Dataset Information

Sirukumab, a human anti-interleukin-6 monoclonal antibody: a randomised, 2-part (proof-of-concept and dose-finding), phase II study in patients with active rheumatoid arthritis despite methotrexate therapy.

ABSTRACT:

Objectives

The safety and efficacy of sirukumab, an anti-interleukin-6 (IL-6) monoclonal antibody, were evaluated in a 2-part, placebo-controlled phase II study of patients with active rheumatoid arthritis (RA) despite methotrexate therapy.

Methods

In Part A (proof-of-concept), 36 patients were randomised to placebo or sirukumab 100 mg every 2 weeks (q2w) through week 10, with crossover treatment during weeks 12-22. In Part B (dose finding), 151 patients were randomised to sirukumab (100 mg q2w, 100 mg q4w, 50 mg q4w, or 25 mg q4w) through week 24, or placebo through week 10 with crossover to sirukumab 100 mg q2w (weeks 12-24). The proportion of patients with an American College of Rheumatology 50 (ACR50) response and the change from baseline in the 28-joint count disease activity score using C-reactive protein (DAS28-CRP) were determined. Safety was evaluated through week 38 in both parts.

Results

The primary endpoint (ACR50 at week 12 in Part B) was achieved only with sirukumab 100 mg q2w versus placebo (26.7% vs 3.3%; p=0.026). Greater improvements in mean DAS28-CRP at week 12 were observed with sirukumab 100 mg q2w versus placebo in Parts A (2.1 vs 0.6, p<0.001) and B (2.2 vs 1.1; p<0.001). The incidence of adverse events (AEs) was similar for sirukumab-treated and placebo-treated patients through week 12 in Part A (70.6% and 63.2%, respectively) and B (67.8% and 66.7%, respectively). Infections were the most common type of AE; one death occurred (Part B, sirukumab 100 mg q2w, brain aneurysm).

Conclusions

Sirukumab-treated patients experienced improvements in the signs/symptoms of RA. Safety results through 38 weeks were consistent with other IL-6 inhibitors.

Trial registration number

NCT00718718.

SUBMITTER: Smolen JS

PROVIDER: S-EPMC4145446 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Sirukumab, a high-affinity human monoclonal antibody that selectively binds to interleukin-6, has demonstrated efficacy in the treatment of rheumatoid arthritis (RA) in global phase 1 and phase 2 studies. The present study evaluated the safety and efficacy of sirukumab, as monotherapy in Japanese patients with RA refractory to methotrexate or sulfasalazine. METHODS:In this phase 3, double-blind study, 122 patients (age ? 20 years) were randomized (1:1, 61 patients in each arm) to sirukumab administered subcutaneously: 50 mg once every 4 weeks (q4w) or 100 mg once every 2 weeks (q2w) through 52 weeks. Disease-modifying anti-rheumatic drugs were allowed after 24 weeks. Safety was assessed and efficacy was evaluated using American College of Rheumatology (ACR) responses, Disease Activity Score C-reactive protein (DAS28-CRP) and Health Assessment Questionnaire-Disability Index (HAQ-DI). RESULTS:Amongst the 122 randomized patients, 99 (81.1%) patients completed the study. Adverse events (AEs) were reported in 114/122 (93.4%) patients and serious AEs were reported in 9/122 (7.4%) patients. No deaths, major cardiovascular AEs, serious gastrointestinal perforations or tuberculosis cases were reported during this study period. Grade 3 hematologic abnormalities (neutropenia and leukopenia) were reported in seven patients and no grade 4 abnormalities were observed. ACR20 responses were observed within 2 weeks, achieved in 47/61 (77.0%, 50 mg q4w) patients and 44/61 (72.1%, 100 mg q2w) patients at week 16 and maintained through week 52. ACR50/70, DAS28-CRP and HAQ-DI responses were also maintained through week 52 in both groups. CONCLUSIONS:Safety findings were comparable between the two treatment groups. The 52-week administration of sirukumab at 50 mg q4w and 100 mg q2w was generally tolerable and with measurable efficacy in Japanese patients with RA refractory to methotrexate and sulfasalazine. TRIAL REGISTRATION:NCT01689532 . Registered 18 September 2012.