Pierre Quartier1, Ekaterina Alexeeva2, Tamàs Constantin3, Vyacheslav Chasnyk4, Nico Wulffraat5, Karin Palmblad6, Carine Wouters7, Hermine I Brunner8, Katherine Marzan9, Rayfel Schneider10, Gerd Horneff11, Alberto Martini12, Jordi Anton13, Xiaoling Wei14, Alan Slade15, Nicolino Ruperto16, Ken Abrams15. 1. RAISE Reference Centre for Rare Diseases, Necker-Enfants Malades, AP-HP, Imagine Institute, Paris University, Paris, France. 2. National Medical Research Center of Children's Health of the Ministry of Health of the Russian Federation, Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation, Moscow, Russia. 3. Semmelweis University, Budapest, Hungary. 4. Saint-Petersburg State Pediatric Medical University, Saint-Petersburg, Russian Federation. 5. University Medical Center Utrecht, Utrecht, The Netherlands. 6. Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden. 7. University Hospitals Leuven, Leuven, Belgium. 8. Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States. 9. Children's Hospital Los Angeles, Los Angeles, California, United States. 10. University of Toronto and Hospital for Sick Children, Toronto, Ontario, Canada. 11. Asklepios Klinik Sankt Augustin, and University Hospital Cologne, Sankt Augustin, Cologne, Germany. 12. Istituto Giannina Gaslini, IRCCS, Genoa, Italy. 13. Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain, and Universitat de Barcelona, Barcelona, Spain. 14. China Novartis Institutes for Biomedical Research, Ltd, Beijing, China. 15. Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, United States. 16. Clinica Pediatrica e Reumatologia, PRINTO, Istituto Giannina Gaslini, IRCCS, Genoa, Italy.
Abstract
OBJECTIVE: To evaluate the efficacy and safety of 2 canakinumab monotherapy tapering regimens in order to maintain complete clinical remission in children with systemic juvenile idiopathic arthritis (JIA). METHODS: The study was designed as a 2-part phase IIIb/IV open-label, randomized trial. In the first part, patients received 4 mg/kg of canakinumab subcutaneously every 4 weeks and discontinued glucocorticoids and/or methotrexate as appropriate. Patients in whom clinical remission was achieved (inactive disease for at least 24 weeks) withcanakinumab monotherapy were entered into the second part of the trial, in which they were randomized 1:1 into 1 of 2 treatment arms. In arm 1, the dose of canakinumab was reduced from 4 mg/kg to 2 mg/kg and then to 1 mg/kg, followed by discontinuation. In arm 2, the 4 mg/kg dose interval was prolonged from every 4 weeks, to every 8 weeks, and then to every 12 weeks, followed by discontinuation. In both arms, canakinumab exposure could be reduced provided systemic JIA remained in clinical remission for 24 weeks with each step. The primary objective was to assess whether >40% of randomized patients in either arm maintained clinical remission of systemic JIA for 24 weeks in the first part of the study. RESULTS: In part 1 of the study, 182 patients were enrolled, with 75 of those patients randomized before entering part 2 of the trial. Among the 75 randomized patients, clinical remission was maintained for 24 weeks in 27 (71%) of 38 patients in arm 1 (2 mg/kg every 4 weeks) and 31 (84%) of 37 patients in arm 2 (4 mg/kg every 8 weeks) (P ≤ 0.0001 for arm 1 versus arm 2 among those meeting the 40% threshold). Overall, 25 (33%) of 75 patients discontinued canakinumab, and clinical remission was maintained for at least 24 weeks in all 25 of these patients. No new safety signals were identified. CONCLUSION: Reduction of canakinumab exposure may be feasible in patients who have achieved clinical remission of systemic JIA, but consistent interleukin-1 inhibition appears necessary to maintain this response.
RCT Entities:
OBJECTIVE: To evaluate the efficacy and safety of 2 canakinumab monotherapy tapering regimens in order to maintain complete clinical remission in children with systemic juvenile idiopathic arthritis (JIA). METHODS: The study was designed as a 2-part phase IIIb/IV open-label, randomized trial. In the first part, patients received 4 mg/kg of canakinumab subcutaneously every 4 weeks and discontinued glucocorticoids and/or methotrexate as appropriate. Patients in whom clinical remission was achieved (inactive disease for at least 24 weeks) with canakinumab monotherapy were entered into the second part of the trial, in which they were randomized 1:1 into 1 of 2 treatment arms. In arm 1, the dose of canakinumab was reduced from 4 mg/kg to 2 mg/kg and then to 1 mg/kg, followed by discontinuation. In arm 2, the 4 mg/kg dose interval was prolonged from every 4 weeks, to every 8 weeks, and then to every 12 weeks, followed by discontinuation. In both arms, canakinumab exposure could be reduced provided systemic JIA remained in clinical remission for 24 weeks with each step. The primary objective was to assess whether >40% of randomized patients in either arm maintained clinical remission of systemic JIA for 24 weeks in the first part of the study. RESULTS: In part 1 of the study, 182 patients were enrolled, with 75 of those patients randomized before entering part 2 of the trial. Among the 75 randomized patients, clinical remission was maintained for 24 weeks in 27 (71%) of 38 patients in arm 1 (2 mg/kg every 4 weeks) and 31 (84%) of 37 patients in arm 2 (4 mg/kg every 8 weeks) (P ≤ 0.0001 for arm 1 versus arm 2 among those meeting the 40% threshold). Overall, 25 (33%) of 75 patients discontinued canakinumab, and clinical remission was maintained for at least 24 weeks in all 25 of these patients. No new safety signals were identified. CONCLUSION: Reduction of canakinumab exposure may be feasible in patients who have achieved clinical remission of systemic JIA, but consistent interleukin-1 inhibition appears necessary to maintain this response.
Authors: Alberto Martini; Daniel J Lovell; Salvatore Albani; Hermine I Brunner; Kimme L Hyrich; Susan D Thompson; Nicolino Ruperto Journal: Nat Rev Dis Primers Date: 2022-01-27 Impact factor: 65.038