Study of Human Anti-TNF Monoclonal Antibody Adalimumab in Children With Polyarticular Juvenile Idiopathic Arthritis (JIA)

A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study of the Safety, Efficacy, and Pharmacokinetics of the Human Anti-TNF Monoclonal Antibody Adalimumab in Children With Polyarticular Juvenile Idiopathic Arthritis

This is a multicenter, Phase 3 randomized, placebo-controlled study designed to evaluate adalimumab in children 4 to 17 years old with polyarticular juvenile idiopathic arthritis (JIA) who are either methotrexate (MTX) treated or non-MTX treated.

The study design for this clinical trial was chosen to evaluate adalimumab in subjects who were either methotrexate (MTX)-naive or had been withdrawn from MTX at least 2 weeks prior to study drug administration (non-MTX stratum) or were inadequate responders to MTX and continued MTX treatment (MTX stratum). The study consisted of 4 phases: a 16-week Open-label Lead-in (OL LI), a 32-week Double-blind (DB) phase, an up to 136-week Open-label Extension Body Surface Area (OLE BSA) phase, and an up to 224-week OLE Fixed Dose (FD) phase. All subjects who met entry criteria were enrolled into one of the appropriate strata and received adalimumab (plus concomitant MTX in the MTX stratum) in the 16 week OL LI phase of the study. All subjects who responded to adalimumab during the OL LI phase were to be enrolled in the DB phase of the study and randomized to receive adalimumab (plus concomitant MTX in the MTX stratum) or placebo (plus concomitant MTX in the MTX stratum). Subjects in the DB phase received either adalimumab (24 mg/m2 BSA up to a maximum of 40 mg total body dose) or placebo subcutaneously (SC) administered every other week (eow). Adalimumab or placebo was administered for an additional 32 weeks or until flare of disease (based on PedACR30 response criteria = a worsening of 30% or more in 3 of the 6 response variables (Parent's global assessment of subject's overall well-being by visual analog scale [VAS], Physician's global assessment [PhGA] of subject's disease severity by VAS, number of active joints [joints with swelling not due to deformity or joints with limitation of passive motion (LOM)], pain, tenderness, or both, number of joints with LOM, Childhood Health Assessment Questionnaire [CHAQ], and CRP levels), a minimum of 2 active joints, and no more than 1 indicator improving by 30% or more), whichever occurred earlier. For subjects who did not have a disease flare, the DB phase was completed at Week 48. Subjects who experienced disease flare during the DB phase or subjects who completed 48 weeks of the study were given the option to receive adalimumab for up to a minimum of 44 weeks (up to a maximum of 136 weeks) in the OLE BSA phase before being eligible to switch to the OLE FD phase. In this phase, subjects received OL adalimumab (24 mg/m2 BSA up to a maximum of 40 mg total body dose SC eow). All subjects who completed at least 44 weeks of OLE BSA treatment were given the opportunity to continue into the OLE FD phase for up to 224 weeks of additional adalimumab exposure. In this phase, subjects weighing less than 30 kg were treated with a fixed dose of 20 mg of adalimumab SC eow. Subjects weighing 30 kg or more were treated with a fixed dose of 40 mg of adalimumab SC eow.

Inclusion Criteria:

• Subjects must have a diagnosis of polyarticular juvenile idiopathic arthritis (JIA) age 4 to 17 by the American College of Rheumatology (ACR) criteria. Disease onset may have been systemic, polyarticular, or pauciarticular. If the disease was systemic onset, then the subjects must be free of any systemic JIA manifestations for at least 3 months before the time of qualification.
• At the time of study screening, the subject must have continuing active disease defined as >= 5 swollen joints and >= 3 joints with limitation of motion (LOM). These joints are not mutually exclusive.
• Subjects may be either naïve to MTX, inadequate responders to MTX, or intolerant to MTX. Intolerance to MTX will be defined by the subject's physician. The MTX must be maintained at a dose of at least 10 mg/m2 body surface area/week for a minimum of 3 months, prior to screening.
• Duration of disease is not limited, but must have been long enough for a subject to have been given an adequate trial of nonsteroidal anti-inflammatory drugs (NSAIDs).
• Have not received other disease-modifying anti-rheumatic drugs (DMARDs) including penicillamine, hydroxychloroquine, sulfasalazine, oral or injectable gold, cyclosporin; or intravenous immunoglobulin (IV Ig); or cytotoxic agents, for at least 4 weeks prior to receiving 1st dose of study drug. Subjects currently on one or more of these DMARDs must demonstrate active disease (defined above) prior to a minimum 4 weeks (28 days) washout of all DMARDs.
• Subjects who are refractory to MTX after 3 months of treatment must demonstrate active disease (defined above) prior to enrollment in the open-label part of the trial.
• Have not received an intra-articular glucocorticoid injection within 4 weeks (28 days) prior to enrollment into the study.
• Have good venous access and stable hematocrit >= 24%.
• All sexually active male and female study participants must be practicing adequate contraception. Post-pubertal females must have a negative serum pregnancy test no greater than 10 days prior to the first dose of study drug.
• Parent or guardian has voluntarily signed and dated an informed consent form, approved by an Institutional Review Board (IRB)/Independent Ethics Committee (IEC), after the nature of the study has been explained and the subject's parent or legal guardian has had the opportunity to ask questions.

Exclusion Criteria:

• Pregnant or nursing female.
• Functional class IV by ACR criteria.
• Laboratory parameters outside limits established in the protocol.
• Medical history, medical condition, or previous treatment not allowed by the protocol.