Tapering Canakinumab Monotherapy in Patients With Systemic Juvenile Idiopathic Arthritis in Clinical Remission: Results From a Phase IIIb/IV Open-Label, Randomized Study

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.

Figure 1

Flow chart of the study design. Cohort 1 comprised patients with systemic juvenile idiopathic arthritis in complete clinical remission (CR) at the last visit of a previous long‐term extension trial of canakinumab (CAN) (ClinicalTrials.gov identifier: NCT00891046) (8). Patients in cohort 1 who were already receiving canakinumab monotherapy could enter directly into part 2 of the study. Cohort 2 comprised newly recruited patients with active disease at baseline. Patients in whom clinical remission was achieved with canakinumab monotherapy for at least 4 weeks in part 1 entered part 2 of the study (as long as the randomization period was still open). Patients in whom these criteria were not met, or in whom criteria were met after randomization was closed, remained in part 1 until study end. Randomization was only to achieve balance between the treatment arms as no comparison between the cohorts was planned. GC = glucocorticoid; MTX = methotrexate; q4w = every 4 weeks.

Figure 2

Flow chart of the study population. In total, 182 individuals entered the study, with 44 discontinuing the study and 138 completing it. Sixty‐three patients remained in part 1 until study end, and 72 patients completed part 2. After reaching the predefined population of 76 patients for part 2 (patients in whom clinical remission [CR] with canakinumab monotherapy was achieved without glucocorticoids [GCs] or methotrexate [MTX]), randomization enrollment was closed, and patients in whom clinical remission was achieved with canakinumab monotherapy after this time remained in part 1 of the study. Among the 62 patients who were not randomized and remained in part 1 until study end, protocol deviations were reported in 4 patients who were not randomized but progressed to the canakinumab tapering treatment arm, with 1 patient enrolled directly from the long‐term extension trial of canakinumab (ClinicalTrials.gov identifier: NCT00891046) (8) and receiving 1 dose according to the dose reduction scheme before discontinuing the study and 3 additional patients in part 1 progressing to the dose interval prolongation treatment arm. These patients were not included in the efficacy analyses of part 2. Y = yes; N = no.

Figure 3

Efficacy of canakinumab in part 1 of the study. A, Percentage of systemic juvenile idiopathic arthritis (JIA) patients with inactive disease (ID) following canakinumab monotherapy. Intent‐to‐treat (ITT) analysis of the full analysis set is shown, with imputation of missing data for nonresponders in the initial 24 weeks of part 1. For each time point, the percentage of patients with inactive disease who received canakinumab monotherapy (with treatment maintained until the end of part 1) is presented. Percentages were calculated from the total ITT population, which included patients who had received glucocorticoids and/or methotrexate. Values indicate percentages, and error bars show the 95% confidence intervals. Of note, no adjustment for multiple comparisons has been performed, and line graphs used are only for descriptive purposes. B, Median Juvenile Arthritis Disease Activity Scores in 27 joints using the C‐reactive protein level (JADAS27‐CRP) in cohorts 1 and 2 (n = 68 and n = 98, respectively). Numbers under the line graph represent the actual number of patients evaluated at each time point. Values indicate median scores, and error bars show the interval between the first and third quartiles. Horizontal lines represent the JADAS cutoff values for high disease activity (HDA) (>8.5), moderate disease activity (MDA) (3.9–8.5), low disease activity (LDA) (1.1–3.8), and inactive disease (≤1). Of note, these cutoff values have been defined for polyarticular JIA and have not been evaluated specifically in systemic JIA.

Figure 4

Proportion of patients in whom complete clinical remission (CR) of systemic juvenile idiopathic arthritis was maintained in part 2 of the study. Intent‐to‐treat (ITT) analysis of the full analysis set with imputation of missing data for nonresponders is shown. Values over bars indicate percentages, values within bars are the number of patients/total number assessed, and error bars show the 97.5% confidence intervals. Only patients in whom clinical remission was maintained for 24 weeks on the first attempt of dose reduction or dose interval prolongation of canakinumab (CAN) were categorized as responders. The proportion of patients in whom clinical remission was maintained in step 1 was significantly higher than the predefined 40% threshold (primary end point) for both treatment arms. No adjustment for multiple comparisons was performed for the remaining data shown, and therefore their presentation is only for descriptive purposes. q4w = every 4 weeks.