panel  
W0,24
Red (stopper) tube 
Serum
2.0
2.0
PK, immunogenicity 
W0.12.24                                        
10.0        10.0 
Quantitative Immunoglobulins G and M 
W0
Red top tube 
Serum
2.0
2.0
Myositis-Specific and Myositis-Associated Ab 
(MSA and MAA) test
W0
Red (stopper) tube 
Serum 
5.0
5.0
Research Immunology Tests at Ross Hall:
1.
FACS Immunophenotyping for CD4, CXCR3, IFNγ (TH1), 
CD4, CCR4, CRTH2, Il4(TH2), CD4, CCR6, Il17α (TH17), 
CD4, CD25, Foxp3 (T regulatory cells), B cell markers, 
macrophage markers along with B71, B72, CTLA4, CT28
2.
Cytokine Human Magnetic 30-Plex Panel
3.
RNA isolation and RNA Quality Check
4.
Illumina Human Gene Bead Chip Panel
W0,12,24
Heparinized tube 
Whole blood
60.0
60.0
IRB NUMBER: 111418
IRB APPROVAL DATE: 05/02/2020


Page 77 of 84
Version 10.5 22April2020                                                                       
5.
Illumina Data Analysis and Ingenuity Pathways Analysis
Urinalysis 
Screen, W0,6,12,18,24, 
25-48
Urine cap 
Urine 
1.0
1.0
Urine pregnancy Test 
Screen, W0,6,12,18,24,
25-48
Urine cap
Urine 
1.0
1.0
(*)  NIH guidelines for limits of blood drawn for research purposes will be followed:
Adult Patients and Volunteers: Blood Drawing Limits for Research Purposes 
The amount of blood that may be drawn from adult patients and volunteers (i.e., those persons 18 years of age or older) for research purposes shall 
not exceed 10.5 mL/kg or 550 mL, whichever is smaller, over any eight week period. The amount of blood to be drawn from volunteers and the frequency of 
collection shall be specified in the clinical research protocol, and exceptions to the 10.5 mL/kg or 550 mL limitations shall be approved by the IRB. 
IRB NUMBER: 111418
IRB APPROVAL DATE: 05/02/2020


Page 78 of 84
Version 10.5 22April2020                                                                       
Pediatric Patients: Blood Drawing Limits for Research Purposes 
For pediatric patients, no more than 5 mL/kg may be drawn for research purposes in a single day, and no more than 9.5 mL/kg may be drawn over any eight-
week period.  
   Table 2a : Summary of blood collection 
                            Blood   Volume ( ml)
                         Children    Adult 
Screen                28.6       35.6                                       
W0                      105.7       114.2 
W6                      14.6       17.7
W12                    86.6       89.6
W18                    14.6       17.7
W24                    92.6        95.6
W 25-48              13.5        16.6                                                                   
IRB NUMBER: 111418
IRB APPROVAL DATE: 05/02/2020


Page 79 of 84
Version 10.5 22April2020                                                                       
APPENDIX F 
ACTION PLAN FOR TREATMENT OF WORSENING OF DISEASE: 
Criteria for disease worsening in a clinical trial, by which patients could be termed treatment failures and offered alternative 
therapies, were preliminarily defined at an IMACS Workshop. These criteria will be incorporated into this trial. 
         . In order to be classified as “worsening” in this trial subjects will have to meet the following criteria: 
(1) Physician global worsening of ≥ 2 cm on the 10 cm visual analog scale (VAS) and a worsening of the manual muscle testing 
by ≥ 20%, or 
(2) Global extra muscular organ disease activity (a composite of constitutional, cutaneous, skeletal, gastrointestinal, pulmonary 
and cardiac activity) worsening by ≥ 2 cm on a 10 cm VAS, or 
(3) 3 of any 6 IMACS core set activity measures worse by ≥ 30%. And 
(4) Subjects will have to meet the above criteria and be classified by the investigator as at least moderately clinically worse. 
Patients who improve by less than 5% in at least 3 of 6 core set measures by week 12, will be  considered to be not 
improved :  These patients may be offered higher dose therapy at 212 mg (87.5 + 125 mg)  for subjects with body weight ≥ 50 
kg or  137.5 mg for subjects with body weight < 50 kg abatacept weekly.  
IRB NUMBER: 111418
IRB APPROVAL DATE: 05/02/2020


Page 80 of 84
Version 10.5 22April2020                                                                       
APPENDIX G
      CLINICAL LABORATORY EVALUATIONS
HEMATOLOGY
SERUM CHEMISTRY
URINALYSIS
Total white blood cell 
count
Differential: 
     Neutrophils
     Lymphocytes
     Monocytes
     Eosinophils
     Basophils
Hematocrit
Hemoglobin
Platelet Count
Lymphocyte 
phenotypingperifascicu
lar
(TBNK by flow 
cytometry )
 Von Willebrand Factor 
antigen
Electrolytes:
     Bicarbonate
     Chloride 
     Potassium           
     Sodium 
     Calcium
     Magnesium
 
     Phosphorus (inorganic)                  
Enzymes:
      Aldolase
      Aspartate aminotransferase 
(AST)
      Alanine aminotransferase (ALT)
      LDH
      CPK
      GGT
      CPK
Other:
 
     BUN
     Creatinine
     QIG panel (IGM, IGG)
     
     Hepatitis B surface antigen  
     Hepatitis C antibody
     TSH
     HIV
     Quantiferon Gold 
     ANA/ENA
pH
Blood
   
Glucose
Protein
Ketones
Nitrites
Bilirubin       
Urobilinogen
Leukocyte esterase        
Microscopic exam  if dipstick
        positive
Urine Pregnancy
IRB NUMBER: 111418
IRB APPROVAL DATE: 05/02/2020


Page 81 of 84
Version 10.5 22April2020                                                                       
     MSA/MAA
     Immunogenicity (HAHA)
     pK
Laboratory test results will be reviewed by the Investigator or Sub-Investigator as they become available.  The Investigator or Sub-Investigator must 
determine the clinical significance of all out-of- range laboratory values.  Possibly drug-related or clinically relevant abnormal values of uncertain 
causality must be repeated.  Any abnormal values that persist should be followed at the discretion of the Investigator.
IRB NUMBER: 111418
IRB APPROVAL DATE: 05/02/2020


Page 82 of 84
Version 10.5 22April2020                                                                       
Appendix H.  Study Personnel and Roles
Rodolfo Curiel, MD, Associate Professor of Medicine, George Washington University, is the Principal Investigator, of the study.  He will 
be responsible for the oversight of all study personnel, procedures and logistics. He will assist with patient recruitment, screening and 
assessment, and oversee data management and analysis.  
Lisa Rider, MD, Deputy Chief, Environmental Autoimmunity Group, NIEHS, NIH and Adjunct Clinical Professor of Medicine, George 
Washington University, will be an Associate Investigator for the study.  She will assist with patient recruitment, screening and assessment, 
and oversee analysis.  
Olcay Jones, MD, PhD, Chief of Pediatric Rheumatology, Walter Reed National Military Medical Center and Adjunct Clinical Associate 
Professor of Medicine, George Washington University, will be an Associate Investigator for the study.  She will assist with patient 
screening and assessment.  
  
Alison Ehrlich, MD, Professor of Dermatology and Chair, Department of Dermatology, George Washington University, will be an 
Associate Investigator for the study.  She will assist with dermatologic assessment of the patients, including photographing skin rashes.  
Kathleen Brindle, MD, Associate Professor of Radiology, George Washington University, will be an Associate Investigator for the study. 
She will read and score the magnetic resonance imaging studies of the thighs/pelvis and also plain x-rays of calcinosis.
Victoria Shanmugan, MD Associate Professor of Medicine. George Washington University. She will oversee the performance of the 
research blood samples, including lymphocyte flow cytometry, cytokine production, gene expression profiling, and Ingenuity Pathway 
Analysis.
Gulnara Mamyrova, MD, PhD, Researcher/GWU Myositis Center Coordinator, Division of Rheumatology, will be an associate 
investigator for the study. She will be responsible for the oversight of all study procedures and logistics. She will assist with patient 
recruitment and screening, regulatory submissions and preparation of reports for the DSMB, as well as data management and analysis.   
IRB NUMBER: 111418
IRB APPROVAL DATE: 05/02/2020


Page 83 of 84
Version 10.5 22April2020                                                                       
Hassan Awal, MD Clinical Research Coordinator, Department of Medicine, The GW MFA, will be an associate investigator for the study. 
He will be responsible for the oversight of all study procedures and logistics. She will assist with patient recruitment and screening, 
regulatory submissions and preparation of reports for the DSMB, as well as assist with data management.   
Other personnel involved with the study include:
Dr. Ira Targoff and staff, Oklahoma Medical Research Foundation, Oklahoma City, OK, will perform the myositis autoantibody testing.  
They will have access to identifiable patient information in their clinical fee for testing program.
IRB NUMBER: 111418
IRB APPROVAL DATE: 05/02/2020


Page 84 of 84
Version 10.5 22April2020                                                                       
Appendix I: COVID19 Addendum San Diego subsite
Due to current state of national emergency due to COVID19 Pandemic, special consideration applies to the protocol as per guidance 
set by Department of Health and Human services, George Washington University Office of Human Research, and Research Guidance 
set by GW Medical Faculty Associates. 
We will be enrolling one patient from San Diego, California with help from Dr Robert Sheets at Rady’s Children’s Hospital’s/ UCSD. 
University of California San Diego will be effectively added as a subsite of The George Washington University Medical Faculty 
Associates. 
The visit that will take place will be run virtually, with Dr Sheets performing the visit assessments with Dr Curial and Dr Rider present via 
ZOOM telemedicine video call. Labs will be collected and processed at UCSD, along with the imagine needed for enrollment visit (chest 
X-Ray and pelvis/thigh MRI). Study drugs will be shipped to UCSD Investigational Drug Services and will be dispensed there to the 
patient as per guidelines. Due to the uncertainty of the pandemic, all the follow up visit might need to be done in San Diego. IRB have 
approved this plan. 
This change in research plan is approved by BMS, the funder of the study. 
IRB NUMBER: 111418
IRB APPROVAL DATE: 05/02/2020