Document Detail


Randomized trial of tocilizumab in systemic juvenile idiopathic arthritis.
MedLine Citation:
PMID:  23252525     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: Systemic juvenile idiopathic arthritis (JIA) is the most severe subtype of JIA; treatment options are limited. Interleukin-6 plays a pathogenic role in systemic JIA.
METHODS: We randomly assigned 112 children, 2 to 17 years of age, with active systemic JIA (duration of ≥6 months and inadequate responses to nonsteroidal antiinflammatory drugs and glucocorticoids) to the anti-interleukin-6 receptor antibody tocilizumab (at a dose of 8 mg per kilogram of body weight if the weight was ≥30 kg or 12 mg per kilogram if the weight was <30 kg) or placebo given intravenously every 2 weeks during the 12-week, double-blind phase. Patients meeting the predefined criteria for nonresponse were offered open-label tocilizumab. All patients could enter an open-label extension.
RESULTS: At week 12, the primary end point (an absence of fever and an improvement of 30% or more on at least three of the six variables in the American College of Rheumatology [ACR] core set for JIA, with no more than one variable worsening by more than 30%) was met in significantly more patients in the tocilizumab group than in the placebo group (64 of 75 [85%] vs. 9 of 37 [24%], P<0.001). At week 52, 80% of the patients who received tocilizumab had at least 70% improvement with no fever, including 59% who had 90% improvement; in addition, 48% of the patients had no joints with active arthritis, and 52% had discontinued oral glucocorticoids. In the double-blind phase, 159 adverse events, including 60 infections (2 serious), occurred in the tocilizumab group, as compared with 38, including 15 infections, in the placebo group. In the double-blind and extension periods combined, 39 serious adverse events (0.25 per patient-year), including 18 serious infections (0.11 per patient-year), occurred in patients who received tocilizumab. Neutropenia developed in 19 patients (17 patients with grade 3 and 2 patients with grade 4), and 21 had aminotransferase levels that were more than 2.5 times the upper limit of the normal range.
CONCLUSIONS: Tocilizumab was efficacious in severe, persistent systemic JIA. Adverse events were common and included infection, neutropenia, and increased aminotransferase levels. (Funded by Hoffmann-La Roche; ClinicalTrials.gov number, NCT00642460.).
Authors:
Fabrizio De Benedetti; Hermine I Brunner; Nicolino Ruperto; Andrew Kenwright; Stephen Wright; Inmaculada Calvo; Ruben Cuttica; Angelo Ravelli; Rayfel Schneider; Patricia Woo; Carine Wouters; Ricardo Xavier; Lawrence Zemel; Eileen Baildam; Ruben Burgos-Vargas; Pavla Dolezalova; Stella M Garay; Rosa Merino; Rik Joos; Alexei Grom; Nico Wulffraat; Zbigniew Zuber; Francesco Zulian; Daniel Lovell; Alberto Martini; ;
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Publication Detail:
Type:  Clinical Trial, Phase III; Journal Article; Multicenter Study; Randomized Controlled Trial; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The New England journal of medicine     Volume:  367     ISSN:  1533-4406     ISO Abbreviation:  N. Engl. J. Med.     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-12-20     Completed Date:  2013-01-02     Revised Date:  2014-02-20    
Medline Journal Info:
Nlm Unique ID:  0255562     Medline TA:  N Engl J Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2385-95     Citation Subset:  AIM; IM    
Data Bank Information
Bank Name/Acc. No.:
ClinicalTrials.gov/NCT00642460
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MeSH Terms
Descriptor/Qualifier:
Adolescent
Anti-Inflammatory Agents, Non-Steroidal / therapeutic use
Antibodies, Monoclonal, Humanized / adverse effects,  therapeutic use*
Arthritis, Juvenile / blood,  drug therapy*
Child
Child, Preschool
Double-Blind Method
Drug Therapy, Combination
Female
Glucocorticoids / therapeutic use
Humans
Infection / chemically induced
Male
Methotrexate / therapeutic use
Neutropenia / chemically induced
Receptors, Interleukin-6 / antagonists & inhibitors*
Transaminases / blood
Grant Support
ID/Acronym/Agency:
17287//Arthritis Research UK; UL1 TR000077/TR/NCATS NIH HHS
Chemical
Reg. No./Substance:
0/Anti-Inflammatory Agents, Non-Steroidal; 0/Antibodies, Monoclonal, Humanized; 0/Glucocorticoids; 0/Receptors, Interleukin-6; 0/tocilizumab; EC 2.6.1.-/Transaminases; YL5FZ2Y5U1/Methotrexate
Investigator
Investigator/Affiliation:
Roger Allen / ; Eileen Baildam / ; Diane Brown / ; Ruben Burgos-Vargas / ; Inmaculada Calvo / ; Jeffrey Chaitow / ; Elizabeth Chalom / ; Elisabetta Cortis / ; Ruben Cuttica / ; Fabrizio De Benedetti / ; Pavla Dolezalova / ; Graciela Espada / ; Berit Flato / ; Stella Maris Garay / ; Julia Garcia-Consuegra / ; Valeria Gerloni / ; Philip Hashkes / ; Michael Henrickson / ; Gerd Horneff / ; Hans-Iko Huppertz / ; Rita Jerath / ; Rik Joos / ; Yukiko Kimura / ; Daniel Lovell / ; Rocio Maldonado Velasquez / ; Evangelia Mantzourani / ; Alberto Martini / ; Kirsten Minden / ; Kevin Murray / ; Barry Myones / ; Kathleen M O'Neil / ; Karen Onel / ; Johannes Roth / ; Jozef Rovensky / ; Rayfel Schneide / ; Antigoni Siamopoulou-Mavridou / ; Clovis A Silva / ; Steven Spalding / ; Olga Vougiouka / ; Patricia Woo / ; Carine Wouters / ; Nico Wulffraat / ; Ricardo Xavier / ; Lawrence Zemel / ; Zbigniew Zuber / ; Francesco Zulian / ; Graciela Espada / ; Roger Allen / ; Jeffrey Chaitow / ; Kevin Murray / ; Clovis A Silva / ; Johannes Roth / ; Gerd Horneff / ; Hans-Iko Huppertz / ; Kirsten Minden / ; Evangelia Mantzourani / ; Antigoni Siamopoulou / ; Olga Vougiouka / ; Elisabetta Cortis / ; Valeria Gerloni / ; Maria del Rocio Maldonado-Velazquez / ; Berit Flato / ; Jozef Rovensky / ; Julia Garcia-Consuegra / ; Despina Eleftheriou / ; Diane Brown / ; Elizabeth Chalom / ; Philip Hashkes / ; Michael Henrickson / ; Rita Jerath / ; Yukiko Kimura / ; Barry Myones / ; Karen Onel / ; Kathleen M O'Neil / ; Steven J Spalding /
Comments/Corrections
Comment In:
N Engl J Med. 2013 Mar 28;368(13):1256   [PMID:  23534567 ]
N Engl J Med. 2012 Dec 20;367(25):2439-40   [PMID:  23252530 ]
N Engl J Med. 2013 Mar 28;368(13):1256-7   [PMID:  23534566 ]
Nat Rev Rheumatol. 2013 Feb;9(2):63   [PMID:  23321610 ]

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