Background/Purpose:   The RAndomized Placebo Phase Study Of Rilonacept in the Treatment of Systemic Juvenile Idiopathic Arthritis (RAPPORT) is a multicenter controlled trial using a 4 week randomized placebo phase.  The study design reasons that if a treatment is effective, subjects who begin active treatment earlier will respond sooner, on average, than subjects who begin active treatment later.  Rilonacept is a fusion protein consisting of human cytokine receptor extracellular domains of both receptor components required for IL-1 signaling:  the IL-1 Type I receptor and the IL-1 receptor accessory protein as well as the Fc portion of human IgG1. 

Methods:   RAPPORT consisted of a double-blind phase (weeks 0-4), a treatment phase (weeks 4-24) and an open label Long Term Extension phase (24 weeks -21 months).  The primary endpoint was time to response, using adapted JIA ACR 30 response criteria requiring absence of fever for 2 weeks and meeting pre-specified criteria for tapering of corticosteroids during the first 12 weeks of the study.  We randomized 71 children with at least 2 active joints from 20 sites 1:1 to 2 arms of the study.  The rilonacept arm subjects received rilonacept (4.4mg/kg loading dose followed by weekly 2.2mg/kg subcutaneously) and placebo arm subjects received placebo for 4 weeks followed by loading dose of rilonacept at week 4 followed by weekly maintenance doses.   After week 14, corticosteroids were dosed according to the treating physician. 

Results:   The time to response was shorter in the rilonacept arm (median 4 weeks; range 2-10 weeks) than in the placebo arm (median 6 weeks; range 2-12 weeks) (Chi-square 7.235; p=0.007). Twenty-six of 35 (79%)patients in the rilonacept arm and 13 of 33 (39%)in the placebo arm met  ACR Pediatric 30 response criteria at week 4 (p=0.004); 21/35 (60%) in the rilonacept arm vs. 10/33 (30%) in the placebo arm met ACR pediatric 50 response criteria  (p=0.015); 14/35 (40%) vs. 4/33 (12%) met  ACR pediatric 70 criteria (p=0.013). Adverse events were similar in the two arms of the study (Table).  Four subjects developed elevations in liver transaminases of ≥ 2 times the upper limit of normal (all while on rilonacept); 2 subjects developed elevations ≥5 times the upper limit of normal. In one, the elevations resolved but recurred on re-challenge and was deemed an SAE. One subject developed EBV induced macrophage activation syndrome.

Conclusion:   This is the first double-blind, randomized, placebo-controlled trial of rilonacept to demonstrate efficacy in sJIA.  Rilonacept treatment was relatively safe.  Significant elevations in aspartate aminotransferase levels were rare but occurred more often in subjects receiving rilonacept than in those on placebo.

¹ The most frequently reported events were defined as events that occurred in at least 10% of all patients during the entire study.