Observational Study of Pediatric Rheumatic Diseases: The CARRA Registry

The original Childhood Arthritis & Rheumatology Research Alliance (CARRA) Registry (Protocol
Number: CRNT_REGST01) was first established in 2010 to advance alliance infrastructure,
facilitate expanded clinical and translational pediatric research, and transform the culture
of pediatric rheumatology toward universal participation in research. This original CARRA
Registry will be referred to throughout the protocol as the CARRA Legacy Registry. Through
the creation of a sophisticated informatics infrastructure, provision of comprehensive site
support and the engagement of families, patients, and communities, the CARRA Registry will
provide the opportunity for affected children at every CARRA Registry site to participate in
high-quality clinical and translational research.

Continuation of the CARRA Registry as described in this protocol will support data collection
on patients with pediatric-onset rheumatic diseases. The CARRA Registry will form the basis
for future CARRA studies. In particular, this observational registry will be used to answer
pressing questions about therapeutics used to treat pediatric rheumatic diseases, including
examining safety questions. The Duke Clinical Research Institute (DCRI) is serving as the
CARRA Clinical and Data Coordinating Center (CDCC) for the protocol.

Traditional exposure-based post-marketing registries of individual therapeutic agents for
juvenile idiopathic arthritis (JIA), systemic lupus erythematosus, and other rheumatic
diseases are inadequate for answering important safety questions for many reasons:

- Sample sizes are too small to detect uncommon but important events

- No unexposed comparators exist to evaluate risk attributable to underlying disease

- Duration of follow-up of individual patients is too short to evaluate many potential
delayed adverse events (AEs)

- Sample sizes are inadequate to assess myriad complex and dynamic concurrent medication
regimens common to treatment of rheumatic diseases

- Selective patient enrollment limits evaluation of co-morbid conditions and other patient
factors

These limitations prevent patients, families, and providers from understanding the true risks
and benefits of therapy in order to make appropriate and informed decisions. They also
prevent drug manufacturers and regulatory agencies from conducting an informed review of
marketed products for these diseases.

A registry based on disease diagnosis rather than specific therapeutic agents overcomes many
of the limitations of exposure-based single-agent registries in the assessment of delayed or
uncommon safety events. Indeed, data from a consolidated disease-based registry "...could
provide the information necessary for individual companies to satisfy post-marketing
requirements and commitments and obviate the need for an individual product registry"
(letters from the United States (US) Food and Drug Administration (FDA) to CARRA, 21 December
2010 and 9 December 2011). This protocol details the foundation of a registry to meet these
objectives.

The CARRA Registry aims to detect and understand the epidemiology of important AEs, including
those that are delayed or uncommon. Subjects followed at active CARRA Registry sites are
eligible for enrollment, regardless of past or current treatment. Each subject will be
followed prospectively for a goal of 10 years duration; the study will continue indefinitely
as resources allow and continued need exists. Data will be systematically collected,
including important patient factors, therapies, serious adverse events (SAEs), and
protocol-defined events of special interest. Selected safety events (e.g., malignancies) will
be adjudicated by a panel of experts via a review of medical records. The CARRA Registry, a
disease-based prospective observational registry, enables both detection of potential safety
signals and hypothesis-driven, rigorous, and adequately-controlled pharmacoepidemiologic
studies of important AEs and their associations with therapeutic agents.

In addition to answering questions about the safety of therapeutics, the data collected in
the CARRA Registry are anticipated to serve many other valuable uses. Within the confines of
observational study design, the effectiveness of therapeutic agents may be examined for
short- and long-term clinical and patient-centered outcomes.

The Registry is the data collection platform for Consensus Treatment Plan (CTP) comparative
effectiveness research in pediatric rheumatic disease. Patients enrolled in the Registry may
also be eligible to be followed as part of a CTP subset. Currently ongoing CTP projects
include:

FiRst line Options for Systemic JIA Treatment (FROST). The purpose of FROST is to compare the
effectiveness of CARRA systemic JIA (sJIA) treatment strategies (biologic vs. non-biologic)
in achieving clinically inactive disease in patients with new-onset sJIA. Additionally, FROST
aims to compare patient/caregiver reported outcomes between treatment strategies. FROST will
enroll 200 new-onset, previously untreated sJIA patients who are starting treatment with one
of the 4 sJIA CTPs (glucocorticoid (GC) only; Methotrexate + GC; IL-1 inhibitor + GC; IL-6 +
GC). Enrollment will occur over 3 years at all CARRA Registry sites. In addition to routine
Registry data collection, patients followed as part of the FROST CTP will complete additional
questionnaires about their disease status and quality of life.

Medication use for pediatric rheumatic diseases is dynamic and not well characterized. The
CARRA Registry represents a powerful data source to follow drug use patterns and provides the
opportunity to study predictors of medication use. Important outcomes are likely to be
influenced by other factors in addition to therapy (e.g., disease severity) and the CARRA
Registry is positioned to help answer these types of questions. Patient-reported outcomes
(PROs) generated by patients outside the context of clinical encounters may be collected in
the Registry to provide a rich, additional dimension of data to better understand rheumatic
diseases. Practitioners may review clinical data from their sites as part of a quality
improvement approach to better outcomes.

Analyses of CARRA Registry data aim to provide results to guide the therapeutic decisions
made by affected children, families, and providers while improving regulatory efficiency and
reducing cost. Ultimately, this approach might serve as a model for successful collaboration
between research community networks, industry, and public agencies to promote the effective
and efficient evaluation of drugs and devices across the regulatory continuum.

Inclusion Criteria:

1. Onset of rheumatic disease prior to age 16 years for JIA and onset prior to age 19
years for all other rheumatic diseases (see appendix A).

2. Subject (and/or parent/legal guardian when required) is able to provide written
informed consent and willing to comply with study procedures.

3. Subject and/or parent/legal guardian can read either English or Spanish.

4. Subject and/or parent/legal guardian is willing to be contacted in the future by study
staff.

Exclusion Criteria:

1. Greater than 21 years of age at the time of enrollment.