Background Innate immunity contributes to the pathogenesis of autoimmune diseases, such as type 1 diabetes, but until now no randomised, controlled trials of blockade of the key innate immune mediator interleukin-1 have been done. We aimed to assess whether canakinumab, a human monoclonal anti-interleukin-1 antibody, or anakinra, a human interleukin-1 receptor antagonist, improved â-cell function in recent-onset type 1 diabetes. Methods We did two randomised, placebo-controlled trials in two groups of patients with recent-onset type 1 diabetes and mixed-meal-tolerance-test- stimulated C peptide of at least 0•2 nM. Patients in the canakinumab trial were aged 6-45 years and those in the anakinra trial were aged 18-35 years. Patients in the canakinumab trial were enrolled at 12 sites in the USA and Canada and those in the anakinra trial were enrolled at 14 sites across Europe. Participants were randomly assigned by computer-generated blocked randomisation to subcutaneous injection of either 2 mg/kg (maximum 300 mg) canakinumab or placebo monthly for 12 months or 100 mg anakinra or placebo daily for 9 months. Participants and carers were masked to treatment assignment. The primary endpoint was baseline-adjusted 2-h area under curve C-peptide response to the mixed meal tolerance test at 12 months (canakinumab trial) and 9 months (anakinra trial). Analyses were by intention to treat. These studies are registered with ClinicalTrials.gov, numbers NCT00947427 and NCT00711503, and EudraCT number 2007-007146-34. Findings Patients were enrolled in the canakinumab trial between Nov 12, 2010, and April 11, 2011, and in the anakinra trial between Jan 26, 2009, and May 25, 2011. 69 patients were randomly assigned to canakinumab (n=47) or placebo (n=22) monthly for 12 months and 69 were randomly assigned to anakinra (n=35) or placebo (n=34) daily for 9 months. No interim analyses were done. 45 canakinumab-treated and 21 placebo-treated patients in the canakinumab trial and 25 anakinra-treated and 26 placebo-treated patients in the anakinra trial were included in the primary analyses. The difference in C peptide area under curve between the canakinumab and placebo groups at 12 months was 0•01 nmol/L (95% CI-0•11 to 0•14; p=0•86), and between the anakinra and the placebo groups at 9 months was 0•02 nmol/L (-0•09 to 0•15; p=0•71). The number and severity of adverse events did not differ between groups in the canakinumab trial. In the anakinra trial, patients in the anakinra group had significantly higher grades of adverse events than the placebo group (p=0•018), which was mainly because of a higher number of injection site reactions in the anakinra group. Interpretation Canakinumab and anakinra were safe but were not effective as single immunomodulatory drugs in recent-onset type 1 diabetes. Interleukin-1 blockade might be more effective in combination with treatments that target adaptive immunity in organ-specific autoimmune disorders.
Bibliographical noteFunding Information:
AM has served on an advisory board for Pfizer and has received grants from Tolerx, Merck, and Osiris Therapeutics. SEG has served on an advisory board for Genentech. RG has received grants from Diamyd and Tolerx. CJG has received grants from Bayhill Therapeutics, Diamyd, and Tolerx. JBM has served on an advisory board for Amgen and has received research grants from Amylin, Biogen, Bristol-Myers Squibb, Diamyd, Eli Lilly, Genentech, Macrogenics, Roche, and Sanofi. PR has served on advisory boards for Amgen, AstraZeneca, and Novo Nordisk, has served on speakers bureaus for Novo Nordisk, and has received grants from Aegera, Andromeda Biotech, Astra Zeneca, Boehringer Ingelheim, Calibra Medical, Eli Lilly, Halozyme, Hoffman-LaRoche, Osiris Therapeutics, Pfizer, and Reata. DKW has received lecture fees from Eli Lilly and Medtronic. DMW has served on advisory boards for DexCom and Genentech and has received grant support from Genentech, Diamyd, and Osiris Therapeutics. JSS was on the Board of Directors for Amylin Pharmaceuticals, DexCom, and Moerae Matrix; served on advisory boards for Sanofi Diabetes and Viacyte; and has received grants from Bayhill Therapeutics, Halozyme, Intuity, Mesoblast, and Osiris Therapeutics. NS is employed by Lilly, Germany; has received grants from Andromeda Biotech, Tolerx, and Roche; has served as a speaker for Novo Nordisk and Sanofi-Aventis; and has served on advisory boards for Boehringer Ingelheim, GlaxoSmith Kline, and Amdromeda Biotech. BBu, DJB, LAD, KCH, SS, DS, JPK, JFB, PP, DM, MYD, LC, AW, HHL, HP, and TM-P declare that they have no conflicts of interest.
The canakinumab trial was sponsored by the Type 1 Diabetes TrialNet Study Group. The Type 1 Diabetes TrialNet Study Group is a clinical trials network funded by the National Institutes of Health (NIH) through the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Allergy and Infectious Diseases, and The Eunice Kennedy Shriver National Institute of Child Health and Human Development, through the cooperative agreements U01 DK061010, U01 DK061016, U01 DK061034, U01 DK061036, U01 DK061040, U01 DK061041, U01 DK061042, U01 DK061055, U01 DK061058, U01 DK084565, U01 DK085453, U01 DK085461, U01 DK085463, U01 DK085466, U01 DK085499, U01 DK085505, U01 DK085509, and contract HHSN267200800019C; the National Center for Research Resources, through Clinical Translational Science Awards UL1 RR024131, UL1 RR024139, UL1 RR024153, UL1 RR024975, UL1 RR024982, UL1 RR025744, UL1 RR025761, UL1 RR025780, UL1 RR029890, UL1 RR031986, and General Clinical Research Center Award M01 RR00400; the JDRF; and the American Diabetes Association. The contents of this Article are solely the responsibility of the authors and do not necessarily represent the official views of the NIH, JDRF, or the American Diabetes Association. Novartis (Basel, Switzerland) provided canakinumab (Ilaris), input regarding dosage, and other suggestions but had no direct involvement with study design, conduct, or management; data collection, analysis or interpretation; or manuscript preparation. There are no agreements concerning confidentiality of the canakinumab trial data between the sponsor and the authors or the institutions named in the credit lines. Roche Diagnostics provided blood glucose monitoring meters and strips to research participants in the canakinumab trial. The anakinra trial was funded by the JDRF international grants 17-2008-1804 and 8-2008-175 in addition to local support provided by individual study centres. Amgen (Thousand Oaks, California, USA) provided and distributed anakinra study drugs but had no direct involvement in the study design, conduct, or management; data collection, analysis or interpretation; or manuscript preparation.