Two randomized trials of canakinumab in systemic juvenile idiopathic arthritis
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, Ruben Cuttica, Wolfgang Emminger, Bernard Lauwerys, Rik Joos, Laurence Goffin, Carine Wouters, Marcia Bandeira, Flavio Sztajnbok, Sheila Knupp, Claudio Len, Isabelle Kone-Paut, Pierre Quartier, Marine Desjonqueres, Michel Fischbach, Tilmann Kallinich, Reinhard Berner, Angelika Thon, Michael Frosch, Gerd Horneff, Ralf Trauzeddel, Elisabeth Weissbarth-Riedel, Maria Trachana, Tamás Constantin, Riva Brik, Yosef Uziel, Yackov Berkun, Judith Barash, Liora Harel, Rolando Cimaz, Stefania Viola, Fabrizia Corona, Valeria Gerloni, Maria Alessio, N M Nico Wulffraat, Berit Flato, Manuel Ferrandiz, Lidia Rutkowska-Sak, Jordi Anton, Inmaculada Calvo, Maria Luz Gamir, Juan Carlos Robledillo, Bo Magnusson, Michael Hofer, Seza Ozen, Huri Ozdogan, Muferet Erguven, Erbil Unsal, Liza McCann, Patricia Woo, Helen Foster, Athimalaipet Ramanan, Alice Chieng, Nicholas Wilkinson, Rayfel Schneider, Kristin Houghton, Lori Tucker, Elie Haddad, Jorge Lopez-Benitez, Daniel Lovell, Paula Morris, Kenneth Schikler, Daniel Kingsbury, Gloria Higgins, Katherine Marzan, Ruben Cuttica, Wolfgang Emminger, Rik Joos, Bernard Lauwerys, Maria Hilario, Sebastiao Radominski, Elie Haddad, Kristin Houghton, Brigitte Bader-Meunier, Marine Desjonqueres, Michel Fischbach, Isabelle Marie, Agnes Mogenet, Richard Mouy, Reinhard Berner, Michael Frosch, Angelika Thon, Ral Trauzeddel, Elisabeth Weibarth-Riedel, Maria Trachana, Judith Barash, Liora Harel, Maria Alessio, Fabrizia Corona, Valeria Gerloni, Jordi Anton, Juan Carlos Robledillos, Erbil Unsal, Alice Chieng, Helen Foster, Athimalaip Ramanan, Nick Wilkinson, Jacqueline Miller, Gloria Higgins, Daniel Kingsbury, Jorge Lopez-Benitez, Katherine Marzan, Paula Morris, Kenneth Schikler, 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, Ruben Cuttica, Wolfgang Emminger, Bernard Lauwerys, Rik Joos, Laurence Goffin, Carine Wouters, Marcia Bandeira, Flavio Sztajnbok, Sheila Knupp, Claudio Len, Isabelle Kone-Paut, Pierre Quartier, Marine Desjonqueres, Michel Fischbach, Tilmann Kallinich, Reinhard Berner, Angelika Thon, Michael Frosch, Gerd Horneff, Ralf Trauzeddel, Elisabeth Weissbarth-Riedel, Maria Trachana, Tamás Constantin, Riva Brik, Yosef Uziel, Yackov Berkun, Judith Barash, Liora Harel, Rolando Cimaz, Stefania Viola, Fabrizia Corona, Valeria Gerloni, Maria Alessio, N M Nico Wulffraat, Berit Flato, Manuel Ferrandiz, Lidia Rutkowska-Sak, Jordi Anton, Inmaculada Calvo, Maria Luz Gamir, Juan Carlos Robledillo, Bo Magnusson, Michael Hofer, Seza Ozen, Huri Ozdogan, Muferet Erguven, Erbil Unsal, Liza McCann, Patricia Woo, Helen Foster, Athimalaipet Ramanan, Alice Chieng, Nicholas Wilkinson, Rayfel Schneider, Kristin Houghton, Lori Tucker, Elie Haddad, Jorge Lopez-Benitez, Daniel Lovell, Paula Morris, Kenneth Schikler, Daniel Kingsbury, Gloria Higgins, Katherine Marzan, Ruben Cuttica, Wolfgang Emminger, Rik Joos, Bernard Lauwerys, Maria Hilario, Sebastiao Radominski, Elie Haddad, Kristin Houghton, Brigitte Bader-Meunier, Marine Desjonqueres, Michel Fischbach, Isabelle Marie, Agnes Mogenet, Richard Mouy, Reinhard Berner, Michael Frosch, Angelika Thon, Ral Trauzeddel, Elisabeth Weibarth-Riedel, Maria Trachana, Judith Barash, Liora Harel, Maria Alessio, Fabrizia Corona, Valeria Gerloni, Jordi Anton, Juan Carlos Robledillos, Erbil Unsal, Alice Chieng, Helen Foster, Athimalaip Ramanan, Nick Wilkinson, Jacqueline Miller, Gloria Higgins, Daniel Kingsbury, Jorge Lopez-Benitez, Katherine Marzan, Paula Morris, Kenneth Schikler
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.).
Source: PubMed