Randomized, double-blind, placebo-controlled trial of the efficacy and safety of rilonacept in the treatment of systemic juvenile idiopathic arthritis

Abstract

Objective: To assess the efficacy and safety of rilonacept, an interleukin-1 inhibitor, in a randomized, double-blind, placebo-controlled trial.

Methods: An initial 4-week double-blind placebo phase was incorporated into a 24-week randomized multicenter design, followed by an open-label phase. Seventy-one children who had active arthritis in ≥2 joints were randomized (1:1) to the 2 arms of the study. Patients in the rilonacept arm received rilonacept (loading dose 4.4 mg/kg followed by 2.2 mg/kg weekly, subcutaneously) beginning on day 0. Patients in the placebo arm received placebo for 4 weeks followed by a loading dose of rilonacept at week 4 followed by weekly maintenance doses. The primary end point was time to response, using the adapted American College of Rheumatology Pediatric 30 criteria coupled with the absence of fever and taper of the dosage of systemic corticosteroids, using prespecified criteria.

Results: The time to response was shorter in the rilonacept arm than in the placebo arm (χ(2) = 7.235, P = 0.007). The secondary analysis, which used the same response criteria, showed that 20 (57%) of 35 patients in the rilonacept arm had a response at week 4 compared with 9 (27%) of 33 patients in the placebo arm (P = 0.016). Exacerbation of systemic juvenile idiopathic arthritis (JIA) was the most common severe adverse event. More patients in the rilonacept arm had elevated liver transaminase levels (including levels more than 3 times the upper limit of normal) compared with those in the placebo arm. Adverse events were similar in the 2 arms of the study.

Conclusion: Rilonacept was generally well tolerated and demonstrated efficacy in active systemic JIA.

Figure 1. Flow of Patients in RAPPORT Trial

RAPPORT, The RAndomized Placebo Phase Study Of Rilonacept in the Treatment of Systemic Juvenile Idiopathic Arthritis. ^a Indicates patients who attended the week 24 study visit. ^b Indicates patients who remained in long term extension until the LTE period ended.

Figure 2. Cumulative Incidence Estimates of Response by Treatment Arm

The cumulative incidence curve shows a higher rate of response in the rilonacept arm compared to the placebo arm. The primary endpoint of response was assessed at bi-weekly study visits during the efficacy period. Response was defined as improvement in the American College of Rheumatology (ACR) Pediatric 30, absence of fevers ≥38.5°C in the previous 2 weeks, and at least 10% taper in systemic corticosteroids from baseline. Missing temperatures were imputed as fever free. Patients were no longer eligible for the primary endpoint if corticosteroids were increased or started based on the non-response algorithm prior to meeting the criteria for response. The cumulative incidence estimation treated non-response as a competing event. The number of patients at risk displayed below the figure shows the number of patients eligible to meet the response designation for the first time at each study week.

Figure 3. Change Over Time in Corticosteroid Dose

Panel A shows the median corticosteroid dose by treatment group during the efficacy period, with I bars representing interquartile range. Panel B shows the median corticosteroid dose aggregated for all patients during the follow-up safety period, with I bars representing interquartile range. Patients’ oral dose at their last visit during the long term extension phase is displayed. The median time on study at the last visit was 16 months, with a range of 8 to 26 months.