A multicentre, double blind, randomised, placebo controlled trial of anakinra (Kineret), a recombinant interleukin 1 receptor antagonist, in patients with rheumatoid arthritis treated with background methotrexate

Abstract

Objective: To assess the efficacy and safety of 100 mg daily anakinra (Kineret), a recombinant form of the naturally occurring interleukin 1 receptor antagonist, plus methotrexate (MTX) in reducing the signs and symptoms of rheumatoid arthritis (RA).

Methods: Patients with active RA (n = 506) despite current treatment with MTX were enrolled in this multicentre, double blind, randomised, placebo controlled study. Patients received subcutaneous injections of anakinra 100 mg/day or placebo. They were assessed monthly for 6 months for improvement in signs and symptoms of RA and for adverse events. The primary efficacy measure was the percentage of patients attaining ACR20 response at week 24.

Results: Significantly greater proportions of patients treated with anakinra compared with placebo achieved ACR20 (38% v 22%; p<0.001), ACR50 (17% v 8%; p<0.01), and ACR70 (6% v 2%; p<0.05) responses. The response to anakinra was rapid; the proportion of patients with an ACR20 response at the first study assessment (4 weeks) was twice as high with anakinra as with placebo (p<0.005). Clinically meaningful and statistically significant responses were also seen in individual components of the ACR response (for example, Health Assessment Questionnaire, pain, C reactive protein levels, and erythrocyte sedimentation rate). Anakinra was well tolerated, with a safety profile, similar to that of placebo with one exception: mild to moderate injection site reactions were more common with anakinra than with placebo (65% v 24%).

Conclusions: This study confirms previous observations from a dose-ranging study showing that anakinra, in combination with MTX, is an effective and safe treatment for patients with RA who have inadequate responses to MTX alone.

Figure 1

(A) Proportions of patients in the anakinra (n = 250) and placebo (n = 251) groups with ACR20, ACR50, and ACR70 responses at the end of the 24 week study period. (B) Proportions of patients completing the study in the anakinra (n = 200) and placebo (n = 187) groups with ACR20 responses at the end of the 24 week study period. (C) Proportions of patients in the anakinra and placebo groups with an ACR20 response, by study week. (D) Proportions of patients in the placebo and anakinra groups with a sustained ACR20 response, defined as an ACR20 response in at least four of the six monthly assessments. Comparisons between study drugs shown as *p<0.05, **p<0.01, and ***p<0.001.

Figure 2

(A) Changes in physician assessment of patient disease activity in the anakinra (n = 250) and placebo (n = 251) groups, by study week. (B) Changes in swollen joint count in the anakinra (n = 250) and placebo (n = 251) groups. (C) Changes in tender/painful joint count in the anakinra (n = 250) and placebo (n = 251) groups. (D) Changes in patient perceptions of overall disease activity in the anakinra (n = 250) and placebo (n = 251) groups. (E) Changes in patient ratings of pain in the anakinra (n = 250) and placebo (n = 251) groups. (F) Changes in patient assessments of functional disability, as measured by the HAQ, in the anakinra (n = 250) and placebo (n = 251) groups. The dashed line indicates the minimal clinically important difference in score. Comparisons between study drugs is shown as *p<0.05, **p<0.01, and ***p<0.001.

Figure 3

(A) Log transformed changes in CRP levels in the anakinra (n = 250) and placebo (n = 251) groups at each study assessment. (B) Changes in ESR in the anakinra and placebo groups at each study assessment. Comparisons between study drugs shown as ***p<0.001.