Efficacy and Safety of Tocilizumab for Polyarticular-Course Juvenile Idiopathic Arthritis in the Open-Label Two-Year Extension of a Phase III Trial

Abstract

Objective: To report the 2-year efficacy and safety of tocilizumab (TCZ) in patients with polyarticular-course juvenile idiopathic arthritis (JIA).

Methods: Patients ages 2-17 years with active polyarticular-course JIA, in whom treatment with methotrexate was unsuccessful, received 16 weeks of open-label intravenous TCZ in part 1 (once every 4 weeks: 8 mg/kg or 10 mg/kg for body weight [BW] <30 kg; 8 mg/kg for BW ≥30 kg). Assessments were based on the JIA-American College of Rheumatology (ACR) response (defined as percentage of improvement in ≥3 of the 6 JIA core response variables [CRVs]). Patients with at least a JIA-ACR30 response (defined as ≥30% improvement in ≥3 of the 6 JIA CRVs without worsening in >1 of the remaining JIA CRVs by >30%) at week 16 were randomly assigned (1:1) to receive TCZ or placebo in part 2. Patients remained in part 2 until either week 40 or the occurrence of JIA flare. Upon starting part 3, all patients received open-label TCZ. At week 104 of the study, efficacy was assessed using JIA-ACR50/70/90 response rates (defined as 50%, 70%, or 90% improvement, respectively), achievement of inactive disease, and the Juvenile Arthritis Disease Activity Score in 71 joints (JADAS-71). Safety was assessed in the all-exposure population per 100 patient-years of exposure.

Results: Overall, 188 patients entered part 1, 166 patients entered part 2, and 160 patients entered part 3. By week 104, among the 188 patients in the modified intent-to-treat group who received TCZ, JIA-ACR50/70/90 response rates were 80.3%/77.1%/59.6%, respectively, the median JADAS-71 score decreased from 3.6 at week 40 to 0.7 at week 104, 51.1% of patients had achieved inactive disease, and 31 of 66 patients who had been receiving glucocorticoids discontinued them. Adverse event (AE) and serious AE rates were 406.5 per 100 patient-years and 11.1 per 100 patient-years, respectively. The infection rate was 151.4 per 100 patient-years, and the serious infection rate was 5.2 per 100 patient-years.

Conclusion: Patients treated with TCZ for polyarticular-course JIA showed high-level disease control for up to 2 years. The TCZ safety profile was consistent with that previously reported.

Figure 1

Summary of juvenile idiopathic arthritis (JIA) patient disposition in the modified intent‐to‐treat (mITT) population. The mITT population for reporting long‐term efficacy was defined as all enrolled patients who received ≥1 dose of tocilizumab (TCZ; n = 188). One patient randomly assigned to receive placebo (PBO) in part 2 withdrew while receiving TCZ 8 mg/kg in part 1; this patient was included among the patients randomly assigned to placebo who withdrew in part 2. * During part 3, 2 patients who had been randomly assigned to TCZ in part 2 withdrew due to adverse events, and 3 patients who had been randomly assigned to placebo in part 2 withdrew due to insufficient therapeutic response (n = 2) or refusal of treatment (n = 1). JIA‐ACR30 = ≥30% improvement in ≥3 of the 6 JIA core response variables defined by the American College of Rheumatology criteria; OL = open‐label.

Figure 2

Proportions of patients in the mITT population (n = 188) achieving JIA‐ACR50/70/90 responses (A) and inactive disease and clinical remission (B) through week 104. Responders achieved JIA‐ACR50/70/90 responses or inactive disease/remission relative to baseline. After week 40, patients who were not randomly assigned in part 2 because they did not achieve at least a JIA‐ACR30 response were included and considered nonresponders. Patients who withdrew due to non–safety‐related reasons were included as nonresponders. For patients who withdrew due to safety reasons, last observation carried forward (LOCF) was used. LOCF was applied to missing ACR core components at each visit. Inactive disease was defined as the absence of active joints, no fever or physical examination features (including active uveitis) attributable to polyarticular‐course JIA, a physician global visual analog scale score of ≤10 mm, and a normal erythrocyte sedimentation rate (<20 mm/hour). Clinical remission was defined as meeting the criteria for inactive disease at all visits in the 6 months before and including the assessment day. See Figure 1 for other definitions.

Figure 3

Median Juvenile Arthritis Disease Activity Score in 71 joints (JADAS‐71) in the long‐term extension (LTE) population (n = 163), according to study visit. All patients with a nonmissing assessment at each time point were included; there was no imputation for missing data. Last observation carried forward was used for missing core components. Dashed horizontal lines show inactive disease (JADAS‐71 <1) and low disease activity (JADAS‐71 <3.8).* The LTE population included all patients randomly assigned in part 2 who received ≥1 dose of tocilizumab (TCZ) either double‐blind or open‐label during parts 2 and 3 (25 patients who did not receive TCZ during parts 2 or 3 had no data from week 40 and were not included).

Figure 4

Proportion of patients in the mITT population (n = 188) with a JIA‐ACR70/90 response at weeks 40 and 104 based on previous biologic use (A), concomitant methotrexate (MTX) use (B), duration of disease (C), and rheumatoid factor (RF) status at baseline (D). Eight patients whose RF status at baseline was unknown were not included in the analsyis of RF status. See Figure 1 for other definitions.