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Canakinumab in patients with systemic juvenile idiopathic arthritis and active systemic features: results from the 5-year long-term extension of the phase III pivotal trials
  1. Nicolino Ruperto1,
  2. Hermine I Brunner2,
  3. Pierre Quartier3,
  4. Tamàs Constantin4,
  5. Nico M Wulffraat5,
  6. Gerd Horneff6,7,
  7. Ozgur Kasapcopur8,
  8. Rayfel Schneider9,
  9. Jordi Anton10,
  10. Judith Barash11,
  11. Reinhard Berner12,
  12. Fabrizia Corona13,
  13. Ruben Cuttica14,
  14. Marine Fouillet-desjonqueres15,
  15. Michel Fischbach16,
  16. Helen E Foster17,
  17. Dirk Foell18,
  18. Sebastião C Radominski19,
  19. Athimalaipet V Ramanan20,
  20. Ralf Trauzeddel21,
  21. Erbil Unsal22,
  22. Jérémy Levy23,
  23. Eleni Vritzali24,
  24. Alberto Martini25,
  25. Daniel J Lovell2,
  26. On behalf of the Paediatric Rheumatology International Trials Organisation (PRINTO) and the Pediatric Rheumatology Collaborative Study Group (PRCSG)
  1. 1 Clinica Pediatrica e Reumatologia, PRINTO, IRCCS Istituto Giannina Gaslini, Genoa, Italy
  2. 2 Division of Rheumatology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA
  3. 3 Centre de référence national pour les maladies inflammatoires rhumatologiques et auto-immunes systémiques rares de l’enfant (RAISE), Unité d'Immunologie, Hématologie et Rhumatologie Pediatrique, Université Paris-Descartes, IMAGINE Institute, Hôpital Necker-Enfants Malades, Paris, France
  4. 4 2nd Department of Pediatrics, Unit of Pediatric Rheumatology-Immunology, Semmelweis University, Budapest, Hungary
  5. 5 Department of Pediatric Immunology and Rheumatology, Wilhelmina Children’s Hospital, Utrecht, The Netherlands
  6. 6 Department of General Paediatrics, Asklepios Klinik Sankt Augustin, Sankt Augustin, Germany
  7. 7 Department of Paediatric and Adolescents Medicine, Medical Faculty, University Hospital of Cologne, Cologne, Germany
  8. 8 Department of Pediatric Rheumatology, Cerrahpasa Medical School, Istanbul University, Istanbul, Turkey
  9. 9 Pediatric Rheumatology, The University of Toronto and Hospital for Sick Children, Toronto, Ontario, Canada
  10. 10 Pediatric Rheumatology, Unidad de Reumatología Pediátrica, Esplugues de Llobregat, Hospital Sant Joan de Déu, Universitat de Barcelona, Barcelona, Spain
  11. 11 Pediatrics, Kaplan Medical Center, Rehovot, Israel
  12. 12 Klinik und Poliklinik für Kinder- und Jugendmedizin, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
  13. 13 Clinica Pediatrica De Marchi, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milano, Italy
  14. 14 Unidad de Reumatología, Hospital General de Niños Pedro de Elizalde, Buenos Aires, Argentina
  15. 15 Service de néphrologie et rhumatologie pédiatrique, Hôpital Universitaire femme mère enfant, Groupement Hospitalier Est, Bron (Lyon), France
  16. 16 Pédiatrie I, Hôpital Universitaire Hautepierre, Strasbourg, France
  17. 17 Newcastle University and Newcastle Hospitals NHS Foundation Trust, Great North Children’s Hospital, Newcastle Upon Tyne, UK
  18. 18 Universitätsklinikum Münster, Klinik für Pädiatrische Rheumatologie und Immunologie, Münster, Germany
  19. 19 Centro de estudos em terapias inovadoras, Hospital de Clínicas da UFPR, Curitiba, Brazil
  20. 20 Department of Pediatric Rheumatology Berlin, Helios Kliniken Berlin-Buch, Children‘s Hospital, Berlin, Germany
  21. 21 Department of Paediatric Rheumatology, Bristol Royal Hospital for Children & Royal National Hospital for Rheumatic Diseases, Bristol, UK
  22. 22 Department of Pediatrics, Division of Pediatric Rheumatology, Dokuz Eylül University Medical Faculty, Balcova, Izmir, Turkey
  23. 23 Biometrical Practice BIOP, Basel, Switzerland
  24. 24 Global Clinical Development, Immunology and Dermatology, Novartis Pharma AG, Basel, Switzerland
  25. 25 Direzione Scientifica, IRCCS Istituto Giannina Gaslini, Genoa, Italy
  1. Correspondence to Dr Nicolino Ruperto, Clinica Pediatrica e Reumatologia, PRINTO, Istituto G. Gaslini, Genova 16147, Italy; nicolaruperto{at}gaslini.org

Abstract

Objectives To evaluate the long-term efficacy and safety of canakinumab in patients with active systemic juvenile idiopathic arthritis (JIA).

Methods Patients (2–19 years) entered two phase III studies and continued in the long-term extension (LTE) study. Efficacy assessments were performed every 3 months, including adapted JIA American College of Rheumatology (aJIA-ACR) criteria, Juvenile Arthritis Disease Activity Score (JADAS) and ACR clinical remission on medication criteria (CRACR). Efficacy analyses are reported as per the intent-to-treat population.

Results 144 of the 177 patients (81%) enrolled in the core study entered the LTE. Overall, 75 patients (42%) completed and 102 (58%) discontinued mainly for inefficacy (63/102, 62%), with higher discontinuation rates noted in the late responders group (n=25/31, 81%) versus early responders (n=11/38, 29%). At 2 years, aJIA-ACR 50/70/90 response rates were 62%, 61% and 54%, respectively. CRACR was achieved by 20% of patients at month 6; 32% at 2 years. A JADAS low disease activity score was achieved by 49% of patients at 2 years. Efficacy results were maintained up to 5 years. Of the 128/177 (72.3%) patients on glucocorticoids, 20 (15.6%) discontinued and 28 (22%) tapered to 0.150 mg/kg/day. Seven patients discontinued canakinumab due to CR. There were 13 macrophage activation syndrome (three previously reported) and no additional deaths (three previously reported). No new safety findings were observed.

Conclusion Response to canakinumab treatment was sustained and associated with substantial glucocorticoid dose reduction or discontinuation and a relatively low retention-on-treatment rate. No new safety findings were observed on long-term use of canakinumab.

Trial registration numbers NCT00886769, NCT00889863, NCT00426218 and NCT00891046.

  • canakinumab
  • clinical trial
  • interleukin-1β
  • long-term extension
  • systemic juvenile idiopathic arthritis.

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

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Footnotes

  • NR and HIB contributed equally.

  • Handling editor Josef S Smolen

  • Contributors The study was designed jointly by academic authors (NR, HIB, AM and DJL) and Novartis, with data collected by PRINTO/PRCSG investigators. The first and subsequent versions of the manuscript were written by NR and HIB, edited by AM and DJL and revised critically by all remaining coauthors. All authors attest to the completeness and veracity of data and data analyses. Consistency in reporting the study data to healthcare authorities and institutional review boards was ensured by Novartis. All authors had full access to study data, reviewed and revised the manuscript and approved the final version to be published. All authors were involved in the decision to submit the manuscript for publication and had the right to accept or reject comments or suggestions.

  • Funding This study was funded by Novartis Pharma.

  • Competing interests NR: consultant and speaker’s bureaus from AbbVie, Ablynx, Amgen, AstraZeneca, Baxalta Biosimilars, Biogen Idec, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli-Lilly, EMD Serono, Gilead Sciences, Janssen, MedImmune, Novartis, Pfizer, R-Pharm, Roche, Sanofi, Servier, Takeda; NR works as a full-time public employee of the public hospital Istituto Giannina Gaslini, which has received contributions from Bristol-Myers Squibb, Hoffman-La Roche, Janssen, Novartis, Pfizer, Sobi for the coordination activity of the PRINTO network. HIB: consultant: AstraZeneca, Bristol-Myers Squibb, Genentech, Janssen, Novartis, Pfizer, Sanofi, Takeda; speaker’s bureaus: Genentech, Novartis Pierre Quartier; has received consultant fees from Novimmune, Novartis and SOBI; has received speaker’s bureaus from Abbvie, BMS, Chugai-Roche, Lilly, Novartis, Pfizer and Sobi; has acted as coordinator or investigator in clinical trials for Abbvie, BMS, Chugai-Roche, Novartis, Sanofi, Sobi; has acted as member of a data monitoring board committee for Sanofi. NMW has received grant/research support from AbbVie; has received consultant fees from AbbVie, Sobi and Novartis. GH has received speaker’s bureaus from AbbVie, Boehringer Ingelheim, Chugai, MSD, Novartis, Pfizer, Roche and Sobi; has received scientific grants from AbbVie, Chugai, MSD, Novartis, Pfizer and Roche. OK has received speaker’s bureaus from Novartis, Roche, Pfizer and Abbvie. RS has received consultant fees from Novartis, Sobi and Novimmune. JLA has received consultant fees and speaker’s bureaus from AbbVie, Gebro, Novartis, Pfizer, Roche, Sanofi and Sobi. RC has received consultant fees and speaker’s bureaus from Bristol-Myers Squibb, Janssen, Novartis, Pfizer, Sanofi, Roche, Lilly and GlaxoSmithKline. HEF has acted as member of advisory boards for AbbVie, Novartis, Pfizer, Sanofi and Sobi; has received unrestricted educational bursaries from Pfizer, Genzyme, BioMarin and Sobi to develop educational resources for healthcare professionals. DF has received grant/research support from Pfizer and Novartis; has received consultant fees from Novartis, Pfizer, Chugai-Roche and Sobi; has received speaker’s bureaus from Novartis. SCR has received grants for clinical research from Novartis. AVR has received honoraria and participated in Advisory Boards for Novartis. RT has received lecture fees from Pfizer and Bristol-Myers Squibb. JL received fees from Novartis for conducting the statistical analysis. EV is an employee of Novartis Pharma, Basel, Switzerland. AM has no conflicts of interest to declare since March 2016 when he became the Scientific Director of the Istituto Giannina Gaslini, because this role does not allow him to render private consultancy resulting in personal income; consultant on behalf of the Istituto Giannina Gaslini: AbbVie, Boehringer, Novartis, R-Pharm. Istituto Giannina Gaslini has received contributions from Bristol-Myers Squibb, Hoffman-La Roche, Janssen, Novartis, Pfizer, Sobi for the coordination activity of the PRINTO network. DJL has received grant/research support from AbbVie, Bristol-Myers Squibb, NIH, Pfizer, Roche; speaker’s bureaus from Genentech; consultant of AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Genentech, GlaxoSmithKline, Janssen, Johnson & Johnson, Novartis, Takeda, UCB. EU, FC, JB, MF, MF-d, RB and TC have nothing to disclose.

  • Patient consent Parental/guardian consent obtained.

  • Ethics approval The study was conducted in accordance with the Declaration of Helsinki, the International Conference on Harmonisation Guidelines for Good Clinical Practice and local regulations. An institutional review board or independent ethics committee at each site approved the protocol, consent form and any other written information provided to patients or their legal representatives.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement All data generated or analysed are included in this article and the supplementary information files.

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