An Open Label, Multi-Center, Phase 3 Efficacy Study of Sub-Q Abatacept in Preventing Extension of Oligoarticular Juvenile Idiopathic Arthritis JIA (Limit-JIA)
Phase: PHASE3
Conditions: Juvenile Idiopathic Arthritis
Sponsor: Duke University

 
 
 
 
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An Open Label, Multi-Center, Phase 3 Efficacy Study of Sub-Q Abatacept 
 (Orencia) in Preventing Extension of Oligoarticular Juvenile Idiopathic Arthritis JIA 
(Limit-JIA) 
 
Phase: 3 
Date:  17February2022 
Protocol Number: Pro00100523 
NCT03841357 
Version: 5 
Principal Investigator  
Laura E. Schanberg, MD (Sponsor, IND Holder) 
Department of Pediatrics 
Duke University Medical Center 
Box 3212 
Durham, NC 27710 
Phone: (919) 684-6601 
Email: laura.schanberg@duke.edu 
 
Principal Investigator 
Mara Becker, MD, MSCE 
Vice Chair, Faculty 
Department of Pediatrics 
Division of Pediatric Rheumatology 
Duke University School of Medicine 
Duke Clinical Research Institute 
Phone: 919.613.1942 
E-Mail: mara.becker@duke.edu 
 
Principal Investigator 
Stephen J. Balevic, MD, MHS 
Assistant Professor 
Adult & Pediatric Rheumatology 
Duke University Medical Center 
Duke Clinical Research Institute 
Phone: 919-668-4833 
300 W Morgan St, Suite 800 
Durham, NC  27701 
Email: stephen.balevic@duke.edu 
 
           
 
 

 
 
 
 
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1.1.1.1  
 
 
 
THIS DOCUMENT CONTAINS INFORMATION THAT IS PRIVILEGED OR 
CONFIDENTIAL AND MAY NOT BE DISCLOSED UNLESS SUCH DISCLOSURE IS 
REQUIRED BY APPLICABLE LAWS AND REGULATIONS. THE INFORMATION IN 
THIS DOCUMENT IS THE PROPERTY OF THE DUKE CLINICAL RESEARCH 
INSTITUTE (DCRI) AND MAY NOT BE REPRODUCED, PUBLISHED, OR DISCLOSED 
TO OTHERS WITHOUT WRITTEN AUTHORIZATION FROM DCRI. 
 
 
 
 

 
 
 
 
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Protocol Version and Amendment Tracking 
 
Version Number/Amendment 
Approval Date 
Protocol Version 1.0 
20December2018 
Protocol Version 2.0 
08May2019 
Protocol Version 3.0 
20Apr2020 
Protocol Version 4.0 
24August 2020 
Protocol Version 5.0 
17February2022 
 
 
 
 
 

 
 
 
 
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PROTOCOL SYNOPSIS 
 
 
Protocol Number 
Version 5.0 
Protocol Title 
An, Open Label, Multi-Center, Phase 3 Efficacy 
Study of Sub-Q Abatacept (Orencia) in Preventing 
Extension of Oligoarticular JIA (Limit-JIA) 
Main Criteria for Inclusion 
• Age ≥ 2 years old and ≤ 16.5 years old 
• Clinical diagnosis of JIA by a pediatric 
rheumatologist within the past 6 months 
• Arthritis affecting ≤ 4 joints between disease 
onset and enrollment 
• Prior or concurrent enrollment in the 
CARRA Registry  
• Weight ≥50 kg (Canadian Sites only) 
Study Objective 
To evaluate the effectiveness of a 24-dose course of 
weekly treatment with a T-cell co-stimulation 
inhibitor (abatacept (Orencia)) plus usual care 
versus usual care subjects from the CARRA 
Registry to prevent polyarthritis (≥5 joints), uveitis, 
or treatment with other systemic medication (s) for 
JIA (i.e. one or more of the following: systemic 
glucocorticoids, DMARD or biologic) medication 
within 12 months of enrollment in children with 
recent-onset limited JIA 
Study Design 
Prospective, open-label clinical trial. with stratified 
enrollment of participants based upon baseline risk 
of developing polyarthritis or uveitis  
Treatment Regimen 
• Abatacept (Orencia) plus usual care for 24 
weekly doses with ongoing usual care and 24 
weeks of follow up for a total of 48 weeks.  
• Usual care for 12 months (48 weeks) as 
recorded in the CARRA Registry 
• Usual care is defined as NSAIDs and/or 
intra-articular glucocorticoids at the 
discretion of the treating provider 
Duration of Study Participation 
12 months (48 weeks) 
End -of Study- Definition 
Date of last study participant’s last visit 
Number of Study Participants 
89 
Number of Sites 
Up to 30 

 
 
 
 
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Primary Endpoint 
Proportion of participants with disease extension 
(development of polyarthritis or uveitis) or need for 
systemic medication (s) for JIA (i.e. one or more of 
the following: systemic glucocorticoids, DMARD or 
biologic) within 12 months post-enrollment.  
Secondary Endpoints 
• PRO group differences including PROMIS® 
measures (pain interference, fatigue, upper 
extremity function, mobility, anxiety, 
depression, and global health) and 
medication side effects (JAMAR), CHAQ 
• Proportion of children achieving clinical 
inactive disease and/or remission 
• Number of new joints with arthritis 
• Cumulative number of glucocorticoid joint 
injections 
• Serious adverse events  
• Juvenile arthritis disease activity scores 
(JADAS) 
• Elapsed time from enrollment to disease 
extension, uveitis or systemic DMARD 
medication use 
• Proportion of participants with disease 
extension (development of polyarthritis or 
uveitis)  
 
Study Schedule Definitions 
• 6 months is equal to 24 weeks or 24 doses of 
abatacept 
• 12 months is equal to 48 weeks 
 
 
 
 

 
 
 
 
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INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices and the investigator brochure, and I agree that it 
contains all necessary details for me and my staff to conduct this study as described. I will personally 
oversee the conduct of this study as outlined herein and will make all reasonable efforts to complete 
the study within the time designated. 
 
I will provide all study personnel under my supervision with copies of the protocol and access to all 
information provided by the sponsor. I will discuss this material with them to ensure that they are fully 
informed about the efficacy and safety parameters and the conduct of the study in general. I am aware 
that, before beginning this study, the institutional review board responsible for such matters must 
approve this protocol in the clinical facility where it will be conducted. I agree to adhere to the 
attached protocol. 
 
I agree to provide all study participants with informed consent, as required by government regulations 
and International Conference on Harmonization guidance. I further agree to report to the sponsor any 
adverse experiences in accordance with the terms of this protocol.  
 
 
________________________________ 
 
 
 
 
 
Principal Investigator Name (print)  
 
 
 
________________________________ 
Signature 
 
 
 
 
________________________________ 
 
Date 
 
 

 
 
 
 
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TABLE OF CONTENTS 
 
 
Protocol Synopsis.................................................................................................................4 
Investigator Statement .........................................................................................................6 
Table of Contents .................................................................................................................7 
Abbreviations .....................................................................................................................10 
1 
Introduction ............................................................................................................13 
2 
Objectives ..............................................................................................................16 
2.1 
Primary Objective ............................................................................................16 
2.2 
Secondary Objectives.......................................................................................16 
2.2.1 
To compare participant and caregiver reported outcomes between the 
different treatment strategies...................................................................16 
2.2.2 
To enhance identification of eligible study participants by leveraging the 
EHR (at selected US sites only). .............................................................16 
2.2.3 
To optimize data completeness by leveraging EHR data (at selected US 
sites only). ...............................................................................................16 
2.2.4 
To improve clinical trial recruitment and retention. ...............................17 
3 
Study Participant Selection ....................................................................................18 
3.1 
Number of Study Participants ..........................................................................18 
3.2 
Clinical Trial Inclusion Criteria .......................................................................18 
3.3 
Clinical Trial Exclusion Criteria ......................................................................18 
3.4 
Candidate Computable Phenotype Criteria (at selected US sites only) ...........19 
3.5 
Ethnography Criteria (at selected US sites only) .............................................19 
4 
Study Design ..........................................................................................................21 
4.1 
Overview of Study ...........................................................................................21 
4.2 
Treatment Arms ...............................................................................................21 
4.3 
Study Assessment ............................................................................................23 
4.3.1 
Schedule of Assessment ..........................................................................23 
4.3.2 
Explanation of Assessments ...................................................................24 
4.3.3 
Recommended Ophthalmology Assessments .........................................27 
4.4 
Screening and Pre-Enrollment Procedures ......................................................28 
4.5 
Screen Failure ..................................................................................................28 
 
 
4.6 
Screening Visit .................................................................................................28 
4.7 
Enrollment Visit  (Within 45 days after Screening Visit; may be a 
combination visit Screening/Enrollment) ........................................................29 
4.8 
Post Enrollment Procedures (Month 3 to Month 12) .......................................29 
4.9 
Immunizations..................................................................................................31 
4.10 
Development and Utilization of EHR based Algorithms for Enhanced Study 
Recruitment at Subset of Trial Sites ................................................................31 
4.11 
Abstraction and Linkage of EHR Data and CARRA Registry Data for 
Assessment and Improvement of Data Completeness .....................................32 
4.12 
Ethnography Study Design ..............................................................................33 
4.12.1 
Patient/Family Recruitment & Enrollment Process ................................33 

 
 
 
 
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4.12.2 
Staff Recruitment & Enrollment Process ................................................35 
4.12.3 
Sites .........................................................................................................35 
4.12.4 
Ethnography Schedule of assessments and Study Timeline ...................36 
4.12.5 
Initial Design of Materials ......................................................................36 
4.12.6 
Ongoing PDSA and Tools Improvement ................................................36 
5 
MyStudies App ......................................................................................................37 
5.1 
Description of the MyStudies Mobile App ......................................................37 
5.2 
Data Access Security and Storage ...................................................................37 
5.3 
Survey Distribution for Mobile App Users ......................................................38 
5.4 
Survey Notifications ........................................................................................38 
6 
Clinical Trial Treatment Interventions...................................................................40 
6.1 
Abatacept (Orencia) – Study Drug ..................................................................40 
6.3 
Storage .............................................................................................................40 
6.4  
Study Drug Discontinuation Criteria ...............................................................40 
6.4.1 
Procedures for Monitoring Study Drug Compliance ..............................41 
6.4.2 
Temporary Discontinuation of Study Drug ............................................41 
6.4.3 
Discontinuation of Study Drug ...............................................................41 
6.4.4   
Study Drug Discontinuation Study Assessments ....................................42 
6.4.5 
Withdrawal from Study...........................................................................42 
6.5 
Concomitant Medications ................................................................................42 
6.6 
Use of Oral Prednisone ....................................................................................42 
6.7 
COVID-19 Guidance .......................................................................................42 
 
7 
ASSESSMENT OF SAFETY ................................ Error! Bookmark not defined. 
7.1 
Definition .........................................................................................................44 
7.2 
Assessment of Adverse Event Severity ...........................................................44 
7.3 
Assessment of Causal Relationship .................................................................44 
7.4 
Expectedness ....................................................................................................45 
7.5 
Protocol-Defined ESIs .....................................................................................45 
7.6 
Serious Adverse Events ...................................................................................46 
7.7 
Reporting to Regulatory Authorities ................................................................47 
7.8 
Pregnancy .........................................................................................................47 
8 
Efficacy Assessments.............................................................................................48 
8.1 
Primary Outcome .............................................................................................48 
8.2 
Secondary Outcomes .......................................................................................48 
8.2.1 
Patient reported outcomes .......................................................................48 
8.2.2 
Enhanced Study Recruitment ..................................................................49 
8.2.3 
Data Completeness..................................................................................49 
8.2.4 
Other Secondary Outcomes ....................................................................50 
9 
Statistical Analysis Plan and Determination of Sample Size .................................51 
9.1 
Statistical Design ............................................. Error! Bookmark not defined. 
9.2 
Primary Analysis .............................................. Error! Bookmark not defined. 
9.3 
Major Secondary Analyses .............................. Error! Bookmark not defined. 
9.4 
Other Planned Analyses ................................... Error! Bookmark not defined. 
9.4.1 
Subgroup Analyses ................................. Error! Bookmark not defined. 

 
 
 
 
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9.4.2 
Power, Sample Size and Type I Error ..... Error! Bookmark not defined. 
9.4.2 
Interim AnalysisGeneral Statistical AnalysesError! Bookmark not defined. 
 
10 
Data and Safety Monitoring ...................................................................................56 
10.1 
Data Safety Monitoring Board .........................................................................56 
10.2 
Required Data ..................................................................................................56 
10.3 
Data Collection and Tracking ..........................................................................56 
11 
Study Responsibilities ............................................................................................57 
11.1 
Investigator Responsibility/Performance .........................................................57 
11.2 
Study Documentation.......................................................................................57 
11.3 
Protocol Deviations ..........................................................................................57 
11.4 
Study Drug Accountability ..............................................................................58 
11.5 
Study Closeout .................................................................................................58 
11.6 
Publication Policies ..........................................................................................58 
11.7 
Record Retention .............................................................................................58 
12 
Ethical Considerations ...........................................................................................60 
12.1 
Informed Consent.............................................................................................60 
12.2 
Confidentiality of Study Participants ...............................................................60 
12.3 
Institutional Review Board/Ethics Committee Review ...................................60 
12.4 
Information Security ........................................................................................61 
13 
References ..............................................................................................................62 
 
 
 

 
 
 
 
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ABBREVIATIONS 
AE 
Adverse Event 
ACR  
American College of Rheumatology 
ALT (SGPT) 
Alanine transaminase 
AM 
Ante Meridiem 
ANA 
Antinuclear Antibodies 
ARCH CDRN 
Accessible Research Commons for Health Clinical Data Research 
Network 
AST (SGOT) 
Aspartate aminotransferase 
BMS 
Bristol-Myers Squibb 
CARRA 
Childhood Arthritis and Rheumatology Research Alliance 
CBC 
Complete Blood count 
CCP 
Cyclic citrullinated peptide 
CDM 
Common data model 
CDRN 
Clinical Data Research Network 
CFR 
Code of Federal Regulations 
CHAQ 
Childhood Health Assessment Questionnaire 
DCRI 
Duke Clinical Research Institute 
dL 
Deciliter  
DMARD 
Disease-modifying anti-rheumatic drug 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
ESI 
Events of special interest 
EHR 
Electronic health record 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability Accountability Act 
HIV 
Human immunodeficiency virus  
HLA-B27 
Human leukocyte antigen B27  
IBD 
Inflammatory bowel disease 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 

 
 
 
 
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ILAR 
International League of Associations for Rheumatology 
IND 
Investigational new drug 
ITT 
Intention to treat 
IRB 
Institutional Review Board 
IV 
Intravenous 
JADAS 
Juvenile Arthritis Disease Activity Score 
JAMAR 
Juvenile Arthritis Multidimensional Assessment Report 
JIA 
Juvenile idiopathic arthritis 
JDM  
Juvenile dermatomycosis 
MAR 
Missing at random 
MCAR 
Missing completely at random 
MD 
Medical Doctor 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
MI 
Multiple imputation 
NP 
Nurse practitioner 
NSAIDs 
Nonsteroidal anti-inflammatory drug 
PCORnet 
Patient-Centered Clinical Research Network  
PDSA 
Plan-Do-Study-Act 
PH 
Proportional hazards 
PHI 
Protected health information 
PI 
Principal Investigator 
PPD 
Purified Protein derivative 
pPH 
Pediatric pulmonary hypertension 
PRO 
Patient-reported outcome 
PROMIS® 
Patient Reported Outcomes Measurement Information System 
RA 
Rheumatoid arthritis  
REB 
Research Ethics Board 
RF 
Rheumatoid factor 
SAC 
Stakeholder Advisory Committee 
SAE 
Serious adverse event 
SOC 
Standard of care 

 
 
 
 
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SQ 
Subcutaneous 
SUN 
Standardization of Uveitis Nomenclature for Reporting Clinical Data 
TB 
Tuberculosis 
ULN 
Upper limit of normal 

 
 
 
 
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1 
INTRODUCTION 
Juvenile idiopathic arthritis (JIA) is a heterogeneous, incompletely understood collection of 
inflammatory arthritides of unknown etiology defined by age at onset prior to 16 years.1 With a 
prevalence of approximately 1 per 1,000 children, and many clinical phenotypes, JIA is one of the 
most common chronic diseases of childhood. JIA often persists into adulthood causing significant 
morbidity and impairing quality-of-life.2-16 More than 50% of children with JIA present with “limited” 
disease, defined as arthritis involving ≤ 4 cumulative joints and no uveitis.17 Children with limited JIA 
may meet criteria for one of 4 separate categories of JIA defined by the International League of 
Associations for Rheumatology (ILAR): oligoarthritis, enthesitis-related arthritis, psoriatic arthritis, 
and undifferentiated arthritis.1 However, scant evidence supports differential treatment of children 
based upon ILAR categories, which are fraught with uncertainties and inconsistencies.18-27 Basing 
treatment decisions upon the number of joints affected to date, in contrast to ILAR categories, was 
endorsed by the 2011 American College of Rheumatology (ACR) Recommendations for the Treatment 
of JIA and more closely reflects current clinical practice.28, 29 Therefore, the Limit-JIA study focuses 
on all children presenting with arthritis of ≤ 4 joints without uveitis. For the purpose of this trial, this 
phenotype is termed “limited JIA”. Irrespective of ILAR category, children with limited JIA may 
develop significant morbidity, with only a minority achieving clinically inactive disease 12-18 months 
after disease onset. 4, 8, 30-32  
Disease extension in limited JIA. Children initially presenting with limited JIA frequently experience 
disease, defined as the development of polyarthritis (≥ 5 joints) or anterior uveitis,  Both polyarthritis 
and uveitis are associated with worse clinical outcomes, including increased long-term physical 
disability and disease activity levels compared to children who present with polyarthritis at the time of 
diagnosis.2, 6, 33-42 Fifty percent or more of children with limited JIA develop extension of oligoarthritis 
to polyarthritis (defined as ≥ 5 joints), including more than 25% within 2 years of disease onset.2, 30, 39, 
43-45  Reported arthritis extension rates vary between studies, likely reflecting genetic and 
environmental variation and methodological differences in the inclusion and follow-up of study 
participants.46  Of note, previous studies focused on the ILAR category of oligoarthritis and did not 
include enthesitis-related arthritis or psoriatic arthritis, which have considerably higher rates of arthritis 
extension.43  
One factor likely contributing to disappointing clinical outcomes for children presenting with early, 
limited JIA is delayed initiation of effective disease modifying anti-rheumatic drugs (DMARDs) 
and/or biologics.35, 47  The development of anterior uveitis is also an important manifestation of limited 
JIA and can lead to permanent ocular disabilities such as glaucoma, cataracts, and vision loss.36-38  
Approximately 20% of children with limited JIA develop anterior uveitis, most often within 2 years of  
arthritis onset.2, 30, 48 The development and subsequent severity of uveitis are often independent of 
arthritis manifestations, i.e., children may develop uveitis without concomitant extension to 
polyarthritis and vice-versa.49 Lastly, a number of children may have persistent, limited JIA but 
inadequate response to treatment with nonsteroidal anti-inflammatory drugs (NSAIDS) and intra-
articular glucocorticoid injections, requiring ongoing systemic treatment with DMARDs or biologic 
agents, even without extension of arthritis or development of new uveitis.50-52   We therefore seek to 
determine whether early treatment with a 24-week course of abatacept (Orencia) will delay, diminish, 
or prevent the important outcomes of polyarthritis or uveitis, or need for systemic DMARD or biologic 
use during the study period and longer-term follow-up in the Childhood Arthritis and Rheumatology 
Research Alliance (CARRA) Registry.  
Rationale for costimulatory blockage treatment for JIA. Abatacept (Orencia) is an approved, standard 
of care treatment for adults with rheumatoid arthritis (RA; USA and Canada) and for children with 

 
 
 
 
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polyarticular JIA (USA [SQ and IV] and Canada [IV form only]). Abatacept (Orencia) selectively 
inhibits a costimulatory signal required for T-cell activation, which is hypothesized to be an early step 
in the development of inflammatory arthritis.  The 50 mg, 87.5 mg and 125 mg, SQ doses are approved 
for use in pediatric patients in the United States, whereas the 125 mg SQ dose is the only form 
approved for use in Canada. 
Clinical trials in adults with RA have established that early treatment with biologic agents and 
DMARDs, during a “window of opportunity,” improves long-term outcomes and reduces future 
disability.54-56 In particular, a randomized, double-blind trial in undifferentiated arthritis (very early 
RA) demonstrated that a 6-month course of abatacept (Orencia) delayed disease progression in the 
majority of participants.57 Unpublished results from an recent study presented at the 2021 American 
College of Rheumatology Annual Meeting showed that a 6 month course of abatacept reversed 
subclinical arthritis in participants at high risk for RA. 57, 58, 67 While such data is currently limited to 
adult RA and not JIA, the results strongly support the study of abatacept (Orencia) as a preventative 
agent for extension of disease in limited JIA. 
Use of Electronic Health Record (EHR) data to improve efficiency in identification of participants with 
early disease and generalizability of study results. In Limit-JIA, treatment success is hypothesized to 
be associated with early treatment of JIA, and it is important to screen potentially eligible participants 
within six months of initial diagnoses.   The ability to screen a high percentage of new onset patients 
would improve both the efficiency of study conduct and the generalizability of study findings to a 
larger non-study population.  A principal focus of this study, therefore, involves the development of 
new, informatics-based screening techniques and procedures to enhance the timeliness and 
representativeness of study participant enrollment.  The use of machine learning techniques to analyze 
EHR data is a promising approach to accomplish this goal; for example, in a recent registry-based 
study of Pediatric Pulmonary Hypertension (pPH) conducted at Boston Children’s Hospital, use of the 
pPH registry alone, when compared against EHR-assisted data analysis approaches, identified fewer 
than half of the pPH patients seen.53 Therefore, incorporating EHR-based study participant 
identification to more rapidly and comprehensively screen potentially eligible, recently diagnosed 
patients is likely to maximize overall study enrollment, minimize ascertainment biases, and improve 
overall study cost-effectiveness and scalability.   
Improving data completeness. Assessment and minimization of missing data relevant to the tested 
hypotheses is critical to reaching clinically and statistically meaningful results.  Performing linkages 
between disparate data sources (e.g. EHR, registry, and patient reported outcome (PRO) data) is likely 
to provide valuable insight into measuring and remediating specific domains of missing data, 
particularly those that are readily available and accurate in the EHR.   
Advanced cohort identification and data linkage activities will be undertaken at a subset of 
participating CARRA Registry sites that are also data partners in the Patient-Centered Clinical 
Research Network (PCORnet) Accessible Research Commons for Health Clinical Data Research 
Network (ARCH CDRN).  We will leverage existing PCORnet Common Data Model (CDM) 
infrastructure at these sites to enhance study participant recruitment and improve data completeness in 
a scalable fashion.  Using a ‘computable phenotype’ for limited JIA will allow participating sites to 
generate screening lists of potential study-eligible participants based on EHR data.  We will also link 
data obtained directly from EHR data sources with conventionally collected CARRA Registry study 
data in order to support data completeness.   
Improving trial recruitment and retention through patient and caregiver engagement in research. 
Barriers and facilitators to trial enrollment, identified by previous surveys, point to issues such as 

 
 
 
 
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burden of visit schedule and how the study participant is approached. Unfortunately, best practices 
aimed at overcoming barriers to screening, recruitment and retention of study participants, particularly 
children, early in disease course are lacking. Unique challenges recruiting children include the 
dynamics of obtaining parental consent, different conception of clinical equipoise, and logistics 
(missing work and school).  A systematic review reported the most common motivating factors for 
parents were health benefit for their child, altruism, trust in research, and the relationship with the 
researcher. Most commonly reported reasons for not participating were fear of risks, distrust in 
research, logistics and disruption of daily life routines. Scant research examining trial recruitment has 
been performed in the JIA population and no studies have examined patients early in disease course.  
According to one of our patient investigators, “Receiving a diagnosis of JIA was an overwhelming 
experience for our family. We had always associated arthritis with old people and never knew children 
could also have arthritis. If we were approached to participate in a research project at this time, we 
would have declined. On top of being overwhelmed and confused by the diagnosis, we had a 
preconceived notion that participating in research meant that we were allowing our child to be a lab 
rat.” This illustrates not only the problem of study enrollment at diagnosis but also the human element 
underlying the problem. Improvement in clinical trial enrollment and retention, especially around the 
time of diagnosis, is likely to be critically dependent upon incorporating a deeper understanding of the 
patient’s and family’s state of mind into the recruitment process. We will therefore explore, develop, 
and implement innovative ethnographic approaches that have been well-established as effective in 
other domains to capture and quantify current knowledge gaps in the lived experience of newly 
diagnosed early JIA in context of research trial participation. 
 

 
 
 
 
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2 
OBJECTIVES   
2.1 
Primary Objective 
To evaluate the effectiveness of a 24-dose course of treatment with the T-cell co-stimulation inhibitor, 
abatacept (Orencia), plus usual care that may include NSAIDs and/or intra-articular glucocorticoids 
versus usual care as derived from the CARRA Registry database, to prevent disease extension 
(development of polyarthritis [defined as ≥ 5 joints with arthritis] or uveitis) or the need for further 
treatment with systemic medication(s) for JIA (i.e. one or more of the following: systemic 
glucocorticoids, DMARD or biologic) medication within 12 months of enrollment in children with 
recent-onset limited JIA. 
Hypothesis 2.1: Early treatment with abatacept (Orencia) will reduce the proportion of children who 
develop polyarthritis or uveitis, or need further treatment with systemic medication(s) for JIA (i.e. 
one or more of the following: systemic glucocorticoids, DMARD or biologic) within 12 months, 
compared to usual care. 
2.2 
Secondary Objectives 
2.2.1 To evaluate the tolerability of weekly SQ abatacept and compare participant and 
caregiver reported outcomes between the treatment arm and standard of care as 
documented in the CARRA Registry.  
Hypothesis 2.2.1:  Patient-Recorded Outcomes (PROs) will remain stable or show improvement at 6 
and 12 months in enrolled patients.  
Hypothesis 2.2.2: There will be statistically significant differences in (PROs) between the two 
treatment strategies that can inform future participants and providers in selecting optimal treatments. 
 
2.2.2 To enhance identification of eligible study participants by leveraging the EHR (at selected 
US sites only).  
We will develop and refine proactive EHR-based processes for identifying study participants with 
recently diagnosed, limited JIA. Collaborating with PCORnet Accessible Research Commons for 
Health (ARCH) CDRN study sites, we will incorporate PCORnet Common Data Model (CDM) EHR 
selection queries to continuously generate screening lists of study-eligible study participants and 
compare with enrollment rates at non-ARCH sites. As feasible, other sites may assist in further 
validating such EHR selection queries using conventional EHR-based reports 
Hypothesis 2.2.2: Incorporation of EHR-based study participant identification methods into 
conventional screening processes will improve enrollment rates for recently diagnosed participants 
with early JIA. 
 
2.2.3 To optimize data completeness by leveraging EHR data (at selected US sites only).  
Relevant data elements from the EHR at participating ARCH CRDN sites will be linked and 
incorporated into the CARRA Registry data warehouse for assessment of missing data domains. 
Linkages will be performed in ongoing completeness-improvement cycles across participating ARCH 
CDRN study sites.  
Hypothesis 2.2.3: Incorporation of EHR data will provide statistically meaningful improvements in 
data completeness.  
 
 
 

 
 
 
 
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2.2.4 To improve clinical trial recruitment and retention. 
We will improve clinical trial recruitment and retention of study subjects early in their disease course 
by identifying barriers and developing improved resources and processes. The study will focus on the 
following four domains of interest: 
1. Understanding of disease/treatment 
2. Trust 
3. Perceived value of research 
4. Time and logistics 
Hypothesis 2.2.4: Integration of design thinking methods and enhanced understanding of enrollment 
barriers will lead to improved enrollment and retention rates of participants in a clinical trial early in 
disease course. 

 
 
 
 
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3 
STUDY PARTICIPANT SELECTION 
3.1 
Number of Study Participants 
Up to 30 centers in the US and Canada will participate in the study to enroll approximately 89 
study participants (80 evaluable patients).   
3.2 
Clinical Trial Inclusion Criteria 
To be eligible for this trial, participants must meet all of the following criteria in order to be included in 
the study: 
1. Age ≥ 2 years old and ≤16.5 years old 
2. Clinical diagnosis of JIA by a pediatric rheumatologist within the past 6 months  
3. Arthritis affecting ≤4 joints between disease onset and enrollment 
4. Enrollment in the CARRA Registry 
5. Participants of childbearing potential must agree to remain abstinent or agree to use an 
effective and medically acceptable form of birth control from the time of written or verbal 
assent to at least 66 days after taking the last dose of study drug. 
6. Weight ≥50 kg (Canadian Sites only) 
 
3.3 
Clinical Trial Exclusion Criteria 
The presence of any of the following will exclude a study participant from inclusion in the study: 
1. Systemic JIA as defined by 2004 ILAR criteria1 
2. Sacroiliitis (clinical or radiographic) 
3. Inflammatory bowel disease (IBD) 
4. History of psoriasis or currently active psoriasis 
5. History of uveitis or currently active uveitis 
6. Prior treatment with systemic medication(s) for JIA (e.g. one or more of the following: 
DMARD or biologic medication)  
7. Current or previous (within 30 days of enrollment) treatment with systemic glucocorticoids 
(A short course of oral prednisone [≤ 14 days] is allowed) 
8. History of active or chronic liver disease 
9. Chronic or acute renal disorder 
10. AST (SGOT), ALT (SGPT) or BUN >2 x ULN (upper limit of normal) or creatinine >1.5 
mg/dL or any other laboratory abnormality considered by the examining physician to be 
clinically significant within 2 months of the enrollment visit   
11. Presence of any medical or psychological condition or laboratory result which would make 
the participant, in the opinion of the investigator, unsuitable for the study  

 
 
 
 
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12. Participation in another concurrent clinical interventional study within 30 days of enrollment 
13. Known positive human immunodeficiency virus (HIV)  
14. Received a live virus vaccine within 1 month of the baseline visit 
15. Current or prior positive Purified Protein Derivative (PPD) test or Quantiferon Gold TB 
16. Pregnant, breast feeding, or planned breast feeding during the study duration 
17. Planned transfer to non-participating pediatric rheumatology center or adult rheumatologist 
in the next 12 months 
18. Active malignancy of any type or history of malignancy 
19. Chronic or active infection or any major episode of infection requiring hospitalization or 
treatment with intravenous (IV) antibiotics within 30 days or oral antibiotics within 14 days 
prior to screening 
20. Primary language other than English or Spanish  
21. Positive for Hepatitis B surface antigen or core antibody 
22. <10 Kg in weight 
23. If a potential subject has symptoms consistent with COVID-19 and/or known COVID-19 
exposure at screening, it is recommended that the site follow CDC guidance regarding testing 
and quarantine requirements. The subject can be re-screened when there is no longer concern for 
active infection. A subject with a positive COVID -19 test may be re-screened. 
3.4 
Candidate Computable Phenotype Criteria (at selected US sites only) 
1. Recent diagnosis codes including oligo-articular JIA as well as undifferentiated/unspecified 
JIA types only, AND  
2. Participants age ≥2 years old and ≤16.5 years old, AND 
3. Seen in pediatric rheumatology clinic with first inclusion criteria diagnosis code within the 
preceding 20 weeks OR scheduled for upcoming pediatric rheumatology clinic visit with prior 
diagnosis of any type of arthritis within the preceding 20 weeks, AND 
4. None of the following prior medications: systemic glucocorticoids, DMARDs OR biologics, 
AND 
5. No prior diagnosis codes for Inflammatory Bowel Disease (IBD), systemic-onset JIA, 
sacroiliitis or ankylosing spondylitis, psoriasis, or uveitis   
 
3.5 
Ethnography Criteria (at selected US sites only) 
 
There are four research study participant populations: 
1. Families who are asked to participate in the clinical trial (Limit-JIA) 
a. Inclusion: Parents/guardians of JIA participants ≥2 years old and ≤16.5 years of age at 
the time of diagnosis, who were asked to participate in Limit-JIA, regardless of decision 
to enroll or not in the Limit-JIA study 
b. Exclusion: Non-English speakers 
2. Site primary investigators 
a. Inclusion: Primary site investigator for Limit-JIA 
b. Exclusion:  Non –English Speakers 

 
 
 
 
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3. Study coordinators 
a. Inclusion: Coordinators participating in the Limit JIA trial 
b. Exclusion: Non-English Speakers 
4.  Clinicians 
a. Inclusion: Pediatric rheumatology providers e.g. Medical Doctors (MDs, DOs) and 
Nurse Practitioners (NPs) at participating sites who are recruiting for the Limit-JIA trial 
but are not the study coordinator or site primary investigator.  
b. Exclusion: Non-English Speakers 

 
 
 
 
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4 
STUDY DESIGN 
4.1 
Overview of Study 
The study treatment consists of an open label 24-dose course of weekly subcutaneous (SQ) abatacept 
(Orencia) plus usual care, versus usual care subject comparators from the CARRA Registry to prevent 
the development of polyarthritis or uveitis, or initiation of systemic glucocorticoid, DMARD, and/or 
biologic medication within 12 months of enrollment in children with recent-onset limited JIA.  Patients 
enrolled in the CARRA Registry receiving usual care who meet Limit-JIA inclusion/exclusion criteria 
will constitute the comparator arm, providing the proportion of children that develop disease extension 
on usual care alone. 
 
There are 6 study visits: screening, enrollment, approximately month 3 (M3 visit), month 6 (M6 visit), 
month 9 (M9 visit), and month 12 (M12 visit [end of study]). The screening visit may be combined 
with the enrollment visit if all procedures can be completed and participant qualifies for the study. 
Clinical trial visits may occur either in person or via telehealth except for the screening or enrollment  
visits.  One of these visits  must be conducted in the clinic.  The month 12 end of study visit must also 
be conducted in the clinic.  
 
In order to enhance study recruitment and timely enrollment, a subset of Limit-JIA US based clinical 
trial sites will incorporate enhanced cohort identification of potential study participants that 
incorporates EHR-based algorithms to predict the presence of limited JIA. Specifically, a ‘computable 
phenotype’ will be utilized to generate screening lists of potentially eligible, recently diagnosed limited 
JIA patients who may be considered for enrollment. These EHR-based screening lists will then be 
further reviewed by site staff for study eligibility.  
 
Study participant identification and enrollment using enhanced screening will be compared to use of 
traditional screening methods alone at this subset of sites.  In addition, at a subset of US based sites, all 
enrolled CARRA Registry participants with JIA will have registry data supplemented by selected EHR 
data elements, which will be linked by the site and made available in the CARRA Data Warehouse, 
enabling analyses of registry data completeness. 
 
In order to gain a better understanding of barriers to recruitment, enrollment and retention, a subset of 
participating US based clinical trial sites will participate in a sub-study focused on the patient journey 
through the clinical trial. This sub-study will follow a quasi-experimental time-series cross-sectional 
study design with initial tools development followed by three rounds of alternating data collection and 
iterative tools development to identify barriers and develop improved resources and processes to 
improve trial recruitment and retention of study participants. 
 
4.2 
Treatment Arms 
Limit-JIA is a prospective open-label clinical trial. Children diagnosed with limited JIA (≤ 4 active 
joints and no uveitis) in the previous 6 months will be treated with a 24-dose course of weekly SQ 
abatacept (Orencia) plus usual care that may include NSAIDs and/or intra-articular glucocorticoids 
followed by 6 months of usual care. Abatacept (Orencia) will be dosed using the weight-based SQ 
pediatric dosing provided in the package insert (Table 1 below).  
 

 
 
 
 
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Table 1: Study drug dosing  
Study drug dose will be adjusted for weight changes during the duration of the study drug 
administration period. 
Study 
Drug 
Dose by 
Weight 
Dosage Form 
Route 
Dosage 
Frequency 
Administration 
abatacept 
(Orencia) 
10 kg to < 25 
kg: 50 mg 
Solution for injection in 
pre-filled syringe 
(50mg in 0.4mL) 
SQ 
Once weekly 
US based 
clinical sites 
only 
abatacept 
(Orencia) 
>25 kg to < 
50 kg: 87.5 
mg 
Solution for injection in 
pre-filled syringe 
(87.5mg in 0.7mL) 
SQ 
Once weekly 
US based 
clinical sites 
only 
abatacept 
(Orencia) 
≥50 kg: 125 
mg 
Solution for injection in 
pre-filled syringe 
(125mg in 1mL) 
SQ 
Once weekly 
US and 
Canadian based 
clinical sites 
 

 
 
 
 
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4.3 
Study Assessment  
4.3.1 Schedule of Assessment 
Table 2: Schedule of Assessments (All assessments except the ophthalmology exams 
and screening and enrollment visits may occur in person or via telehealth.)  
 
Screen 
Visit 
Enrollment 
Visit (Baseline) 
(≤45 days) 
M3 
(+/-2 
weeks) 
M6 
(+/-2 
weeks) 
M9 
(+/-2 
weeks) 
M12 
End of Study1 
(+/-2 weeks) 
Interim Visits2 
 
Inclusion/Exclusion 
Criteria 
X 
X 
 
 
 
 
 
Consent/Assent 
X 
 
 
 
 
 
 
Demographic 
Information 
X 
X 
 
 
 
 
 
Enrollment 
X10 
X 
 
 
 
 
 
Past Medical Hx (per 
CARRA registry) 
X 
 
 
 
 
 
 
Physical Exam 
X 
X 
X 
X 
X 
X 
X 
Active Joint Count 
X 
X 
X 
X 
X 
X 
X 
Concomitant Meds (per 
CARRA registry) 
X 
X 
X 
X 
X 
X 
X 
Study Drug Adherence 
 
 
X 
X 
 
 
 
Dose/Instructions 
 
X 
 
 
 
 
 
Drug Dispensation  
 
X12 
X12 
 
 
 
 
Ophthalmology Exam3 
     X               See Ophthalmology Assessment Table 3 below 
The 1st Dose of study drug cannot be administered until after the screening eye exam has confirmed no 
disease.  The M12 End of Study eye exam can be done up to 4 weeks after the end of study visit.       
MyStudies App 
enrollment 
 
X 
 
 
 
 
 
Physician Global 
 
X 
X 
X 
X 
X 
X 
Parent Global 
 
X 
X 
X 
X 
X 
X 
PROMIS®  Measures7 
X 
X 
X 
X 
X 
X 
X 
CHAQ 
 
X 
 
X 
 
X 
X 
JAMAR  
 
X 
X 
X 
 
 
X 
Duration of Morning 
Stiffness (Patient 
Reported) 
X 
X 
X 
X 
X 
X 
X 
JADAS 
 
X 
X 
X 
X 
X 
X 
SAEs & ESIs (Per 
CARRA registry) 
X 
X 
X 
X 
X 
X 
X 
Quantiferon Gold/TB 
screen (drug can be 
administered in the 
absence of   test results.  
Patient families will be 
instructed to not 
administer drug until a 
X 
X11 
 
 
 
 
 

 
 
 
 
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Screen 
Visit 
Enrollment 
Visit (Baseline) 
(≤45 days) 
M3 
(+/-2 
weeks) 
M6 
(+/-2 
weeks) 
M9 
(+/-2 
weeks) 
M12 
End of Study1 
(+/-2 weeks) 
Interim Visits2 
 
negative result is 
confirmed) 
Urine pregnancy 
screen8 
 
X8 
X8 
X8 
X8 
X8 
X8 
CBC 
X5 
 
X4 
X4 
 
 
 
HBsAg9  
X 
 
 
 
 
 
 
CMP 
X5 
 
X4 
X4 
 
 
 
ESR/CRP4 
X4 
 
X4 
X4 
X4 
X4 
 
ANA 
X6 
 
 
 
 
 
 
HLA-B27, RF, anti-
CCP (Per CARRA 
Registry) 
X 
 
 
 
 
 
 
Covid-19 Survey13 
The patient/guardian will complete the Covid 19 Survey using the MyStudies App every week before 
study drug administration.  
1 End of study visit should be conducted at the end of the follow up period or if the participant discontinues the study for 
any reason, including development of polyarticular JIA or anterior uveitis, escape from treatment arm, safety concern, or 
withdrawal of consent. 
2 Interim visits occur whenever a study participant is evaluated clinically outside of the regularly scheduled study visit 
schedule for symptoms concerning for active arthritis, new anterior uveitis, or SAEs. 
3 Baseline Ophthalmology exam may occur at any time between the screening visit and the enrollment visit, including on 
the day of the screening visit or the enrollment visit. Prior baseline exam will be accepted if done within 45 days of 
enrollment.  
4 Only if obtained as SOC.  Not required specifically for study.  
5 Screening CBC and CMP must be obtained within 2 months prior to enrollment. If not available or abnormal from 
previous SOC labs, CBC and CMP must be obtained prior to enrollment.  
6 ANA results required prior to enrollment. 
7 See Table 5 for specific instructions. 
8 For females with childbearing potential and should be repeated at any time during study duration per standard of care 
by participant’s provider. 
9Subjects who have not been screened for Hepatitis B as part of SOC will get one as part of screening or enrollment. Study 
drug can be dispensed prior to obtaining study results. Patient families will be instructed to not administer drug until a 
negative result is confirmed. If test results are positive, the subject will be discontinued from the study.   
10Enrollment may occur during screening visits or at a separate specific enrollment visit. 
11Subjects who did not have a Quantiferon Gold or TB test as part of SOC will get one as part of screening or enrollment. 
Study drug cannot be administered in the absence of a negative test result.  
12A 3- or 6-month supply of abatacept will be provided at the enrollment visit.  Re-supply will occur at M3 if a 3-month 
supply was provided at enrollment.   
 
4.3.2 Explanation of Assessments  
• Informed consent and assent (if applicable): Obtained prior to any study related 
procedure.  
 
• Telehealth: The provision of healthcare remotely by means of telecommunications 
technology. 
 
• Screening: Screening is defined as having signed consent to participate in the Limit-JIA 
study. 
 

 
 
 
 
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• Enrollment : May occur at the time of screening visit if all required data are available or 
up to 45 days after obtaining consent.   
 
• Demographic Information:  Relevant subject information that includes date of 
collection, date of birth, age, gender and ethnicity. 
 
• Past Medical History: Relevant JIA history, including date of onset of symptoms, date 
of diagnosis, specific joints ever affected. Relevant comorbid conditions. 
 
• Physical Exam: Basic examination of organ systems other than musculoskeletal, 
including vital signs with temperature.  
 
• Active Joint Count: Active arthritis is defined as joints with swelling not due to bony 
enlargement or joints with limitation of motion accompanied by either pain on motion 
and/or tenderness. For the purposes of counting affected joints, each toe counts as a 
single joint irrespective of whether it is the proximal interphalangeal joint (PIP), the distal 
interphalangeal joint (DIP), or both that are affected, consistent with previous clinical 
trials conducted in JIA. Participants must have a diagnosis of limited JIA by a pediatric 
rheumatologist.  Patients do not need an active joint at time of enrollment to be eligible 
for the study. A patient who has been treated with systemic medication(s) is no longer 
eligible for the study. 
 
• Duration of Morning Stiffness: Assessment of the duration of soreness and restricted 
movement upon awakening.  This is a patient reported parameter. 
 
• COVID-19 Survey- Assessment of COVID-19 symptoms via MyStudies App or paper. 
 
• Concomitant Medications: Record all medications taken for treatment of study disease 
taken more than a year prior to Baseline, please complete as much information as 
possible, including best estimate of at least the year of start and stop. Please complete a 
new log line each time a dose is changed. 
 
• Study Drug Adherence: Family report of administration of SQ abatacept (Orencia) via 
medication adherence diary (MyStudies App or paper diary). 
 
• Physician Global: Physician Global Assessment of disease activity on 21-point scale 
from 0 to 10 in increments of 0.5 
 
• Patient Reported Outcomes Measurement Information System (PROMIS®) & other 
PRO Measures Appendix A): PROMIS® fatigue, mobility, upper extremity function, 
pain interference, anxiety, depression, and global health measures will be administered 
via tablet or paper short-forms to the participant and/or guardian per CARRA Registry 
protocols. Other PROs collected are the Parent Global Assessment of overall wellbeing 
(11-point scale, 0 to 10 in increments of 1) and the Childhood Health Assessment 
Questionnaire (CHAQ). JAMAR, Covid Survey.  Refer to Appendix for assessment 
details. 
 

 
 
 
 
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• Serious Adverse Events (SAEs):  Occurrence of any serious adverse events from time 
of informed consent.  
 
• Events of Special Interest (ESIs): Protocol-defined adverse events of special interest 
will be collected from time of informed consent. Refer to 7.5. 
 
• TB screen: Participants can be screened by either Quantiferon Gold assay or PPD per the 
treating physician.  If a Quantiferon Gold or PPD has been performed within the prior 6 
months and is negative, it need not be repeated at screening, unless the participant has 
changed from low to high risk. Subjects may be enrolled before PPD or Quantiferon Gold 
assay TB results are reported.  Subjects who did not have a Quantiferon Gold or PPD as 
part of SOC will get one as part of screening or enrollment. However, study drug can be 
dispensed prior to obtaining study results. Patient families will be instructed not to 
administer drug until a negative result is confirmed.  If test results are positive, the 
subject will be discontinued from the study.  
 
• Urine pregnancy screen: Menstruating females must have a negative urine pregnancy 
test at enrollment and for the duration of the trial.  The test may be repeated at any time 
during study duration per standard of care by participant’s provider. 
 
• Laboratory Assessments 
 
o ANA 
 ANA results drawn at or after diagnosis of JIA may be used.  
 ANA results are required prior to enrollment. 
 
o HLA-B27, RF, CCP:  
 If these were obtained during initial evaluation for JIA, they do not need to 
be repeated.   
 Results are not required prior to enrollment and are not part of the study 
eligibility criteria. 
 
o CBC/CMP : 
 Screening CBC (hemoglobin, platelets and white blood cell count) and 
CMP (ASP/ALT/Creatinine) must be obtained within 2 months prior to 
enrollment. If not available or abnormal from previous SOC labs, CBC 
and CMP must be obtained prior to enrollment. 
 Month 3/6: Only if obtained as SOC.  Not required specifically for study. 
 
o ESR/CRP:  
 Results not needed prior to enrollment. Results will be captured at each 
study visit if obtained as part of SOC; however, not required as part of the 
Limit-JIA study 
 
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 All patients receiving abatacept should be screened clinically and undergo 
serologic testing if indicated for viral hepatitis prior to use as anti-
rheumatic therapy may cause reactivation of hepatitis B.  
 Subjects who have not been screened for Hepatitis B as part of SOC will 
get one as part of enrollment. Study drug can be dispensed prior to 
obtaining study results. Patient families will be instructed to not 
administer drug until a negative result is confirmed. If test results are 
positive, the subject will be discontinued from the study.  
 
 
4.3.3 Recommended Ophthalmology Assessments 
The frequency of ophthalmology assessment for each participant depends on the presence or 
absence of known risk factors for JIA associated uveitis including ANA status and age at onset 
of JIA as per Table 3 below.  Per protocol, a screening ophthalmology exam is required within 
45 days prior to enrollment. A subject may complete the rheumatology screening visit and then 
have the screening ophthalmology exam performed after enrollment.  In this case, the 1st Dose of 
study drug cannot be administered until after the screening eye exam has confirmed no 
uveitis.      
The Month 12 (end of study) eye exam is also required; however, it can be obtained up to 4 
weeks after the end of study visit. 
The presence of active anterior uveitis will be defined according to the Standardization of Uveitis 
Nomenclature for Reporting Clinical Data (SUN criteria)62: the presence of 1 or more cells in 
each 1mm x 1mm slit beam field (Grade 0.5+ or trace cells).  During the study, evaluation for 
anterior uveitis follow SOC intervals described by the Heiligenhaus modification of the 
American Academy of Pediatrics recommendations63. 
 
Table 3: Recommended Schedule of Ophthalmology Exam 
 
ANA 
Age at 
JIA 
Onset 
Screen 
Visit**  
M 3 
M 6 
M 9 
M 
12*** 
Oligoarthritis*  
(Q3 months) 
+ 
≤ 6 
X 
X 
X 
X 
X 
Oligoarthritis*  
(Q6 months) 
+ 
> 6 
X 
 
X 
 
X 
Oligoarthritis* 
(Q6 months) 
– 
≤ 6 
X 
  
X 
 
X 
Oligoarthritis* 
(Q12 months) 
– 
> 6 
X 
  
 
  
X 
Enthesitis-related 
arthritis 
+ or –  
Any 
X 
  
 
  
X 

 
 
 
 
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*Includes ILAR categories of oligoarthritis, psoriatic arthritis (if no current active psoriasis or history of 
psoriasis), and undifferentiated arthritis. 
 ** Screening ophthalmology exam required within 45 days of enrollment. 
*** Month 12 screening required within 4 weeks of End of Study visit.  
  
4.4 
Screening and Pre-Enrollment Procedures 
All eligible study participants will be recruited from CARRA Registry sites.  
 
All participants are also consented and enrolled in the CARRA Registry and will have a CARRA 
Global ID number.  Additionally, study participants will be assigned a Limit-JIA study 
participant number at the time the consent is signed.  
 
 
For the purpose of this study the term enrolled will be defined as having signed consent. 
Children with limited JIA who have provided assent if required and whose parent/legal guardians 
have given written permission will be screened for Limit-JIA. If they meet all inclusion and no 
exclusion criteria, they will be enrolled into the study. They will concurrently consent and enroll 
into the CARRA Registry protocol (if not already enrolled in the CARRA Registry).  Written or 
electronic informed consent will be obtained per each enrolling site’s or the central IRB’s 
requirements. 
4.5 
Screen Failure 
Any participant who completes the screening visit, but is subsequently found to be ineligible for 
the study (e.g lab test results out of range/positive) will be a screen failure. 
 
If a subject is started on systemic DMARDS, biologics, or systemic glucocorticoids between 
screening and enrollment then this subject will also be considered a screen failure. 
 
4.6 
Screening Visit (either the screening visit or enrollment visit must be in person to 
confirm the diagnosis) 
Research staff will document informed consent from the parent/guardian, and if applicable, child 
assent according to local regulations for all study participants who satisfy eligibility criteria. The 
following information will be recorded in the CRF: 
1. Consent/Assent  
2. Past medical history 
3. Physical examination 
4. Joint exam – active joint count 
5. Concomitant medications 
6. TB screening  
7. Hepatitis screening (if indicated) 
8. CBC 
9. CMP 
10. ESR/CRP (only if obtained as SOC) 
11. ANA 

 
 
 
 
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12. HLA-B27, RF, CCP (if obtained as SOC) 
13. Ophthalmology Exam 
14. Urine Pregnancy Test if indicated 
4.7 
Enrollment Visit (Within 45 days after Screening Visit; may be combined with the 
Screening visit)  
1. Review of Inclusion/Exclusion criteria to be performed prior to enrollment 
2. Physical examination 
3. Joint Exam - Active joint count 
4. Interval history - If enrollment occurs at a different visit than screening. Interval history 
to include interval use of systemic DMARDS, NSAIDs, biologics and intra-articular 
glucocorticoid injections, new co-morbid conditions, any encounters with health care 
professionals.  
5. Concomitant medications 
6. Results of urine pregnancy screen 
7. Enrollment in MyStudies App 
8. SAE & ESI review and reporting 
9. Physician Global Assessment 
10. Parent Global Assessment 
11. PROMIS® measures – See Table 5 
12. CHAQ 
13. Juvenile Arthritis Multidimensional Assessment Report (JAMAR)         
14. Juvenile Arthritis Disease Activity Score (JADAS) 
15. Drug Dispensation (a 3 month or a 6 month supply can be provided) 
16. Dose Instructions/Administration 
17. Ophthalmology Exam (if not available at screening) 
4.8 
Post Enrollment Procedures (Month 3 to Month 12; in person or via telehealth) 
  Month 3/Month 6 (+/- 2 weeks; in person or via telehealth) 
1. Physical examination  
2. Joint Exam - Active joint count 
3. Interval history to include interval use of NSAIDs and intra-articular glucocorticoid 
injections, new co-morbid conditions (including psoriasis), encounters with health care 
professionals (specifically in response to uveitis, active arthritis, or serious adverse 
events). 
4. Drug dispensation (Month 3 only – re-supply, only if a 3 month supply was provided at 
Baseline) 
5. Drug adherence  
6. Ophthalmology exam per Table 3 
7. Concomitant Medications 
8. Physician Global Assessment 
9. Parent Global Assessment 
10. Selected PROMIS® measures – See Table 5 
11. CHAQ (6 month only) 
12. JAMAR 
13. JADAS 
14. SAEs 

 
 
 
 
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15. ESIs 
16. ESR/CRP/ CBM/ CMP (Only if obtained as SOC) 
17. Data entry of SOC labs if available 
18. Results of urine pregnancy screen -May be repeated at any time during study duration per 
standard of care by participant’s provider. 
 
Month 9/ (+/- 2 weeks; in person or via telehealth) 
1. Physical Examination 
2. Joint Exam - active joint count 
3. Interval history to include interval use of NSAIDs and intra-articular glucocorticoid 
injections, new co-morbid conditions (including psoriasis), encounters with health care 
professionals (specifically in response to uveitis, active arthritis, or serious adverse 
events). 
4. Concomitant medications 
5. Ophthalmology exam per Table 3 
6. Physician Global Assessment 
7. Parent Global Assessment 
8. Selected PROMIS® measures – See Table 5  
9. JADAS 
10. SAEs 
11. ESIs 
12. ESR/CRP/CBC/CMP (Only if obtained as SOC)  
13. Data entry of SOC labs if available 
 
Month 12 End of Study Visit  (+/- 2 weeks; in person only) 
1. Physical examination 
2. Joint Exam - active joint count 
3. Interval history to include interval use of NSAIDs and intra-articular glucocorticoid 
injections, new co-morbid conditions (including psoriasis), with health care 
professionals (specifically if related to uveitis, active arthritis, or serious adverse 
events). 
4. Concomitant medications 
5. Ophthalmology exam per Table 3  
- 
Ophthalmology exam may be up to 4 weeks after the Month 12 visit  
- 
Record results if performed as part of standard of care.  
6. Physician Global Assessment  
7. Parent Global Assessment 
8. Selected PROMIS® measures – see Table 5 
9. CHAQ 
10. JADAS 
11. SAEs 
12. ESIs 
13. ESR/CRP/ CBC/ CMP (Only if obtained as SOC) 
14. Data entry of SOC labs if available 
 
 

 
 
 
 
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Interim Visit (in person or via telehealth) 
1. Physical examination  
2. Joint Exam - Active joint count 
3. Interval history to include interval use of NSAIDs and intra-articular glucocorticoid 
injections, new co-morbid conditions (including psoriasis), encounters with health 
care professionals (specifically in response to uveitis, active arthritis, or serious 
adverse events). 
4. Concomitant Medications 
5. Drug Adherence (If subject is currently taking study drug at time of interim visit) 
6. Ophthalmology exam 
7. Physician Global Assessment 
8. Parent Global Assessment   
9. Selected PROMIS® measures – see Table 5 
10. CHAQ  
11. JAMAR 
12. JADAS 
13. SAEs 
14. ESIs 
15. ESR/CRP/ CBC/ CMP (Only if obtained as SOC) 
4.9 
Immunizations 
• No live vaccines administered within one month of enrollment.  
• Live vaccines are prohibited during abatacept administration and for three (3) 
months after administration of the last abatacept dose. 
• With regards to vaccinations for COVID-19, the guidance set forth by the 
American College of Rheumatology should be followed.  Refer to the COVID-19 
Vaccine Clinical Guidance Summary for Patients with Rheumatic and 
Musculoskeletal Diseases developed by the ACR COVID-19 Vaccine Clinical 
Guidance Task Force. Version 4 from August 19, 2021 states that the abatacept 
dose should be held both one week prior and one week after the first COVID-19 
vaccine dose (only). There should be no interruption around the second vaccine 
dose.68 
 
4.10 Development and Utilization of EHR based Algorithms for Enhanced Study 
Recruitment at Subset of Trial Sites (US Based Sites Only) 
 
The comprehensive and timely screening of all potentially eligible study participants is an 
important determinant of study success for Limit-JIA. An aim of this study is therefore the 
development and utilization of algorithms and processes employing Electronic Health Record 
(EHR) data for such cohort screening. The development of such algorithms has previously been 
utilized for other pediatric chronic diseases (e.g. pediatric pulmonary hypertension) by the 
Accessible Research Commons for Health Clinical Data Research Network (ARCH CDRN); this 
approach will be further developed to enhance recruitment for Limit-JIA. 
 
A subset of Limit-JIA study sites that also participate in the ARCH CDRN, as well as other 
Limit -JIA sites wishing to participate in this phase of the study, will (1) execute cohort 

 
 
 
 
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definition queries against their site’s local clinical research data warehouse, resulting in the 
generation of a list of potentially eligible study participants, and (2) perform manual chart review 
on the list of their site’s potentially eligible subjects, resulting in a refined list of potentially 
study-eligible subjects who may subsequently be approached for study participation according to 
usual, IRB-approved mechanisms for doing so at each individual Limit-JIA study site. 
 
These initial cohort definition queries and chart review activities will undergo iterative 
refinement to develop progressively more responsive sets of classifiers (a “computable 
phenotype”) that optimally balances sensitivity vs specificity regarding subject study eligibility. 
As part of this process, sites participating in development of the computable phenotype will 
develop a ‘gold standard’ list of patients known to have limited JIA (‘positive’ cases) and 
patients known to not have limited JIA (‘negative’ cases). These activities will consist of EHR 
data set analyses and chart review activities only. The data sets generated for this purpose will 
not be used for subject recruitment or enrollment, although subjects included in the computable 
phenotype validation cohort may be enrolled in Limit-JIA and/or the CARRA Registry but will 
not have been identified for enrollment via this process. We estimate that up to 100 individuals 
per group (positive and negative cases) per site will be identified, with positive cases identified 
via available methods (e.g. using a validated list from chronic disease registries, billing records, 
etc., which may vary at each site). The negative case group will consist of individuals matched to 
possess similar characteristics, e.g. age and gender, but who do not have limited JIA. 
Identification of these case groups will be accomplished via queries of a site’s clinical data 
warehouse and using chart review. 
4.11 Abstraction and Linkage of EHR Data and CARRA Registry Data for Assessment 
and Improvement of Data Completeness (US Based Sites Only) 
Data that is manually abstracted from the EHR and expressly collected for registry and other 
clinical studies represents a ‘gold-standard’ that is typically difficult, if not impossible, to obtain 
at the same level of fidelity via automated extraction from EHR data warehouses. However, 
manual data abstraction is much more costly and difficult to accomplish than automated 
processes of mining EHR data that obtain lower-fidelity data. For this study, we therefore 
employ a hybrid approach for a sub set of sites in which a core of manually curated study data 
will be augmented by linkage with a subject’s selected EHR data elements. Categories of EHR 
data elements to be collected include demographics, dates of encounters, diagnoses, problem 
lists, family history, social history, procedures, medications, laboratory data, radiology data, 
physician specialties, patient-reported outcomes, and related information. 
 
At the subset of sites participating in EHR data abstraction and linkage, EHR data elements for 
participants enrolled in this study, as well as other subjects with JIA enrolled in the larger 
CARRA Registry, will undergo linkage to Limit-JIA and CARRA Registry data using site 
medical record numbers and the corresponding mappings to CARRA Registry unique subject 
identifiers.  Each participating site will then compose a limited data set of selected EHR data 
elements using the CARRA Registry subject identifier for each consented participant as a coded 
identifier. This data set will then be securely transferred to the CARRA Data Warehouse. The 
combined study, registry, and EHR data will be made available to study investigators and 
analysts enabling estimation of registry data completeness (see Analysis Plan, Section 8.3, and 
“Major Secondary Analyses"). 

 
 
 
 
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4.12   Ethnography Study Design (US Based Sites Only) 
The ethnography sub-study will follow a quasi-experimental, time-series cross-sectional study 
design with up to three observations and iterative design occurring between each step.  The aim 
of this sub-study at select US sites is to improve clinical trial recruitment and retention of study 
participants by identifying barriers and developing improved resources and process. The 
coordinating center for the sub study is LIFT. The sub study activities are covered by a separate 
IRB approval and protocol managed by LIFT.  
4.12.1 Patient/Family Recruitment & Enrollment Process 
 
 
Figure 1: Flowchart of study participant/family recruitment and enrollment process. 
1. Families who meet the inclusion criteria for Limit-JIA will be asked by the site 
study team to participate in the main Limit-JIA study. 
2. After completing the main Limit-JIA consent process, regardless of whether the 
family decides to participate in the main study, families will be presented 

 
 
 
 
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information about the ethnography sub study along with two copies of a 
Permission to Contact form for them to sign providing permission for them to be 
contacted by LIFT, the sub study-coordinating center.  
3. Families who agree to be contacted will complete and sign the contact 
permission form, leaving one copy for the site study team and keeping the other 
for their own records.  
4. The site coordinator contacts LIFT within 48 hours via secure email provides a 
copy of the permission to contact form to the LIFT study manager, which 
includes the study participant name, parent/family member name, email, and 
telephone number.   
5. The LIFT study manager contacts families who have agreed to be contacted to 
provide additional information about the sub-study, address any questions, and 
schedule the interview.  
6. The LIFT study manager and/or researcher will consent the family/participants at 
the time of the interview and complete the appropriate study components (e-
survey, telephone survey, in-home immersion). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
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4.12.2 Staff Recruitment & Enrollment Process 
 
Figure 2: Flowchart of staff recruitment and enrollment process. 
  
1. During site activation, all associated site staff members (clinicians, site investigators, and 
study coordinators) will receive information and an email containing a digital consent 
forms for participation in the sub-study. 
2. Study staff will receive bi-weekly emails asking if they have screened an eligible Limit-
JIA patient in the past week. Study staff that have seen an eligible Limit-JIA patient will 
follow a Calendly® link to schedule a 30-minute telephone interview, to take place 
within the next 10 business days. Study staff that have not seen an eligible Limit-JIA 
patient will receive no additional inquiry for this study week but will be included in all 
future email requests for information. 
3. LIFT study manager will coordinate with site staff to collect appropriate data based on 
the study sample.  
4. Repeat steps 2 through 3 for the duration of the study cycle. 
4.12.3 Sites  
Limit-JIA will be conducted at approximately 40 sites.  This sub-study will be conducted at a 
subset of US based sites. 
 
 
 

 
 
 
 
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4.12.4 Ethnography Assessments and Study Timeline 
 
In addition to collecting information about the patient/family experience the following 
information will be collected about each patient: age, gender, race/ethnicity. The participant will 
have the option to decline providing this information. 
4.12.5 Initial Design of Materials (US Based Sites Only) 
Version 1 of the recruitment and retention materials will be prepared in consultation with the 
Stakeholder Advisory Committee (SAC) and the Design Process Improvement Group (DIG). 
Both groups include parents, participants, payers, and site coordinators, using examples from 
prior LIFT studies. Recruitment to the Limit-JIA trial will begin with V1 of the recruitment 
materials. 
4.12.6 Ongoing PDSA and Tools Improvement (US Based Sites Only) 
PDSA cycles will be used to improve recruitment and retention materials and messaging for the 
Limit-JIA trial. Virtual immersions and telephone interviews will be used during the PDSA 
cycles of the study. Transition from each observation phase to the design phase will occur when 
saturation has been achieved. The number of PDSA cycles necessary will be determined based 
on the level of saturation during each data collection phase and the pace of participant 
enrollment. Feedback from participants will be incorporated to improve the recruitment materials 
at each cycle.  The DIG, an extension of the Limit-JIA SAC for the ethnography study, provides 
design input and oversight over tools improvement. 

 
 
 
 
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5 
MYSTUDIES APP 
5.1 
Description of the MyStudies Mobile App 
The FDA MyStudies App is designed to facilitate the input of real world data directly by patients 
which can be linked to electronic health data supporting traditional clinical trials, pragmatic 
trials, observational studies and registries. This platform has been developed under sponsorship 
of the FDA and private sector partners as open source software, enabling the app and associated 
data storage to be configured by organizations conducting clinical research according to their 
needs and utilizing their own branding. 
 
All users of the MyStudies Mobile App will be asked to register for the app using a unique email 
address. The email address is used to confirm that the registrant is a real person. The user will 
receive a confirmation email with a confirmation code. The user will not be officially registered 
in the app until they enter the code in the app. This registration code is distinct from a patient 
token, which each subject will be provided by study staff for use in enrolling in the study. All 
users must consent to a study before completing any study surveys. The site maintains control of 
the release of patient tokens for the app and will only release them once the consent to participate 
has been signed by the parent/legal guardian.   
 
Study participants may be alerted to new surveys by “push notifications.” A notification will pop 
up on their smart phone screen, telling them a new survey is available. Participants will be able 
to turn off notifications of new surveys at any time. The use of push notifications does not 
require any personal identifiers, such as a cell phone number.  
5.2 
Data Access Security and Storage 
Data collected by the MyStudies mobile app will be transferred to and stored with the project 
vendor/collaborator LabKey.  
 
All personal health information collected and stored on the LabKey platform for this study will 
be deleted from that platform within 60 days of completion of study data analysis, unless such 
data collection and usage subsequently becomes governed by another IRB-approved protocol, 
such as for the CARRA Registry. 
 
Harvard Pilgrim Health Care Institute (HPHCI, the coordinating center for MyStudies mobile 
app, will use the platform hosted by LabKey Software, to provide a set of unique patient 
enrollment tokens for distribution to the study cohort. HPHCI will distribute these tokens to 
study site personnel, and study site personnel will assign and distribute a token to each 
participant as they identify and enroll them in the study cohort. Study personnel will maintain the 
linkage of token associations with participant identifiers. 
 
Participants respond to questionnaires in the MyStudies mobile app at their convenience for as 
long they are available in the app. Data are stored locally on the app until the participant 
indicates they have completed the questionnaire or task by tapping “done” on the final screen.  
Data will be encrypted during transmission and in the LabKey Server. Participants can optionally 
use a Passcode/TouchID/FaceID (depending on phone capabilities) to prevent others who may be 
using their phone from accessing the MyStudies app.  
 

 
 
 
 
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Only designated staff at HPHCI will have access to patient-reported data captured by the 
MyStudies mobile app and housed within the LabKey platform. Designated CARRA Registry 
staff will have access to view and download MyStudies subject data, including individual-level 
data, and link individual-level data with other CARRA Registry data using MyStudies and 
CARRA Registry subject identifiers. The HPHCI designated staff may create data queries, 
review aggregated query results, and view individual-level data without otherwise downloading 
patient data. 
5.3 
Survey Distribution for Mobile App Users 
Surveys will be distributed to app users who have consented to the study on the following 
schedule: 
 
 
Study Arm 1 (Intervention group) 
• One question survey asking on what date the medication was last administered.  
o Schedule: Available immediately after enrollment in the study in the app 
o Duration: Available until completed by the patient 
o Other notes: 
 The response to this question will be used as the anchor date for the 
medication administration survey 
• Covid-19 Survey 
o Schedule: Weekly, starting on anchor date + 1 week 
o Duration: Available for 12 months (48 weeks)  based on enrollment date of 
patient in the app 
 
• Medication Administration Survey 
o Schedule: Weekly, starting on anchor date + 1 week 
o Duration: Available for 48weeks post enrollment 
• Uveitis Survey 
o Schedule: Available continuously 
o Duration: Available for 12 months (48 weeks) based on enrollment date of 
patient in the app 
o Other notes: 
 Appointment dates do not need to be entered in the app. 
  
 
5.4 
Survey Notifications 
Participants may receive the following phone notifications when using the app to participate in 
this study. 
 
• A new activity is available/an activity is about to expire 
o Text: A new run of the scheduled activity <activity name>, is now available and 
is valid until <Month, DD, YYYY TT>. Your participation is important. Please 
visit the study to complete it now. 
• A one-time activity is starting 
o Text: The activity <activity name>, is now available to take. Please visit the study 
to complete it. 

 
 
 
 
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• New run of weekly/monthly existing activity 
o Text: A new run of the <weekly/monthly/ > activity <activity name>, is now 
available. Please visit the study to complete it. 
• Weekly activity is set to expire 
o Text: The current run of the weekly activity <activity name>, will expire in 24 
hours. Your participation is important. Please visit the study to complete it now. 
• The study is paused via the WCP 
o Text: The study <study name > has been paused We will notify you when it is 
resumed. 
• The study is resumed via the WCP 
o Text: The study <study name as given in WCP 50 char max> has been resumed. 
Visit the study to start participating in activities again. 
• The study is close the study via the WCP 
o Text: The study <study name > has been closed. We thank you for your 
participation. 
• A new resource has been added 
o Text: custom 
 

 
 
 
 
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6 
CLINICAL TRIAL TREATMENT INTERVENTIONS 
All eligible participants will be enrolled to receive treatment with 24-doses of weekly SQ 
abatacept (Orencia) plus usual care. 
6.1 
 Abatacept (Orencia) – Study Drug 
Participants enrolled to receive SQ abatacept (Orencia) will receive training and study materials 
(3 month or 6 month drug supply) on the day of enrollment. The first dose should be 
administered at the site or at home with telehealth guidance from the investigator or other study 
staff once all test results have been verified. All study participants enrolled will be trained by the 
study staff on study drug administration. A resupply of IP will occur at the three-month visit if a 
6-month supply was not provided at enrollment.   
 
The 50 mg, 87.5 mg and 125 mg SQ doses that are approved for use in pediatric patients in the 
United States will be supplied by a US-based depot. The 125 mg SQ dose approved for use in 
Canada will be sourced from a Canadian vendor. 
 
6.2  Potential Benefits/Risks of Abatacept (Orencia) 
The safety profile of abatacept (Orencia) is well-established, with infection (primarily upper 
respiratory tract) and injection site reactions most common.59, 60 
6.3 
Storage 
Study drug solution supplied in prefilled syringe should be refrigerated at 2°C to 8°C (36°F to 
46°F). Do not use study drug beyond the expiration date on the prefilled syringe.  Protect from 
light by storing in the original package until time of use. Do not allow the prefilled syringe to 
freeze. 
6.4  Study Drug Discontinuation Criteria 
Study participants who permanently stop study drug in Limit-JIA should be encouraged to 
continue in the study. If for any reason a study participant must permanently stop study drug, every 
effort should be made by the Site Investigator/staff to keep the study participant in the Limit-JIA 
study to collect important safety and clinical data.  
Withdrawal from the Limit-JIA study does not automatically withdraw the study participant from 
the CARRA Registry. 
Study participant must be permanently discontinued from the study drug if the following occurs:  
• Positive urine pregnancy test 
 
• Non-compliance with study drug. Study participants’ compliance with study treatment will 
be assessed throughout the study. Participants who miss more than one dose should be re-
educated on the requirement for treatment compliance. Every effort will be made to keep 
participants in the study and to re-educate those who continue to miss doses. Participants 
who continue to be non-compliant after multiple visit assessments may be permanently 
discontinued from study drug at the discretion of the Site Investigator after consultation 
with the sponsor.  
 

 
 
 
 
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• Non-compliance with weekly diary. Study participants’ must complete their weekly 
electronic or paper diary between study visits. Participants who are non-compliant after 
multiple visit assessments may be permanently discontinued from study drug at the 
discretion of the Site Investigator after consultation with the sponsor. 
 
• Serious Infection 
 
• Physician discretion  
 
• 
Achievement of any of the primary outcomes as defined in the protocol (disease 
extension, uveitis and/or need for escalation of systemic therapies)   
 
• SAE attributed to abatacept  
 
• AE attributed to abatacept that at the discretion of the site PI warrants drug 
discontinuation.  
 
• Conversion to positive PPD or Quantiferon Gold assay result that occurs during the study 
(if tested as standard of care)  
 
6.4.1 Procedures for Monitoring Study Drug Compliance 
The participant/parent will be given a patient diary (electronic app or paper diary) and will be 
instructed how and when to use the study drug.  The study participant diary will be reviewed at 
each visit throughout the study to confirm the study participants’ compliance with study drug 
throughout the study. Participants who are non-compliant should be re-educated on the importance 
of treatment compliance 
6.4.2 Temporary Discontinuation of Study Drug 
Abatacept can be temporarily held for a maximum of 2 weeks for significant viral infections or 
for bacterial infections requiring antibiotics.  Patients may continue/resume study drug at 
discretion of physician. Temporary discontinuation of study drug for COVID-19 infection should 
be handled the same as temporary discontinuations for other viral infections. Study drug 
administration in COVID-19 positive patients will be handled per physician discretion, following 
CDC and American College of Rheumatology COVID-19 guidelines.  With regards to 
vaccinations for COVID-19, administration of abatacept will follow the guidance set forth by the 
American College of Rheumatology to hold SQ abatacept one week prior and one week after the 
first COVID-19 vaccine dose (only).  There is no interruption around the second vaccine dose.68 
 
6.4.3 Discontinuation of Study Drug  
Study participants may choose to stop taking study drug before the end of the study. A 
participant may also be asked to stop study drug at the Site Investigator’s discretion. 
Participants who have permanently discontinued study drug are not required to withdraw from 
the study. Participants who have permanently discontinued study drug and have not withdrawn 
consent may continue in the study and complete all remaining protocol specified visits.  
 

 
 
 
 
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6.4.4   Study Drug Discontinuation Study Assessments  
The site Investigator must make every effort to have the study participant return to the clinic as 
soon as possible after the participant permanently discontinues study drug to determine if they 
want to withdraw from the study. If the participant choses to withdraw from the study every 
attempt should be made to have all evaluations and procedures as outlined in the Schedule of 
Events performed. (see Table 2 in Section 4.3.1)  
6.4.5 Withdrawal from Study  
There are no pre-determined protocol-specific study withdrawal criteria, however, study 
participants may choose to withdraw from the study at any time and withdraw their consent from 
further participation in the study. The Site Investigator must document the reason (if specified by 
the participant) for the withdrawal of consent.  Participants who wish to withdraw from further 
participation in the study should be encouraged to return to the clinic as soon as possible to 
complete the M12 End of Study Visit. Every attempt should be made to have all evaluations and 
procedures as outlined in the Schedule of Events performed. (see Table 2 in Section 4.3.1)  
6.5 
Concomitant Medications  
Record all medications taken for treatment of study disease.  Please complete a new log line each 
time a dose is changed. 
 
If a screened and consented subject is started on systemic DMARD, biologic, or systemic 
glucocorticoids between screening and enrollment then this subject will be considered a screen 
failure. 
 
6.6 
Use of Oral Prednisone  
A short course of oral prednisone (≤ 14 days) is allowed in the first month after enrollment or prior 
to enrollment if local COVID-19 conditions limit availability of intra-articular glucocorticoid 
injections and total active joint count is ≤ 4.  Patients treated with a short course (≤ 14 days) will 
not be considered to have met the primary outcome for systemic medication use.  Prednisone 
dosing should be limited to 20 mg/day. 
 
6.7  
COVID-19 Guidance 
The following strategies will be employed during the clinical trial to optimize participant safety: 
• Provide a fact sheet to all screened subjects on the symptoms of COVID-19 
• Administer a COVID-19 questionnaire related to exposure history and physical 
symptoms 
• Obtain and document current temperature at screening and throughout study period. If a 
potential subject has a temperature greater than 100.4, the subject cannot be enrolled into 
the trial until they have been afebrile for at least 48 hours and had negative COVID-19 
testing. Subjects who develop a fever during the trial will be instructed to follow-up with 
their local provider for consideration of COVID-19 testing.  
• The re-start of study drug after COVID-19 infection is at the discretion of the PI, 
following ACR guidance. 
• See Section 4.9 (Immunizations) and Section 6.4.2 (Temporary Discontinuation for Study 
Drug) for additional information on COVID-19 guidance 

 
 
 
 
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• The COVID-19 Vaccine Clinical Guidance Summary for Patients with Rheumatic and 
Musculoskeletal Diseases developed by the ACR COVID-19 Vaccine Clinical Guidance 
Task Force can be found at the following site:  
https://www.rheumatology.org/Portals/0/Files/COVID-19-Vaccine-Clinical-Guidance-
Rheumatic-Diseases-Summary.pdf  
 
 
 
 
 
 
 
 

 
 
 
 
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7 
ASSESSMENT OF SAFETY 
The sponsor has engaged DCRI Safety Surveillance to oversee real-time serious adverse event 
(SAE) collection, evaluation, and, as applicable, expedited regulatory reporting for this study. A 
medical monitor will be responsible for evaluating site reported SAEs to confirm protocol 
specific serious reporting criteria, causality assessment, and expectedness compared to the 
product label. 
7.1 
Definition 
Only Events of Special Interest (ESIs), serious and non-serious, and SAEs will be collected for 
this study and reported in the RAVE EDC. COVID-19 and related symptoms that meet the 
criteria of an SAE will be considered unexpected/unanticipated SAEs and reported in the RAVE 
EDC. 
 
Disease progression will not be reported as an ESI or SAE but will be reflected in the visit joint 
exams. 
 
Safety will be assessed following initial informed consent, throughout the study and for 30 days 
post last study dose and it will be assessed by frequency and incidence of ESIs and SAEs. A data 
safety monitoring board (DSMB) will be convened to review data and safety information from 
study participants throughout the study. 
7.2 Assessment of Adverse Event Severity  
The determination of AE severity rests on medical judgment of a medically qualified 
investigator. The site will use the current version of the Common Terminology Criteria for 
Adverse Events (CTCAE) version 5.0  Event severity will be assessed at event onset and event 
severity most extreme (CTCAE level).  The severity of AEs will be graded using the following 
definitions:  
Grade 1: Mild 
Grade 2: Moderate 
Grade 3: Severe but not immediately life threatening 
Grade 4: Life-threatening consequences 
Grade 5: Death related to AE 
7.3 
Assessment of Causal Relationship 
A medically qualified investigator must assess the relationship of any Event to the use of study 
drug, based on available information, using the following guidelines: 
Not related: There is not a reasonable causal relationship between the study drug and the 
AE.  
Unlikely related: No temporal association or cause of the event has been identified, or 
the drug or biologic cannot be implicated. 
Possibly related: There is reasonable evidence to suggest a causal relationship between 
the drug and AE. 

 
 
 
 
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Probably related: There is evidence to suggest a causal relationship between the drug 
and AE, and the influence of other factors is unlikely. 
Definitely related: Clearly related evidence of a causal relationship between drug and 
AE. 
7.4 
Expectedness 
The expectedness of an SAE shall be determined according to the most current product label. 
Any SAE that is not identified in nature, severity, or specificity in the current product label is 
considered unexpected. 
7.5 
Protocol-Defined ESIs   
The following are commonly expected events in JIA and will not be collected as AEs, but will be 
reported to the study database via the SAE/ESI eCRF. 
 
• Anaphylaxis 
• Aplastic anemia 
• Bleeding events requiring transfusion or hospital evaluation 
• Cardiovascular event (myocardial infarction or stroke) 
• Demyelinating disease 
• Gastrointestinal perforation 
• Hepatic Events 
• Hepatitis 
• Hypercholesterolemia 
• Hypersensitivity reactions 
• Infections treated with IV anti-infective(s) 
• Inflammatory bowel disease 
• Interstitial lung disease 
• Leukopenia 
• Lipoid pneumonia 
• Macrophage activation syndrome 
• Malignancy 
• Mycobacterium tuberculosis infection 
• Myocardial infarction  
• Neutropenia 
• New autoimmune disease (e.g., systemic lupus erythematosus) 
• Optic neuritis 
• Other opportunistic infections (Other opportunistic infections (e.g., Legionella, Listeria, 
systemic infections due to endemic mycoses [Coccidioides, Blastomyces, Histoplasma], 
Pneumocystis, Aspergillus, Nocardia, Cryptococcus, Toxoplasma, Varicella Reactivation 
[shingles]) 
• Pregnancy and pregnancy outcome 
• Progressive multifocal leukoencephalopathy (JC virus) 
• Psoriasis 
• Pulmonary alveolar proteinosis 

 
 
 
 
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• Pulmonary hypertension 
• Severe injection site reactions 
• Stroke 
• Thrombocytopenia 
• Uveitis 
• Worsening of autoimmune diseases (per investigator discretion)  
7.6 
Serious Adverse Events 
A serious adverse event is any untoward medical occurrence that, at any dose: 
• Results in death 
• Is life-threatening  
NOTE: The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in which the 
participant was at immediate risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if more severe.  
• 
Requires inpatient hospitalization or prolongation of hospitalization unless hospitalization 
is for:  
– 
Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
– 
Elective or pre-planned treatment for pre-existing condition that is unrelated to 
the indication under study and has not worsened since the start of the drug of 
interest 
– 
Social reasons and/or respite care in the absence of deterioration in the 
participant’s general condition  
• 
Results in disability/incapacity. 
NOTE: The term disability means a substantial disruption of a person’s ability to conduct normal 
life functions. This definition is not intended to include experiences of relatively minor medical 
significance, such as headache, nausea, vomiting, accidental trauma (e.g. sprained ankle) which 
may interfere or prevent everyday life functions but do not constitute a substantial disruption.  
• Is a congenital anomaly or birth defect.  
• Medically significant, e.g., defined as an event that jeopardizes the participant or may 
require medical or surgical intervention to prevent one of the outcomes listed above (e.g. 
may require treatment on an emergency outpatient basis for an event not fulfilling any of 
the definitions of a SAE given above and not resulting in hospital admission.  
 
This determination is based on the opinion of either the investigator or sponsor (e.g., if either 
believes it is serious, it must be considered an SAE). 
 
Regardless of causality, the investigator must report within 24 hours of knowledge of the event, 
via RAVE EDC system, all SAEs and ESIs occurring between informed consent and Month 12 
End of Study Visit or 30 days after the last dose of study drug if early termination from the 
study. If the eCRF system is temporarily unavailable, the SAE, including investigator-
determined causality assessment, should be reported to DCRI Safety Surveillance via a paper 
back-up SAE form. Upon return of the availability of the EDC system, the most current SAE 
information must be entered into the eCRF.  DCRI Safety Surveillance will notify Bristol Myers 
Squibb (BMS) of reported SAEs within 2 business days of awareness by DCRI Safety 
Surveillance. 
 

 
 
 
 
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The investigator must report, via RAVE EDC system, when important follow-up information 
(final diagnosis, outcome, results of specific investigations, etc.) becomes available after 
submission of the initial SAE/ESI information. Follow-up information should be submitted 
according to the same process used for reporting the initial event as described above (i.e., within 
24 hours of knowledge, via RAVE EDC system). All SAEs and ESIs will be followed through 
resolution, stabilization, or end of study.  
7.7 
Reporting to Regulatory Authorities 
Adverse events which meet the criteria of serious, related to study drug, and unexpected for 
abatacept (Orencia) per its package insert, may qualify for reporting to regulatory authorities.  
The site investigator will assess any SAE occurring at their site and evaluate it for relationship to 
study drug.  
 
Informing US FDA: The site investigator is required to complete and submit a voluntary 
MedWatch Report to FDA for events confirmed by the sponsor as a suspected, unexpected, 
serious adverse reaction (SUSAR) at: https://www.accessdata.fda.gov/scripts/medwatch/. 
 
Informing Health Canada: Reporting an adverse drug reaction (ADR) (i.e. a SUSAR) to Health 
Canada is a sponsor obligation. The sponsor or designee will notify Health Canada and all 
participating investigators of fatal or life-threatening SUSARs no later than 7 calendar days after 
receipt and of non-fatal or non-life-threatening SUSARs no later than 15 calendar days after 
receipt via a CIOMS I Form.  
 
Informing the IRB/REB: The site investigator will be responsible for reporting serious adverse 
events and unanticipated problems involving risks to study participants to their local IRBs/REBs 
in accordance with local regulations.  
7.8 
Pregnancy 
If, following initiation of abatacept (Orencia), it is subsequently discovered that a study 
participant is pregnant or may have been pregnant at the time of abatacept (Orencia) exposure, or 
within 5 half-lives (66 days) after product administration, abatacept (Orencia) will be 
permanently discontinued in an appropriate manner (e.g., dose tapering if necessary for 
participant).  
 
During the course of the trial, female study participants will be instructed to contact the site 
investigator immediately if they become pregnant. The study participant will discontinue study 
drug. The site investigator must report any pregnancy occurring during the trial on the 
appropriate Pregnancy Surveillance Form. While pregnancy is not considered an SAE, it must be 
reported within 24 hours of knowledge of the pregnancy, the same timelines as an SAE. The 
pregnancy must be followed to determine outcome (including premature termination) and status 
of mother and infant.  The Site PI is responsible for following the participant’s pregnancy to final 
outcome. DCRI Safety Surveillance will notify BMS of any pregnancy within 2 business days of 
awareness by DCRI Safety Surveillance. Any associated SAEs/ESIs that occur to the mother or 
fetus/infant will be recorded on the SAE/ESI eCRF, as appropriate.  
 
 

 
 
 
 
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8 
EFFICACY ASSESSMENTS   
8.1 
Primary Outcome 
The primary outcome is the occurrence of any of the following: polyarthritis, active anterior 
uveitis, or initiation of systemic DMARDs and/or biologics, including systemic glucocorticoids 
(IV or PO) within 12 months of enrollment. 
(a) Polyarthritis is defined as a cumulative total of ≥5 active joints with arthritis since disease 
onset. The active joint count will be assessed at each study visit from baseline through month 
12. Active arthritis is defined as joints with swelling not due to bony enlargement or joints 
with limitation of motion accompanied by either pain on motion and/or tenderness. For the 
purposes of counting affected joints, each toe counts as a single joint irrespective of whether 
it is the proximal interphalangeal joint (PIP), the distal interphalangeal joint (DIP), or both 
that are affected, consistent with previous clinical trials. Joint counts will be documented 
using a dedicated case report form (eCRF) at each study visit, tracking both specific joints 
and number of joints involved.61   
(b) The presence of active anterior uveitis, defined according to the Standardization of Uveitis 
Nomenclature for Reporting Clinical Data (SUN criteria) as the presence of one or more cells 
in each 1mm x 1mm slit beam field (Grade 0.5+, trace cells), 62 will be assessed at standard 
of care ophthalmology visits as described by the Heiligenhaus modification of the American 
Academy of Pediatrics recommendations (see Table 2 in Section 4.3.1). Results will be 
collected using the existing CARRA Registry uveitis specific eCRF.  
(c) Use of systemic DMARDs and/or biologics, including systemic glucocorticoids (IV or PO) 
will be captured on the concomitant medication eCRF at each study visit. 
8.2 
Secondary Outcomes  
8.2.1 Patient reported outcomes 
Patient-reported outcomes (PROs), related to pain, fatigue, functional ability, anxiety, depression, 
global health, family impact, and other medication side effects will be collected and analyzed.  
PROMIS® measures will be used for each of the outcomes of interest where available. 
Caregiver/proxy-report will be obtained for participants able to complete the forms in English or 
in Spanish, and by self-report for children ≥ 8 years of age. The existing iPAD-based, CARRA 
Registry electronic PRO system will be utilized.  
The following PRO instruments will be used.  
• PROMIS® pediatric measures selected by the patient/family partners (pain interference, 
fatigue, functional ability) that have undergone preliminary validation in JIA.64,65 
• PROMIS® pediatric measures of anxiety, depression, and global health. 
• Side effects of medications, assessed by the yes/no question 11 in the JAMAR.66  
 
 
 
 
 

 
 
 
 
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Table 5:  Description of PROs  
8.2.2 Enhanced Study Recruitment (US Based Sites Only) 
The outcome for screening efficacy using enhanced study recruitment will be assessed as the 
marginal difference for successful identification of study participants who meet the limited JIA 
inclusion criteria.   We will compare absolute and relative numbers of eligible participants 
identified by computable phenotype augmented screening lists vs screening lists generated by 
current, ad-hoc processes alone. In addition, the efficiency of augmented screening will be 
assessed as the number of additional records requiring manual screening and chart review in 
order to identify one additional eligible participant.   
8.2.3 Data Completeness 
The main outcome for data completeness will be the rate of missing data utilizing same-site 
comparison.  We will assess and compare the relative differences in data completeness by data 
elements of interest (i.e. hospitalizations, abnormal lab values of interest, occurrence of 
infections) before and after EHR data linkage at participating sites. Additional outcomes may 
include metrics of research coordinator time required to achieve various thresholds of data 
Outcome 
Measure 
Timing 
Source 
Pain  
 PROMIS®  
pediatric pain 
interference  
Every study visit 
Parent-proxy 
or child (if ≥ 
8 years) 
Fatigue 
PROMIS® pediatric 
fatigue; short form 
Every study visit 
Parent-proxy 
or child (if ≥ 
8 years) 
Functional 
Ability 
PROMIS® upper 
extremity function 
and mobility 
 
 
Every study visit  
Parent-proxy 
or child (if ≥ 
8 years) 
 
CHAQ 
Baseline, 6M, 12M 
Parent-proxy 
or child (if ≥ 
8 years) 
Anxiety 
PROMIS® pediatric 
emotional distress – 
anxiety; short form 
 
Baseline, 6M, 12M 
Parent-proxy 
or child (if ≥ 
8 years) 
Depression 
PROMIS® pediatric 
emotional distress – 
depression; short 
form 
Baseline, 6M, 12M 
Parent-proxy 
or child (if ≥ 
8 years) 
Global Health 
PROMIS® pediatric 
global health 
measure (PGH-7) 
Every study visit 
Parent-proxy 
or child (if ≥ 
8 years) 
Other 
medication side 
effects  
JAMAR (Juvenile 
Arthritis 
Multidimensional 
Arthritis Report) 
question #11 
Baseline, 3M, 6M 
 
Parent-proxy 
or child (if ≥ 
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completeness across sites that utilize data linkage in comparison to sites that do not employ data 
linkage.  For sites not employing data linkage, study data of representative samples of enrolled 
study participants may be analyzed via chart review of EHR data to estimate the completeness of 
data.      
 
8.2.4  Other Secondary Outcomes 
Other outcomes describing the clinical course of study participants will include 
• Proportion of children achieving clinical inactive disease and/or remission  
• Number of new joints with arthritis. 
• Cumulative number of glucocorticoid joint injections. 
• Serious adverse events.  
• Juvenile arthritis disease activity (JADAS) scores. 
• Elapsed time from enrollment to disease extension, uveitis or systemic medication use. 
• Proportion of participants with disease extension (development of polyarthritis or uveitis). 
 

 
 
 
 
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9 
STATISTICAL ANALYSIS PLAN AND DETERMINATION OF SAMPLE SIZE 
9.1 
Statistical Design 
The primary objective of LIMIT-JIA is to evaluate the effectiveness of a 24-dose course of 
abatacept (Orencia) plus usual care (including NSAIDs and/or intra-articular glucocorticoids) 
versus usual care alone, to prevent development of polyarthritis or uveitis, or initiation of 
treatment with other systemic medication(s) for JIA (i.e. one or more of the following: systemic 
glucocorticoids, DMARD or biologic) within 12 months of enrollment in children with recent-
onset limited JIA.  
 
Secondary objectives include comparison of participants and caregiver reported outcomes 
between the different treatment strategies. 
 
The analysis population will include data from two parts of Limit-JIA.  In Part I participants 
were randomly assigned to receive abatacept + usual care or usual care alone.  Part II participants 
will all be assigned to receive abatacept + usual care.  
 
Part I enrolled participants into a randomized open-label multicenter trial with a planned sample 
size of 306 JIA participants recruited from CARRA Registry sites.  Participants were randomly 
allocated (1:1) to receive 24 weeks of abatacept plus usual care or usual care alone.  
Randomization was stratified on uveitis risk (higher and lower) and polyarthritis risk (higher and 
lower).  Upon completion of 24 weeks of randomized treatment, each participant was to receive 
usual care and undergo follow-up for assessment of outcomes for an additional 12 months.  
Planned duration of the study for each participant was 18 months.  Due to slow accrual and 
apparent loss of equipoise, enrollment into Part I has been discontinued 17February2022  As of 
October 29, 2021, 37 participants have been randomized in Part I. Part I participants will 
continue follow-up as planned. 
 
Part II is a non-randomized continuation of LIMIT-JIA with planned enrollment of 80 evaluable 
participants receiving abatacept.  Participants will receive 24 doses of abatacept plus usual care. 
Upon completion of 24 doses, each participant will receive usual care and undergo follow-up for 
assessment of outcomes for an additional 6 months.  Planned duration of the study for each 
participant is 12 months.  Part II will assess the efficacy of abatacept in prevention of disease 
extension by comparison of outcomes between participants enrolled in the abatacept arm and 428 
CARRA Registry patients who would have met major eligibility criteria for LIMIT-JIA.       
 
Statistical analysis of this study is planned upon study completion, when all participants in Part II 
have completed 12 months of follow-up or have withdrawn from the study.   
 
Definition of analysis population will follow intention-to-treat (ITT) principles including, as 
much as possible, all enrolled participants evaluated for the outcome(s) being analyzed.    An 
exception will be for safety analyses, wherein participants will be included corresponding to 
treatment actually received.   
 
 

 
 
 
 
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9.2 
Primary Analysis 
 
The primary outcome is the proportion of participants experiencing disease extension, 
(development of polyarthritis or uveitis, or initiation of systemic medications during the 12-
month period following enrollment).  Participants will undergo evaluations for polyarthritis 
every 3 months during the 12-month duration of the study. Ophthalmological examinations for 
uveitis will be performed for enrolled participants according to the schedule in Table 3. 
 
The primary analysis will compare the disease extension rate in the group of patients assigned to 
receive abatacept in Part II to a weighted average of disease extension rates observed in 6 cohorts 
(total of 428 patients) from the CARRA Registry who would have met the entry criteria for 
LIMIT-JIA.  [See Appendix: Modification of Study Design and Rationale for Discontinuing 
Randomization to Control Arm] 
 
The primary analysis will use the logistic regression model, log (π / (1 – π)) = TRT, where TRT 
is the assigned treatment arm (abatacept or control).  This analysis will test the null hypothesis 
that the disease extension rates in the abatacept and control arms are equal. The odds ratio with 
95% confidence limits will describe the estimated treatment effect. 
 
A secondary analysis of the disease extension rate will include a stratification factor for Part (I or 
II) and an interaction term (TRT x PART).  This analysis will assess the homogeneity of 
treatment effect between Part I and Part II.  Due to the small number of participants randomized 
to the control arm, statistical power to detect a TRT x PART interaction is limited. 
 
For Parts I and II, the analysis population for the primary endpoint will consist of participants 
whose disease status is determined at 12 months.  In case some participants are not evaluated at 
12 months, sensitivity analyses may be performed including simulated data for the participants 
with unobserved primary outcome.  Simulations will be conducted under a variety of 
assumptions about the distribution of the unobserved outcomes including 1) under the null 
hypothesis, 2) under alternative hypotheses unfavorable to the abatacept plus usual care 
treatment arm and, if appropriate, 3) according to plausible patterns determined by taking into 
account factors such as baseline disease status, length of follow-up, and magnitude and variance 
of estimated treatment effect from observed data.  Non-random patterns of missing data may be 
considered.  If the estimated treatment effects and conclusions from hypothesis testing are 
generally consistent between the primary and sensitivity analyses, the primary analysis will be 
considered accurate. 
 
Methods used to account for missing data will be described in more detail in the Statistical 
Analysis Plan. 
9.3 
Major Secondary Analyses 
Secondary analyses will be done for two study populations.  Participants randomized in Part I or 
assigned to the abatacept arm in Part II will comprise the enrolled population [N approximately 
equal to 126 (37 Part I, 89 Part II].  The overall study population [N approximately equal to 554] 
will include the enrolled population and 428 patients from the CARRA Registry whose disease 
extension results provided the control mean in Part II.    
 

 
 
 
 
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Secondary analyses for the enrolled population 
 
Secondary analyses will generally be conducted as planned in Part I, although estimation of 
treatment effects or treatment by factor differences will be imprecise, since more than 80% of 
participants in the enrolled population are expected to receive abatacept.  
 
Description of the time to disease extension will include cumulative incidence curves for the 
composite primary outcome and for the components disease extension, uveitis, and initiation of 
DMARDs or other biologic medication.  
 
Descriptive analyses will summarize participant and caregiver reported outcomes (continuous 
outcomes of pain interference, fatigue, upper extremity function, mobility, anxiety, depression 
and global health PROMIS® modules, medication side effects (JAMAR), and the CHAQ). These 
outcomes will be measured at baseline and follow-up visits as shown in Table 5, and will be 
analyzed using a mixed model for repeated measures. Preliminary analyses will be performed to 
identify a parsimonious covariance structure among the repeated measures.  The model will 
include as fixed effects treatment, time, treatment x time interaction, the baseline value of the 
outcome and the two stratification variables, the risk categories for polyarthritis and uveitis. 
Time will be treated as a categorical variable. The restricted maximum likelihood (REML) 
method of estimation and the Kenward-Roger degrees of freedom correction will be used. 
Contrasts will be constructed among the model parameters to test specific hypotheses.  Overall 
treatment effect will be assessed by testing the null hypothesis of no treatment difference 
averaged over time.  If the treatment x time interaction is significant at α=0.10, additional 
descriptive tests may be done for treatment differences at specific time-points.  Since more than 
80% of participants in the enrolled population are expected to receive abatacept, there will be 
limited statistical power to determine treatment effects on these outcomes. 
 
 
Secondary analyses for the overall study population 
 
Inclusion of data from 428 CARRA Registry patients may provide important information on the 
impact of treatment on time to disease extension and PROs.  Since treatment assignment for the 
overall study population is not random, it is anticipated that causal inference techniques such as 
inverse probability or overlap weighting will be useful in determining the comparability of the 
Registry patients and participants enrolled in LIMIT-JIA.   
 
The timing of evaluations for disease extension and PROs and missing data patterns are expected 
to differ between participants enrolled in LIMIT-JIA and CARRA Registry patients.  Techniques 
such as multiple imputation may be used to enable modeling of the overall study population. 
 
Details of the analysis of treatment effect for the overall study population will be provided in a 
separate SAP. 
 
 
 
 

 
 
 
 
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9.4 
Other Planned Analyses 
Other planned analyses for the enrolled population 
 
In addition to assessment of treatment differences in PROs, other secondary outcomes include 
proportion of children achieving clinically inactive disease and/or remission; number of new 
joints with arthritis; cumulative number of glucocorticoid joint injections; serious adverse events; 
juvenile arthritis disease activity (JADAS) scores; elapsed time from enrollment to disease 
extension, uveitis or initiation of DMARD or other biologic treatment. 
 
Sensitivity analyses will be performed to assess the impact of COVID-19 – including measures 
taken in response to the pandemic such as telehealth visits, missed visits or oral prednisone use 
on the primary study endpoint. COVID-19 infections will be included in the safety analyses.  
 
Other planned analyses for the overall population 
 
To be described in a separate SAP. 
9.4.1 Subgroup Analyses 
 
Subgroup analyses for enrolled population 
 
For the primary composite outcome, a formal test of homogeneity of treatment effect among 
baseline risk categories is planned. Exploratory comparisons will be carried out in the ITT 
population for the primary outcome, the components of the primary outcome, and for the two 
primary PROMIS® measures (pain interference and mobility), comparing the results between 
subgroups in order to determine clinical and biological factors associated with each. Subgroups 
will include the different ILAR categories of JIA (enthesitis-related arthritis, psoriatic arthritis, 
and undifferentiated arthritis compared to oligoarthritis); demographic factors (age, sex, race); 
inflammatory markers at time of enrollment (normal or elevated ESR, CRP); presence or absence 
of autoantibodies (antinuclear antibody, rheumatoid factor, ccp); genetic marker human 
leukocyte antigen B27 (HLA-B27); the number of joints and specific joints affected prior to 
enrollment; and the duration of disease prior to enrollment. Statistical comparison of treatment 
effects in subgroups will be done by the addition of a term denoting subgroup membership in the 
model used to compare the two treatment arms. We will test the subgroup-by-treatment 
interaction at the 0.15 level. Graphical displays such as forest plots, showing treatment effects 
and 95% confidence limits within subgroups may be used to display results. The subgroup 
analyses in this study are exploratory and should be considered hypothesis-generating.  
Subgroup analyses for the overall study population 
To be described in a separate SAP. 
9.4.2 Power, Sample Size and Type I error 
The trial sample size was determined by the intended statistical comparison of the primary 
outcome (proportion of participants with disease extension) between the abatacept plus usual 
care and historical care usual care treatment arms [See Appendix: Modification of Study Design 
and Rationale for Discontinuing Randomization to Control Arm].  It is assumed that the 
proportion of participants with disease extension will be 34.3% in the usual care arm, and that 

 
 
 
 
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this rate will be reduced to 15% in the abatacept plus usual care arm.  With 1-sided type 1 error = 
0.025, 80 evaluable participants enrolled into the abatacept + usual care arm (compared with the 
historical control mean from 428 patients) would provide > 95% power using logistic regression.   
Assuming 10% of participants will not be evaluable, we will enroll up to 89 patients to receive 
abatacept + usual care arm. See Table 7.  Hypothesis testing will be done with the Wald statistic 
testing the effect of the factor for treatment (abatacept + usual care, vs usual care) in the logistic 
model with factors for intercept and treatment.   
 
Subgroup or other non-primary analyses may be done by inclusion of additional factors to the 
logistic regression model. 
 
Table 7: Simulated power for sample sizes in the experimental arm of 10, 20, …, 80; assuming 
type I error = 0.025 one-sided. 
 
Sample size (evaluable) 
in experimental arm 
 
N =  
Number to enroll 
assuming a 10% 
inevaluable rate 
Power * 
20 
23 
0.332 
30 
34 
0.591 
40 
45 
0.742 
50 
56 
0.824 
60 
67 
0.900 
70 
78 
0.934 
80 
89 
0.956 
* For Rex and Rc = disease extension rates in the experimental and control arms, resp.  H0: Rex = Rc = 
0.343 (estimated from the historical control group), and H1: Rex < 0.15 (i.e. < Rc – 0.193).  Power was 
calculated by simulation of the logistic model, where extension rates followed a binomial distribution [Rc 
= 0.343, N = 428] in the control arm, and [Rex = 0.15, N (for N = 20, 30, …,80 as shown in the table)].  
Type I error is 0.025, one-sided. 
A sample size of eighty evaluable patients (all enrolled in the abatacept + usual care arm) will 
provide > 95% power to reject the null hypothesis that the disease extension rate is ≥ 34.3 % 
assuming one-sided type I error ≤ 0.025 and a true disease extension rate in the abtacept + usual 
care arm ≤ 15%.  To allow for an inevaluable rate up to 10%, enrollment will be expected to be 
approximately eighty-nine patients. 
 
9.5.4 Interim Analysis 
Interim analyses, with stopping boundaries for futility and efficacy, are planned after 
approximately 40% (n = 32) and 80% (n = 64) of Part II participants have been followed for one 
year.  Details will be provided prior to initiation of Part II. 
 
 
 

 
 
 
 
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10 DATA AND SAFETY MONITORING 
10.1 Data Safety Monitoring Board 
An independent DSMB will monitor the progress of the study and ensure that it meets the 
highest standards of ethics and study participant safety. 
The DSMB will be formed specifically to oversee trial progression with regards to serious 
adverse events and events of special interests. Responsibilities of the DSMB will include review 
of accumulated safety data and assessments to ensure the safety of study participants and overall 
integrity of the study, provide recommendations regarding the further conduct of the study and 
identify safety issues which may suggest risk to the participants already enrolled in the study or 
prospective participants. A DSMB charter will outline the membership, responsibilities, scope of 
activities, meeting frequency and communication plan between committee, sponsor and study 
sites. There will be three members of the DSMB who will collectively have competence and 
experience of JIA disease (in children), conduct of clinical studies, and interpretation of clinical 
study data  
Membership, functions and operating procedures of DSMB and other organizational groups for 
this study will be defined in a separate document.  Operating procedures for the DSMB will be 
established before the first review of the data.  
10.2 Required Data 
All required data for the clinical objectives of the study will be entered into the electronic case 
report form (eCRF). All required data for the PRO surveys will be collected per the CARRA 
Registry protocol. All required data for the patient entered data will be entered via the MyStudies 
app through their personal device or via a paper diary supplied by the study and then manually 
entered by the study team. 
10.3  Data Collection and Tracking 
Data will be collected directly from participants (via paper or electronic questionnaires and/or 
personal interview) during study visits as well as via electronic entry on their mobile devices 
using the MyStudies App or paper diaries between study visits. Data collection may be 
supplemented by data extracted from the study participant’s medical record from dates on, 
before, between, and subsequent to baseline and follow up visits.  
 

 
 
 
 
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11 STUDY RESPONSIBILITIES 
11.1 Investigator Responsibility/Performance 
Site investigators will ensure that source documents for the study will be made available in a 
timely manner to the sponsor or health authority inspectors. Site investigators will be required to 
maintain study participant’s clinical source documents that corroborate data collected on the 
eCRF as well as investigator study files. Additionally investigators shall: 
 
1. Grant sponsor or their delegate access to study participant records to verify the entries 
on the eCRF 
2. Ensure the accuracy, completeness, and timeliness of data reported to the sponsor in 
the eCRFs, including reporting of SAEs and ESIs 
3. Assure appropriate safeguarding of participants  health information  
4. Maintain adequate and accurate records to enable the study’s conduct to be 
documented and its data to be subsequently verified. These documents should include 
the investigator's study file and study participant clinical source documents, including 
the ICF. The investigator must keep these on file after completion or discontinuation 
of the study for the duration specified by the study contract and any local and federal 
regulations. 
5. Ensure that all study staff are trained and qualified to perform the duties they are 
assigned to perform, consistent with the Site Delegation Log. 
 
Investigators agree to have and use quality control and quality assurance systems to ensure that 
all work incidental to this protocol is conducted and data are generated, documented, and 
reported in compliance with the protocol, accepted standards of GCP, and all applicable federal, 
state, and local laws, rules, and regulations relating to the conduct of this study. 
11.2 Study Documentation 
Participant source documents are the physician’s study participant records maintained at the study 
site. In most cases, the source documents will be the hospital’s or the physician’s medical records. 
The information collected on the CRFs must match those source documents. In some cases, a 
portion of the source documents for a given study participant may be the CRF or participant diary 
(electronic app or paper diary).   
11.3 Protocol Deviations 
A protocol deviation is defined as an event where the investigator or site personnel did not 
conduct the study according to the investigational plan (protocol) and/or the investigator 
agreement. As a result of deviations, corrective actions are to be developed by the site and 
implemented promptly. 
  
It is the responsibility of site personnel to use continuous vigilance to identify and report 
deviations to the sponsor.  
 
All deviations from the protocol must be addressed in study case report forms. A completed copy 
of the protocol deviation form must be maintained in the regulatory file. Protocol deviations 
must be submitted to the local IRB/IEC per their guidelines. The site PI/study staff is responsible 
for knowing and adhering to their IRB requirements. 

 
 
 
 
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11.4 Study Drug Accountability 
In accordance with local regulatory requirements, the pharmacy, Site Investigator or designated 
site staff must maintain accurate records demonstrating receipt of study drug, date and amount of 
study drug received, to whom and by whom administered or dispensed (participant accounting) 
and accounts of returned study drug and any study drug accidentally or deliberately destroyed. 
Study drug accountability records must be maintained throughout the course of the study.  
At the end of the study period, neither the sponsor nor Bristol-Myers Squibb Company will 
continue to supply study drug to participants/Site Investigators unless the study is extended. The 
site investigator is responsible to ensure that the participant receives appropriate standard of care 
or other appropriate treatment in the independent medical judgement of the Site Investigator to 
treat the condition under study. 
11.5 Study Closeout 
The end of the study is when the last study participant completes the last visit.  
Upon completion of the study (defined as all study participants have completed all follow-
up- visits, all eCRFs are complete, and all queries have been resolved), the sponsor will notify 
the site of closeout, and a study closeout visit will be performed. At the end of the study, any 
remaining study drug will be destroyed locally. A certificate of destruction must be issued and 
provided to the sponsor.  The sponsor’s monitor will ensure that the Site PI’s regulatory files are 
up-to-date and complete and that any outstanding issues from previous visits have been resolved. 
Other issues to be reviewed at the closeout visit include discussing retention of study files, 
possibility of site audits, publication policy, and notifying the IRB of study closure. 
11.6 Publication Policies 
The sponsor will register the study and post study results regardless of outcome on a publicly 
accessible website in accordance with applicable laws and regulations.  
 
11.7 Record Retention 
The investigator should maintain a record of the location(s) of essential documents as defined in 
the ICH GCP Guideline including source documents and should have control of and continuous 
access to all essential documents and records generated by the investigator/institution before 
during and after the study. 
 
All documents and data relating to the study will be kept securely by the investigator in a secure 
file and/or electronically.  The storage system using during the study and for archiving 
(irrespective of the type of media used) should provide for document identification version 
history, search and retrieval.  The data will be available for evaluation and/or audits from Health 
authorities, the sponsor or sponsor representatives. 
 
The records should be retained by the investigator according to local regulations or as specified 
in the Clinical Trial Agreement. 
 

 
 
 
 
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If the investigator relocates, retires, or for any reason withdraws from the study, the study 
records may be transferred to an acceptable designee, such as another investigator or another 
institution.  Archiving on behalf of the investigator can also be delegated to the sponsor. 

 
 
 
 
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12  ETHICAL CONSIDERATIONS 
12.1 Informed Consent 
Before any study-related activities are initiated, consent will be obtained from all participants 
who can provide legally effective consent. For participants who are under the age of majority, 
parental permission will be obtained from a parent or legal guardian on the participant’s behalf 
and the child’s assent will be obtained per local requirements.  If a study participant attains the 
age at which she/he can provide legally effective consent under applicable state law, the 
participant will be asked to provide informed consent on his/her own behalf.   
 
12.2 Confidentiality of Study Participants 
Study participant confidentiality will be maintained throughout the study. A unique participant 
identification code will be used that allows linkage of all data reported for each participant. 
To protect study participant confidentiality, research datasets will be maintained as coded or de-
identified data, and linkages between research datasets and medical record numbers will be 
limited to appropriately trained staff using approved mechanisms for medical record review. 
Linkage tables between coded identifiers and medical record numbers will be maintained 
separately from the research datasets. Medical chart reviews will take place at the site level only 
and only designated, trained individuals approved by the local IRB/REB will be allowed to 
access these charts for purposes of review and validation. Abstracted data from medical record 
review will be recorded with the coded study participant identifiers only. All data will be housed 
in approved locations and electronic systems. 
Participant information collected in this study will comply with all national and local laws and 
regulations. . All records will be kept confidential and secure. Participant records will not be 
released to anyone other than the sponsor, authorized CARRA Registry and Limit-JIA research 
study personnel, and responsible regulatory authorities when requested. In all cases, caution will 
be exercised to assure participants’ data are treated confidentially and in keeping with 
established, industry-standard data privacy practices. 
 
12.3 Institutional Review Board/Ethics Committee Review 
Before initiating this study, the protocol, site-specific informed consent/assent forms, HIPAA 
Authorization forms (US only), recruitment materials, and other relevant information will be 
reviewed by a properly constituted IRB/REB or reliant IRB for each participating clinical site. 
Documentation of IRB approval for this protocol, site-specific informed consent/assent forms, 
HIPAA Authorization forms, recruitment materials, study participant questionnaires and any 
other material reviewed by the site’s IRB/REB will be sent to and reviewed by the sponsor 
before site initiation. Any amendments to the protocol, and/or revisions to the informed consent 
documents will be approved by each IRB/REB before local implementation. The site investigator 
will provide the sponsor with documentation of all IRB approvals. 
 

 
 
 
 
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12.4 Information Security 
All sites will follow their institution’s guidelines for data security and confidentiality.  Other than 
CARRA Registry participant contact information and identifiers used for purposes of participant 
data linkage, which are captured in the web-based research subject management platform used 
for all CARRA Registry subjects according the policies and procedures regulated by the CARRA 
Registry protocol at participating sites, all direct identifiers will remain at the local site.  Each 
site in the network has infrastructure in place to monitor and ensure data security, including 
HIPAA requirements (US only). 
 
The participating sites involved in computable phenotype and/or EHR data completion aims will 
use their clinical data warehouses and/or EHR systems to generate disease-specific cohort lists.  
A set of study participant coded identifiers will be generated; appropriately authorized site staff 
will then use these coded subject identifiers to generate an EHR data set consisting of the 
requested EHR records for study participants. For the medical chart review validation process, 
the authorized site staff will generate a cross-reference table linking the coded identifiers to the 
study participants’ medical record numbers, which will be made separately accessible to the site 
PI and/or his/her approved designates at each site. While data available for review may vary 
across sites, the anticipated categories of information to be reviewed include: diagnoses, 
procedures, pathology results, encounters, labs, vitals, medications, clinical notes, x-rays, and 
demographics.  
 

 
 
 
 
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