Treatment of rheumatoid arthritis with anakinra, a recombinant human interleukin‐1 receptor antagonist, in combination with methotrexate: Results of a twenty‐four–week, multicenter, randomized, double‐blind, placebo‐controlled trial

Abstract

Objective. To evaluate the efficacy and safety of anakinra in combination with methotrexate (MTX) in patients with active rheumatoid arthritis (RA).Methods. Patients with moderate-to-severe active RA who were receiving MTX for 6 consecutive months, with stable doses for >3 months (those with disease duration of >6 months but <12 years) were randomized into 6 groups: placebo or 0.04, 0.1, 0.4, 1.0, or 2.0 mg/kg of anakinra administered in a single, daily, subcutaneous injection. The primary efficacy end point was the proportion of subjects who met the American College of Rheumatology 20% improvement criteria (attained an ACR20 response) at week 12.Results. A total of 419 patients were randomized in the study. Patient demographics and disease status were similar in the 6 treatment groups. The ACR20 responses at week 12 in the 5 active treatment plus MTX groups demonstrated a statistically significant (P ‫؍‬ 0.001) dose-response relationship compared with the ACR20 response in the placebo plus MTX group. The ACR20 response rate in the anakinra 1.0-mg/kg (46%; P ‫؍‬ 0.001) and 2.0-mg/kg (38%; P ‫؍‬ 0.007) dose groups was significantly greater than that in the placebo group (19%). The ACR20 responses at 24 weeks were consistent with those at 12 weeks. Similar improvements in anakinra-treated subjects were noted in individual ACR components, erythrocyte sedimentation rate, onset of ACR20 response, sustainability of ACR20 response, and magnitude of ACR response. Anakinra was safe and well tolerated. Injection site reaction was the most frequently noted adverse event, and this led to premature study withdrawal in 7% (1.0-mg/kg group) to 10% (2.0-mg/kg group) of patients receiving higher doses.Conclusion. In patients with persistently active RA, the combination of anakinra and MTX was safe and well tolerated and provided significantly greater clinical benefit than MTX alone.

Anakinra, a recombinant human interleukin‐1 receptor antagonist (r‐metHuIL‐1ra), in patients with rheumatoid arthritis: A large, international, multicenter, placebo‐controlled trial

“…Other than ISRs, the most common adverse event was worsening of symptoms of RA, occurring in 223 anakinra patients (20% of those reporting adverse events) and 78 placebo patients (27.6% of those reporting adverse events). These adverse event rates are consistent with those observed in previous clinical studies of anakinra in patients with RA (24,25). In the anakinra group, the rate of ISRs was higher among Serious adverse events occurred at a similar frequency in the 2 treatment groups, with 86 patients in the anakinra group (7.7%) and 22 patients in the placebo group (7.8%) experiencing serious events.…”

“…The other notable difference between treatments was the occurrence of ISRs. There were significantly more ISRs in the anakinra group (72.6%) than in the placebo group (32.9%), an observation that is consistent with previous studies of anakinra (24,25) and other injected biologic agents (29)(30)(31)(32)(33) in the treatment of patients with RA. As in those studies, the ISRs observed in the present study were typically mild to moderate.…”

“…The results showed a very similar safety profile in both treatment groups. In addition, the safety observations from this study were similar to observations in other anakinra studies conducted in more restrictive patient populations (24,25). During the initial 6 months of the study, no treatment-related difference was apparent in the rates of adverse events (92.0% in the anakinra group versus 92.2% in the placebo group), serious adverse events (7.7% versus 7.8%), infections (41.2% versus 43.5%), discontinuation from the study due to adverse events (13.4% versus 9.2%), malignancy (0.4% versus 1.8%), or death (0.4% in both groups).…”

“…The unrestricted severity of patients' disease, use of background medications (excluding TNF inhibitors), and the wide range of comorbid conditions permitted are in notable contrast to the restrictions placed on these variables in typical efficacy studies used to gain approval of new therapies. Previous studies of anakinra have either excluded all concomitant DMARD use (24) or limited concomitant drug use to MTX (25). Studies of other recently introduced biologic response modifiers have had similar restrictions (29)(30)(31)(32)(33).…”

“…A recombinant form of human IL-1Ra, anakinra (recombinant methionyl human IL-1 receptor antagonist [r-metHuIL-1ra]), is a competitive antagonist of IL-1 that blocks the actions of IL-1 without any detectable agonist activity. In previously completed controlled clinical trials, anakinra provided significant symptomatic improvement when used as monotherapy or in combination with methotrexate (24,25). In addition, anakinra monotherapy slowed the radiographically observed progression of RA (24,26).…”