Efficacy and safety of tocilizumab in patients with polyarticular-course juvenile idiopathic arthritis
Tocilizumab treatment results in significant improvement maintained over time, of pcJIA signs and symptoms and have a safety profile consistent with that for adults with rheumatoid arthritis.
Juvenile idiopathic arthritis (JIA) is a heterogeneous group of chronic arthritis of unknown cause with an onset before 16 years of patient age. Substantial proportions of patients have polyarticular-course JIA (pcJIA) and are at risk for profound disability.
Juvenile idiopathic arthritis (JIA) is a heterogeneous group of chronic arthritides of unknown cause with an onset before 16 years of patient age. Substantial proportions of patients have polyarticular-course JIA (pcJIA) and are at risk for profound disability. Although these patients may respond to methotrexate (MTX) or biological agents approved for pcJIA, up to 30% continue to have active disease. Interleukin-6 (IL-6) is increased in the serum and synovial fluid of patients with pcJIA and correlated with the severity of joint involvement and with C-reactive protein (CRP) levels. Tocilizumab is a humanized, monoclonal, antihuman IL-6 receptor (IL-6R) antibody that binds to membrane and soluble IL-6R, inhibiting IL-6–mediated signaling.
- Rationale behind research
- Substantial proportions of patients have polyarticular-course JIA (pcJIA) and are at risk for profound disability.
- Although patients may respond to MTX or biological agents approved for pcJIA, up to 30% continue to have active disease.
To evaluate the efficacy and safety of tocilizumab in patients with active pcJIA and inadequate responses to MTX
- Primary outcome: The efficacy of proportion of patients with JIA- flare occurred in part two of the study (weeks 16–40).
- Secondary outcome: Evaluated at week 40 included JIA-ACR 30/50/70/90 responses, change from baseline in JIA-CRVs, adverse event (AE) and clinically inactive disease.
- Time points
- Efficacy: Baseline, week 2, week 4 and every 4 week up to 40 week
- Adverse events: Baseline, week 2, week 4 and every 4 week up to 40 week
Baseline: Baseline was similar across all groups, except to body weight based dosing regimen.
- Primary outcomes
- The primary end point at week 40 in part 2 was met, there were significantly more JIA-flares in the placebo group than in patients remaining on tocilizumab (39/81 (48.1%) vs. 21/82 (25.6%); adjusted difference in flare rate: −0.21; 95% CI−0.35 to −0.08;p=0.0024).
Figure 1: Patients with Juvenile Idiopathic Arthritis ACR 30 Flare
- Secondary outcomes
- The study part 1 was completed by 168 (89.4%) of 188 patients achieving JIA-ACR30 response. Higher-level JIA-ACR70 and JIA-ACR90 responses were attained by 117 (62.2%) of 188 and 49 (26.1%) of 188 patients, respectively. All six JIA-CRVs markedly improved from baseline to week 16. JIA-ACR30/50/70/90 response rates were numerically lower in the 8 mg/kg less than 30 kg group than in the other two groups.
- Overall, 159 (84.6%) patients reported at least one adverse event (AE). Rates of AEs/100 PY of exposure were similar across the three groups (8 mg/kg for 30 kg or more, 501.9; 10 mg/kg for less than 30 kg, 445.6; 8 mg/kg for less than 30 kg, 471.9). A total of 16 AEs in 16 (8.5%) patients were considered severe, and seven AEs led to study discontinuation.
Figure 2: Juvenile Idiopathic Arthritis ACR 30/70/90 Responses
Tocilizumab treatment provided sustained and clinically meaningful improvement for patients with pcJIA on monthly dosing of 8 mg/kg in patients weighing 30 kg or more and 10 mg/kg in patients weighing less than 30 kg. The safety profile of tocilizumab in this patient population was consistent with that seen in adults with RA.
This study allowed for the acquisition of data on the magnitude of the therapeutic effect of tocilizumab in patients with active pcJIA (part 1) and for the demonstration that this effect was indeed due to tocilizumab (part 2). The biological agent-naive patients experienced a lower incidence of flare regardless of assignation to tocilizumab or placebo. The concomitant use of MTX yielded fewer flare events, regardless of assignation to tocilizumab or placebo. The pattern of AEs observed in this study of patients with pcJIA is consistent with the known safety profile of tocilizumab reported in other phase 3 studies. Although the withdrawal design of this study was valuable in minimizing placebo treatment in children with pcJIA, it had potential limitations. Lead-in treatment of placebo patients with tocilizumab limited the ability to determine safety and efficacy differences over the limited withdrawal period, especially because the biological effects of tocilizumab might have endured beyond the time taken to clear the drug.