The safety and efficacy of KINERET have been evaluated in three randomized, double-blind, placebo-controlled trials of 1790 patients ≥ 18 years of age with active rheumatoid arthritis (RA). An additional fourth study was conducted to assess safety. In the efficacy trials, KINERET was studied in combination with other disease-modifying antirheumatic drugs (DMARDs) other than Tumor Necrosis Factor (TNF) blocking agents (Studies 1 and 2) or as a monotherapy (Study 3).

Study 1 involved 899 patients with active RA who had been on a stable dose of methotrexate (MTX) (10 to 25 mg/week) for at least 8 weeks. All patients had at least 6 swollen/painful and 9 tender joints and either a C-reactive protein (CRP) of ≥ 1.5 mg/dL or an erythrocyte sedimentation rate (ESR) of ≥ 28 mm/hr. Patients were randomized to KINERET or placebo in addition to their stable doses of MTX. The first 501 patients were evaluated for signs and symptoms of active RA. The total 899 patients were evaluated for progression of structural damage.

Study 2 evaluated 419 patients with active RA who had received MTX for at least 6 months including a stable dose (15 to 25 mg/week) for at least 3 consecutive months prior to enrollment. Patients were randomized to receive placebo or one of five doses of KINERET subcutaneous daily for 12 to 24 weeks in addition to their stable doses of MTX.

Study 3 evaluated 472 patients with active RA and had similar inclusion criteria to Study 1 except that these patients had received no DMARD for the previous 6 weeks or during the study. Patients were randomized to receive either KINERET or placebo. Patients were DMARD-naïve or had failed no more than 3 DMARDs.

Study 4 was a placebo-controlled, randomized trial designed to assess the safety of KINERET in 1414 patients receiving a variety of concurrent medications for their RA including some DMARD therapies, as well as patients who were DMARD-free. The TNF blocking agents etanercept and infliximab were specifically excluded. Concurrent DMARDs included MTX, sulfasalazine, hydroxychloroquine, gold, penicillamine, leflunomide, and azathioprine. Unlike Studies 1, 2 and 3, patients predisposed to infection due to a history of underlying disease such as pneumonia, asthma, controlled diabetes, and chronic obstructive pulmonary disease (COPD) were also enrolled [see Adverse Reactions ( 6)] . 

In Studies 1, 2 and 3, the improvement in signs and symptoms of RA was assessed using the American College of Rheumatology (ACR) response criteria (ACR 20, ACR 50, ACR 70). In these studies, patients treated with KINERET were more likely to achieve an ACR 20or higher magnitude of response (ACR 50and ACR 70) than patients treated with placebo ( Table 3). The treatment response rates did not differ based on gender or ethnic group. The results of the ACR component scores in Study 1 are shown in Table 4. 

Most clinical responses, both in patients receiving placebo and patients receiving KINERET, occurred within 12 weeks of enrollment.

A 24-week study was conducted in 242 patients with active RA on background methotrexate who were randomized to receive either etanercept alone or the combination of KINERET and etanercept. The ACR 50response rate was 31% for patients treated with the combination of KINERET and etanercept and 41% for patients treated with etanercept alone, indicating no added clinical benefit of the combination over etanercept alone. Serious infections were increased with the combination compared to etanercept alone [see Warnings and Precautions ( 5.1)] . 

In Study 1, the effect of KINERET on the progression of structural damage was assessed by measuring the change from baseline at month 12 in the Total Modified Sharp Score (TSS) and its subcomponents, erosion score, and joint space narrowing (JSN) score. 2Radiographs of hands/wrists and forefeet were obtained at baseline, 6 months and 12 months and scored by readers who were unaware of treatment group. A difference between placebo and KINERET for change in TSS, erosion score (ES) and JSN score was observed at 12 months ( Table 5). 

The disability index of the Health Assessment Questionnaire (HAQ) was administered monthly for the first six months and quarterly thereafter during Study 1. Health outcomes were assessed by the Short Form-36 (SF-36) questionnaire. The 1-year data on HAQ in Study 1 showed more improvement with KINERET than placebo. The physical component summary (PCS) score of the SF-36 also showed more improvement with KINERET than placebo but not the mental component summary (MCS).