The multicenter, randomized, double-blind, placebo-controlled phase 3 SIRROUND-D trial demonstrated that sirukumab, a human monoclonal antibody that selectively binds to the interleukin-6 cytokine with high affinity, resulted in significant reduction in rheumatoid arthritis (RA) signs and symptoms, and inhibited radiographic progression at week 52 compared with placebo in patients with active RA despite disease-modifying antirheumatic drug (DMARD) treatment. This report presents long-term efficacy through week 104 of the SIRROUND-D trial, and safety through week 120.
In this phase 3 study, patients (n = 1670) were randomized to receive subcutaneous sirukumab 50 mg every 4 weeks, sirukumab 100 mg every 2 weeks, or placebo every 2 weeks. Eligible patients had moderate-to-severe active RA, as defined by ≥6/66 swollen and ≥6/68 tender joints and minimum C-reactive protein (CRP) ≥8.0 mg/L that was refractory to DMARDs. The study design allowed rerandomization of eligible patients on the placebo arm to receive sirukumab if they showed <20% improvement in swollen/tender joints at week 18 or 40 or still were receiving placebo at week 52. From weeks 52 to 104, sirukumab was administered in a blinded, active-controlled period, followed by a 16-week safety phase to week 120.
Efficacy outcomes were analyzed for patients on study treatment at week 52, and included American College of Rheumatology 20%/50%/70%/90% improvement criteria (ACR20/ACR50/ACR70/ACR90) responses, Disease Activity Score 28 (DAS28) CRP remission, Short Form-36 (SF-36) Health Survey Mental Component Score (MCS) and physical component summary (PCS) scores, and Health Assessment Questionnaire Disability Index (HAQ-DI). All patients who received ≥1 doses of sirukumab were assessed for treatment-emergent adverse events (AEs) and serious AEs.
A total of 1402 patients were included in the efficacy analyses from weeks 52 to 104 (at week 52: sirukumab, 944; placebo, 458). Baseline patient and disease characteristics were similar across treatment arms. Among patients originally randomized to sirukumab, a similar proportion of patients achieved ACR20/ACR50/ACR70/ACR90 responses and DAS28-CRP remissions at weeks 52 and 104. At week 104, the sirukumab-treated patients in each dose group maintained their ACR20 (90%) and ACR50 (79%) responses achieved at week 52. For each SF-36 MCS and PCS score and HAQ-DI outcome, the clinically meaningful improvements from baseline achieved were comparable at weeks 52 and 104. Among patients originally randomized to placebo who crossed over to sirukumab, week 104 responses were similar to those for patients originally randomized to sirukumab.
At week 120 follow-up, the safety analysis showed that the 2 sirukumab dose arms had similar incidences of AEs (50 mg every 4 weeks, 89.0%; 100 mg every 2 weeks, 88.2%) and serious AEs (50 mg every 4 weeks, 20.0%; 100 mg every 2 weeks, 17.4%). The most common AEs (≥10%) experienced by patients who received sirukumab treatment were elevated liver enzymes, upper respiratory tract infection, nasopharyngitis, and injection-site erythema; the most frequently reported serious AEs were infections and infestations.
The findings of this long-term analysis of the SIRROUND-D trial are consistent with the results of the primary analysis, and show that the improvements in signs and symptoms of RA and health-related physical and emotional well-being achieved with sirukumab treatment were maintained in patients with active RA despite DMARDs, without emergence of any new safety signals through week 120.
Thorne C, et al. ACR 2017. Abstract 1908.