Tapering Canakinumab Monotherapy in Patients With Systemic Juvenile Idiopathic Arthritis in Clinical Remission: Results From a Phase IIIb/IV Open-Label, Randomized Study
Pierre Quartier, Ekaterina Alexeeva, Tamàs Constantin, Vyacheslav Chasnyk, Nico Wulffraat, Karin Palmblad, Carine Wouters, Hermine I Brunner, Katherine Marzan, Rayfel Schneider, Gerd Horneff, Alberto Martini, Jordi Anton, Xiaoling Wei, Alan Slade, Nicolino Ruperto, Ken Abrams, Paediatric Rheumatology International Trials Organisation and the Pediatric Rheumatology Collaborative Study Group, W Emminger, A Ulbrich, S Fodor, C Wouters, L Desomer, B Lauwerys, B Brichard, C Boulanger, G Levy, L Goffin, P-Q Le, M Bandeira, C Feitosa Pelajo, S Knupp Feitosa, C Costa, M Felix Rodrigues, C Almeida da Silva, L Mattei de, K Kozu, Ronald Laxer, K Houghton, L Tucker, K Morishita, A Mogenet, R Mouy, B Bader Meunier, C Meyzer, M Semeraro, O Ben-Brahim, I Kone-Paut, C Galeotti, L Rossi, P Dusser, B Cherquaoui, A Belot, A Duquesne, F Caroline, L Audrey, M Desjonqueres, I Foeldvari, A Kienast, B Willig, E Weissbarth-Riedel, A Froehlich, D Barthel, J Peitz, S Wintrich, T Geikowski, A Schulz, M Hufnagel, M Hirdes, R Kubicki, J Kirschner, A Janda, A Jacob, C Emerich, A Raab, G Ngoumou, K Minden, M Lieber, S-L von Stuckrad, R Trauzeddel, D Haselbusch, H Kolbeck, J Kuemmerle Deschner, S Hansmann, T Schleich, I Magunia, J Riethmuller, N Anders, H Lehmann, J de Laffolie, T Lutz, J Grulich-Henn, J Pfeil, A Helling-Bakki, A Ponyi, D Garan, I Orban, K Sevcic, Y Butbul, R Brik, M Helo, P Hashkes, O Toker, R Haviv, Y Uziel, R Haviv, V Moshe, M Rothschild, L Harel, G Amarilyo, R Tal, M Said, I Tirosh, S Spielman, M Gerstein, A Ravelli, B Schiappapietra, G Varnier, M Finetti, M Marasini, R Caorsi, S Rosina, S Federici, I Pontikaki, P Meroni, V Gerloni, N Ughi, T Ubiali, M Alessio, R Della Casa, S Vastert, J Swart, A van Royen-Kerhof, E Schatorje, G Van Iperen-Schutte, L Rutkowska-Sak, I Szczygielska, M Kwiatkowska, M Marusak-Banacka, P Gietka, K Isaeva, R Denisova, L Snegireva, M Dubko, M Kostik, N Buchinskaia, O Kalashnikova, S Avrusin, V Masalova, E Nunez Cuadros, G Diez, R Galindo Zavala, R Bou Torrent, E Iglesias, J Calzada, V Bittermann, A Boteanu, M L Gamir, D Clemente Garulo, J C Lopez Robledillo, R Merino, R Alcobendas, A Remesal, S Murias, I Calvo, B Lopez, I Gonzalez, L Fernandez, Bo Magnusson, O Kasapcopur, K Barut, A Adrovic, S Sahin, M Erguven, R Gozdenur Savci, S Ozen, S Demir, Y Bilginer, Z S Avci, E D Batu, Andreas Reiff, Anusha Ramanatham, Diana Brown, Bracha Shaham, Shirley Parks, Michal Cidon, G Higgins, C Spencer, J Rossette, K Jones, S Bout Tabaku, S Farley, S Akoghlanian, Pierre Quartier, Ekaterina Alexeeva, Tamàs Constantin, Vyacheslav Chasnyk, Nico Wulffraat, Karin Palmblad, Carine Wouters, Hermine I Brunner, Katherine Marzan, Rayfel Schneider, Gerd Horneff, Alberto Martini, Jordi Anton, Xiaoling Wei, Alan Slade, Nicolino Ruperto, Ken Abrams, Paediatric Rheumatology International Trials Organisation and the Pediatric Rheumatology Collaborative Study Group, W Emminger, A Ulbrich, S Fodor, C Wouters, L Desomer, B Lauwerys, B Brichard, C Boulanger, G Levy, L Goffin, P-Q Le, M Bandeira, C Feitosa Pelajo, S Knupp Feitosa, C Costa, M Felix Rodrigues, C Almeida da Silva, L Mattei de, K Kozu, Ronald Laxer, K Houghton, L Tucker, K Morishita, A Mogenet, R Mouy, B Bader Meunier, C Meyzer, M Semeraro, O Ben-Brahim, I Kone-Paut, C Galeotti, L Rossi, P Dusser, B Cherquaoui, A Belot, A Duquesne, F Caroline, L Audrey, M Desjonqueres, I Foeldvari, A Kienast, B Willig, E Weissbarth-Riedel, A Froehlich, D Barthel, J Peitz, S Wintrich, T Geikowski, A Schulz, M Hufnagel, M Hirdes, R Kubicki, J Kirschner, A Janda, A Jacob, C Emerich, A Raab, G Ngoumou, K Minden, M Lieber, S-L von Stuckrad, R Trauzeddel, D Haselbusch, H Kolbeck, J Kuemmerle Deschner, S Hansmann, T Schleich, I Magunia, J Riethmuller, N Anders, H Lehmann, J de Laffolie, T Lutz, J Grulich-Henn, J Pfeil, A Helling-Bakki, A Ponyi, D Garan, I Orban, K Sevcic, Y Butbul, R Brik, M Helo, P Hashkes, O Toker, R Haviv, Y Uziel, R Haviv, V Moshe, M Rothschild, L Harel, G Amarilyo, R Tal, M Said, I Tirosh, S Spielman, M Gerstein, A Ravelli, B Schiappapietra, G Varnier, M Finetti, M Marasini, R Caorsi, S Rosina, S Federici, I Pontikaki, P Meroni, V Gerloni, N Ughi, T Ubiali, M Alessio, R Della Casa, S Vastert, J Swart, A van Royen-Kerhof, E Schatorje, G Van Iperen-Schutte, L Rutkowska-Sak, I Szczygielska, M Kwiatkowska, M Marusak-Banacka, P Gietka, K Isaeva, R Denisova, L Snegireva, M Dubko, M Kostik, N Buchinskaia, O Kalashnikova, S Avrusin, V Masalova, E Nunez Cuadros, G Diez, R Galindo Zavala, R Bou Torrent, E Iglesias, J Calzada, V Bittermann, A Boteanu, M L Gamir, D Clemente Garulo, J C Lopez Robledillo, R Merino, R Alcobendas, A Remesal, S Murias, I Calvo, B Lopez, I Gonzalez, L Fernandez, Bo Magnusson, O Kasapcopur, K Barut, A Adrovic, S Sahin, M Erguven, R Gozdenur Savci, S Ozen, S Demir, Y Bilginer, Z S Avci, E D Batu, Andreas Reiff, Anusha Ramanatham, Diana Brown, Bracha Shaham, Shirley Parks, Michal Cidon, G Higgins, C Spencer, J Rossette, K Jones, S Bout Tabaku, S Farley, S Akoghlanian
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) 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.
Trial registration: ClinicalTrials.gov NCT02296424.
© 2020 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.
Figures
References
- Petty RE, Southwood TR, Manners P, Baum J, Glass DN, Goldenberg J, et al. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol 2004;31:390–2.
- Prakken B, Albani S, Martini A. Juvenile idiopathic arthritis. Lancet 2011;377:2138–49.
- Ravelli A, Martini A. Juvenile idiopathic arthritis. Lancet 2007;369:767–78.
- Martini A, Ravelli A, di Fuccia G, Rosti V, Cazzola M, Barosi G. Intravenous iron therapy for severe anaemia in systemic‐onset juvenile chronic arthritis. Lancet 1994;344:1052–4.
- Consolaro A, Giancane G, Alongi A, van Dijkhuizen EH, Aggarwal A, al‐Mayouf SM, et al. Phenotypic variability and disparities in treatment and outcomes of childhood arthritis throughout the world: an observational cohort study. Lancet Child Adolesc Heal 2019;3:255–63.
- Vastert SJ, Kuis W, Grom AA. Systemic JIA: new developments in the understanding of the pathophysiology and therapy. Best Pract Res Clin Rheumatol 2009;23:655–64.
- Pascual V, Allantaz F, Arce E, Punaro M, Banchereau J. Role of interleukin‐1 (IL‐1) in the pathogenesis of systemic onset juvenile idiopathic arthritis and clinical response to IL‐1 blockade. J Exp Med 2005;201:1479–86.
- Ruperto N, Brunner HI, Quartier P, Constantin T, Wulffraat NM, Horneff G, et al. 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. Ann Rheum Dis 2018;77:1710–9.
- Ruperto N, Quartier P, Wulffraat N, Woo P, Ravelli A, Mouy R, et al. A phase II, multicenter, open‐label study evaluating dosing and preliminary safety and efficacy of canakinumab in systemic juvenile idiopathic arthritis with active systemic features. Arthritis Rheum 2012;64:557–67.
- Ruperto N, Brunner HI, Quartier P, Constantin T, Wulffraat N, Horneff G, et al. Two randomized trials of canakinumab in systemic juvenile idiopathic arthritis. N Engl J Med 2012;367:2396–406.
- Quartier P, Allantaz F, Cimaz R, Pillet P, Messiaen C, Bardin C, et al. A multicentre, randomised, double‐blind, placebo‐controlled trial with the interleukin‐1 receptor antagonist anakinra in patients with systemic‐onset juvenile idiopathic arthritis (ANAJIS trial). Ann Rheum Dis 2011;70:747–54.
- De Benedetti F, Brunner HI, Ruperto N, Kenwright A, Wright S, Calvo I, et al. Randomized trial of tocilizumab in systemic juvenile idiopathic arthritis. N Engl J Med 2012;367:2385–95.
- Ruperto N, Martini A. Current and future perspectives in the management of juvenile idiopathic arthritis. Lancet Child Adolesc Heal 2018;2:360–70.
- Ter Haar NM, van Dijkhuizen EH, Swart JF, van Royen‐Kerkhof A, el Idrissi A, Leek AP, et al. Treatment to target using recombinant interleukin‐1 receptor antagonist as first‐line monotherapy in new‐onset systemic juvenile idiopathic arthritis: results from a five‐year follow‐up study. Arthritis Rheumatol 2019;71:1163–73.
- Quartier P, Taupin P, Bourdeaut F, Lemelle I, Pillet P, Bost M, et al. Efficacy of etanercept for the treatment of juvenile idiopathic arthritis according to the onset type. Arthritis Rheum 2003;48:1093–101.
- Horneff G, Schmeling H, Biedermann T, Foeldvari I, Ganser G, Girschick HJ, et al. The German etanercept registry for treatment of juvenile idiopathic arthritis. Ann Rheum Dis 2004;63:1638–44.
- Ravelli A, Consolaro A, Horneff G, Laxer RM, Lovell DJ, Wulffraat NM, et al. Treating juvenile idiopathic arthritis to target: recommendations of an international task force. Ann Rheum Dis 2018;77:819–28.
- Magnani A, Pistorio A, Magni‐Manzoni S, Falcone A, Lombardini G, Bandeira M, et al. Achievement of a state of inactive disease at least once in the first 5 years predicts better outcome of patients with polyarticular juvenile idiopathic arthritis. J Rheumatol 2009;36:628–34.
- Vannucci G, Cantarini L, Giani T, Marrani E, Moretti D, Pagnini I, et al. Glucocorticoids in the management of systemic juvenile idiopathic arthritis. Pediatr Drugs 2013;15:343–9.
- Guzman J, Kerr T, Ward LM, Ma J, Oen K, Rosenberg AM, et al. Growth and weight gain in children with juvenile idiopathic arthritis: results from the ReACCh‐Out cohort. Pediatr Rheumatol 2017;15:68.
- Lovell DJ, Giannini EH, Reiff AO, Kimura Y, Li S, Hashkes PJ, et al. Long‐term safety and efficacy of rilonacept in patients with systemic juvenile idiopathic arthritis. Arthritis Rheum 2013;65:2486–96.
- Wallace CA, Ruperto N, Giannini E, on behalf of the Childhood Arthritis and Rheumatology Research Alliance, Pediatric Rheumatology International Trials Organization, and the Pediatric Rheumatology Collaborative Study Group . Preliminary criteria for clinical remission for select categories of juvenile idiopathic arthritis. J Rheumatol 2004;31:2290–4.
- Brunner HI, Lovell DJ, Finck BK, Giannini EH. Preliminary definition of disease flare in juvenile rheumatoid arthritis. J Rheumatol 2002;29:1058–64.
- Brunner HI, Rider LG, Kingsbury DJ, Co D, Schneider R, Goldmuntz E, et al. Pediatric Rheumatology Collaborative Study Group: over four decades of pivotal clinical drug research in pediatric rheumatology [review]. Pediatr Rheumatol Online J 2018;16:45.
- Ruperto N, Martini A. Networking in paediatrics: the example of the Paediatric Rheumatology International Trials Organisation (PRINTO). Arch Dis Child 2011;96:596–601.
- Sun H, Van LM, Floch D, Jiang X, Klein UR, Abrams K, et al. Pharmacokinetics and pharmacodynamics of canakinumab in patients with systemic juvenile idiopathic arthritis. J Clin Pharmacol 2016;56:1516–27.
- Giannini EH, Ruperto N, Ravelli A, Lovell DJ, Felson DT, Martini A. Preliminary definition of improvement in juvenile arthritis. Arthritis Rheum 1997;40:1202–9.
- Consolaro A, Bracciolini G, Ruperto N, Pistorio A, Magni‐Manzoni S, Malattia C, et al. Remission, minimal disease activity, and acceptable symptom state in juvenile idiopathic arthritis: defining criteria based on the juvenile arthritis disease activity score. Arthritis Rheum 2012;64:2366–74.
- Consolaro A, Ruperto N, Bracciolini G, Frisina A, Gallo MC, Pistorio A, et al. Defining criteria for high disease activity in juvenile idiopathic arthritis based on the Juvenile Arthritis Disease Activity Score. Ann Rheum Dis 2014;73:1380–3.
- Consolaro A, Ruperto N, Bazso A, Pistorio A, Magni‐Manzoni S, Filocamo G, et al. Development and validation of a composite disease activity score for juvenile idiopathic arthritis. Arthritis Care Res 2009;61:658–66.
- Ruperto N, Ravelli A, Pistorio A, Malattia C, Cavuto S, Gado‐West L, et al. Cross‐cultural adaptation and psychometric evaluation of the Childhood Health Assessment Questionnaire (CHAQ) and the Child Health Questionnaire (CHQ) in 32 countries: review of the general methodology. Clin Exp Rheumatol 2001;19:S1–9.
- Nordal EB, Zak M, Aalto K, Berntson L, Fasth A, Herlin T, et al. Validity and predictive ability of the juvenile arthritis disease activity score based on CRP versus ESR in a Nordic population‐based setting. Ann Rheum Dis 2012;71:1122–7.
- McErlane F, Beresford MW, Baildam EM, Chieng SEA, Davidson JE, Foster HE, et al. Validity of a three‐variable Juvenile Arthritis Disease Activity Score in children with new‐onset juvenile idiopathic arthritis. Ann Rheum Dis 2013;72:1983–8.
- Vastert SJ, de Jager W, Noordman BJ, Holzinger D, Kuis W, Prakken BJ, et al. Effectiveness of first‐line treatment with recombinant interleukin‐1 receptor antagonist in steroid‐naive patients with new‐onset systemic juvenile idiopathic arthritis: results of a prospective cohort study. Arthritis Rheumatol 2014;66:1034–43.
- Grom AA, Ilowite NT, Pascual V, Brunner HI, Martini A, Lovell D, et al. Rate and clinical presentation of macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis treated with canakinumab. Arthritis Rheumatol 2016;68:218–28.
- Committee for Medicinal Products for Human Use . Guideline on immunogenicity assessment of therapeutic proteins. URL: . European Medicines Agency. May 2017.
- Schulz KF, Altman DG, Moher D, on behalf of the CONSORT Group . CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. BMC Med 2010;8:18.
- Foell D, Wulffraat N, Wedderburn LR, Wittkowski H, Frosch M, Gerss J, et al. Methotrexate withdrawal at 6 vs 12 months in juvenile idiopathic arthritis in remission: a randomized clinical trial. JAMA 2010;303:1266–73.
- Lovell DJ, Johnson AL, Huang B, Gottlieb BS, Morris PW, Kimura Y, et al. Risk, timing, and predictors of disease flare after discontinuation of anti–tumor necrosis factor therapy in children with polyarticular forms of juvenile idiopathic arthritis with clinically inactive disease. Arthritis Rheumatol 2018;70:1508–18.
Source: PubMed