Canakinumab treatment for recent-onset type 1 diabeties mellitus: a multicenter randomized, placebo-controlled trial

Background: Blocking the action of the pro-inflammatory cytokine interleukin-1 (IL-1) reduces beta-cell secretory dysfunction and apoptosis in vitro, diabetes incidence in animal models of Type 1 diabetes mellitus (T1D), and glycaemia via improved beta-cell function in patients with T2D. We hypothesised that canakinumab, a monoclonal antibody to IL-1B, improves beta-cell function in patients with new-onset T1D. Methods: In an individually randomised, two-group parallel trial involving 12 sites in US, 69 patients aged 6-45 with T1D, < 12 weeks of symptoms, and assigned by centralised computer-generated blocked randomisation with locked computer-file concealment to treatment with 2 mg/kg (maximum 300 mg) canakinumab (n=45) or placebo (n=22) monthly for 12 months as add-on to conventional therapy. Participants and care-givers, but not data monitoring unit, were masked to group assignment. The primary end-point was change in the two-hour area-under-the-curve C-peptide response to MMT 12 months. Transcriptional signatures were induced in healthy cryopreserved human donor peripheral blood mononuclear cells (UPN727) through exposure to 40% subject serum in a 9 hour co-culture. Sixty-Three randomly selected subjects (43 Canakinumab treatment; 20 placebo treatment) were analysed blindedly to treatment assignment. The statistical significance of differential gene expression was determined through ANalysis Of VAriation (ANOVA) and false discovery rates (FDR) using Partek Genomics Suite 6.5.