Two randomized trials of canakinumab in systemic juvenile idiopathic arthritis.

Abstract

BACKGROUND:

Interleukin-1 is pivotal in the pathogenesis of systemic juvenile idiopathic arthritis (JIA). We assessed the efficacy and safety of canakinumab, a selective, fully human, anti-interleukin-1β monoclonal antibody, in two trials.

METHODS:

In trial 1, we randomly assigned patients, 2 to 19 years of age, with systemic JIA and active systemic features (fever; ≥2 active joints; C-reactive protein, >30 mg per liter; and glucocorticoid dose, ≤1.0 mg per kilogram of body weight per day), in a double-blind fashion, to a single subcutaneous dose of canakinumab (4 mg per kilogram) or placebo. The primary outcome, termed adapted JIA ACR 30 response, was defined as improvement of 30% or more in at least three of the six core criteria for JIA, worsening of more than 30% in no more than one of the criteria, and resolution of fever. In trial 2, after 32 weeks of open-label treatment with canakinumab, patients who had a response and underwent glucocorticoid tapering were randomly assigned to continued treatment with canakinumab or to placebo. The primary outcome was time to flare of systemic JIA.

RESULTS:

At day 15 in trial 1, more patients in the canakinumab group had an adapted JIA ACR 30 response (36 of 43 [84%], vs. 4 of 41 [10%] in the placebo group; P<0.001). In trial 2, among the 100 patients (of 177 in the open-label phase) who underwent randomization in the withdrawal phase, the risk of flare was lower among patients who continued to receive canakinumab than among those who were switched to placebo (74% of patients in the canakinumab group had no flare, vs. 25% in the placebo group, according to Kaplan-Meier estimates; hazard ratio, 0.36; P=0.003). The average glucocorticoid dose was reduced from 0.34 to 0.05 mg per kilogram per day, and glucocorticoids were discontinued in 42 of 128 patients (33%). The macrophage activation syndrome occurred in 7 patients; infections were more frequent with canakinumab than with placebo.

CONCLUSIONS:

These two phase 3 studies show the efficacy of canakinumab in systemic JIA with active systemic features. (Funded by Novartis Pharma; ClinicalTrials.gov numbers, NCT00889863 and NCT00886769.).

• Authors: Nicolino Ruperto, Hermine I Brunner, Pierre Quartier, Tamás Constantin, Nico Wulffraat, Gerd Horneff, Riva Brik, Liza McCann, Ozgur Kasapcopur, Lidia Rutkowska-Sak, Rayfel Schneider, Yackov Berkun, Inmaculada Calvo, Muferet Erguven, Laurence Goffin, Michael Hofer, Tilmann Kallinich, Sheila K Oliveira, Yosef Uziel, Stefania Viola, Kiran Nistala, Carine Wouters, Rolando Cimaz, Manuel A Ferrandiz, Berit Flato, Maria Luz Gamir, Isabelle Kone-Paut, Alexei Grom, Bo Magnusson, Seza Ozen, Flavio Sztajnbok, Karine Lheritier, Ken Abrams, Dennis Kim, Alberto Martini, Daniel J Lovell, PRINTO, PRCSG
• Journal: The New England journal of medicine (N Engl J Med) Vol. 367 Issue 25 Pg. 2396-406 (Dec 20 2012) ISSN: 1533-4406 [Electronic] United States
• PMID: 23252526 (Publication Type: Clinical Trial, Phase III, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Glucocorticoids
• Interleukin-1beta
• canakinumab
• Methotrexate

Topics

• Adolescent
• Anti-Inflammatory Agents, Non-Steroidal (therapeutic use)
• Antibodies, Monoclonal (adverse effects, therapeutic use)
• Antibodies, Monoclonal, Humanized
• Arthritis, Juvenile (complications, drug therapy)
• Child
• Child, Preschool
• Double-Blind Method
• Drug Therapy, Combination
• Female
• Glucocorticoids (therapeutic use)
• Humans
• Infections (chemically induced)
• Interleukin-1beta (antagonists & inhibitors)
• Kaplan-Meier Estimate
• Macrophage Activation Syndrome (etiology)
• Male
• Methotrexate (therapeutic use)
• Neutropenia (chemically induced)
• Thrombocytopenia (chemically induced)