title: Interleukin-1 antagonism in type 1 diabetes of recent onset: two multicentre, randomised, double-blind, placebo-controlled trials.
abstract: 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 β-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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  National Institutes of Health and Juvenile Diabetes Research Foundation.
authors.affiliation: University of Minnesota, Minneapolis, MN, USA.
authors.forename: Antoinette
authors.initials: A
authors.lastname: Moran
authors.forename: Brian
authors.initials: B
authors.lastname: Bundy
authors.forename: Dorothy J
authors.initials: DJ
authors.lastname: Becker
authors.forename: Linda A
authors.initials: LA
authors.lastname: DiMeglio
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Gitelman
authors.forename: Robin
authors.initials: R
authors.lastname: Goland
authors.forename: Carla J
authors.initials: CJ
authors.lastname: Greenbaum
authors.forename: Kevan C
authors.initials: KC
authors.lastname: Herold
authors.forename: Jennifer B
authors.initials: JB
authors.lastname: Marks
authors.forename: Philip
authors.initials: P
authors.lastname: Raskin
authors.forename: Srinath
authors.initials: S
authors.lastname: Sanda
authors.forename: Desmond
authors.initials: D
authors.lastname: Schatz
authors.forename: Diane K
authors.initials: DK
authors.lastname: Wherrett
authors.forename: Darrell M
authors.initials: DM
authors.lastname: Wilson
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Krischer
authors.forename: Jay S
authors.initials: JS
authors.lastname: Skyler
authors.forename: Linda
authors.initials: L
authors.lastname: Pickersgill
authors.forename: Eelco
authors.initials: E
authors.lastname: de Koning
authors.forename: Anette-G
authors.initials: AG
authors.lastname: Ziegler
authors.forename: Bernhard
authors.initials: B
authors.lastname: Böehm
authors.forename: Klaus
authors.initials: K
authors.lastname: Badenhoop
authors.forename: Nanette
authors.initials: N
authors.lastname: Schloot
authors.forename: Jens Friis
authors.initials: JF
authors.lastname: Bak
authors.forename: Paolo
authors.initials: P
authors.lastname: Pozzilli
authors.forename: Didac
authors.initials: D
authors.lastname: Mauricio
authors.forename: Marc Y
authors.initials: MY
authors.lastname: Donath
authors.forename: Luis
authors.initials: L
authors.lastname: Castaño
authors.forename: Ana
authors.initials: A
authors.lastname: Wägner
authors.forename: Hans Henrik
authors.initials: HH
authors.lastname: Lervang
authors.forename: Hans
authors.initials: H
authors.lastname: Perrild
authors.forename: Thomas
authors.initials: T
authors.lastname: Mandrup-Poulsen
mesh_terms: D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D002096:C-Peptide / Q000187:drug effects; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007155:Immunologic Factors / Q000627:therapeutic use*; D050417:Insulin-Secreting Cells / Q000187:drug effects; D053590:Interleukin 1 Receptor Antagonist Protein / Q000627:therapeutic use*; D007375:Interleukin-1 / Q000037:antagonists & inhibitors; D008297:Male; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D002096:C-Peptide; D007004:Hypoglycemic Agents; D007155:Immunologic Factors; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; C541220:canakinumab
references.citation: Lancet. 2011 Jul 23;378(9788):319-27
references.pmid: 21714999
references.citation: Diabetologia. 1996 Nov;39(11):1306-12
references.pmid: 8932996
references.citation: J Clin Invest. 2002 Sep;110(6):851-60
references.pmid: 12235117
references.citation: N Engl J Med. 2008 Oct 30;359(18):1909-20
references.pmid: 18843118
references.citation: Diabetes Care. 2003 Mar;26(3):832-6
references.pmid: 12610045
references.citation: N Engl J Med. 2012 Feb 2;366(5):433-42
references.pmid: 22296077
references.citation: Diabetes Care. 2009 Jul;32(7):1244-9
references.pmid: 19366957
references.citation: N Engl J Med. 2009 Nov 26;361(22):2143-52
references.pmid: 19940299
references.citation: Ann Intern Med. 1998 Apr 1;128(7):517-23
references.pmid: 9518395
references.citation: Nat Rev Endocrinol. 2010 Mar;6(3):158-66
references.pmid: 20173777
references.citation: J Clin Endocrinol Metab. 2007 Sep;92(9):3705-11
references.pmid: 17595242
references.citation: Lancet. 2011 Jul 30;378(9789):412-9
references.pmid: 21719096
references.citation: Diabetes. 2004 Feb;53(2):426-33
references.pmid: 14747294
references.citation: Diabetes. 2012 Jan;61(1):145-54
references.pmid: 22043003
references.citation: Clin Immunol. 2010 Aug;136(2):170-3
references.pmid: 20483667
references.citation: Diabetes. 2012 Oct;61(10):2525-33
references.pmid: 22751696
references.citation: Diabetes Care. 2008 Oct;31(10):1966-71
references.pmid: 18628574
references.citation: Diabetologia. 1987 Jul;30(7):474-80
references.pmid: 3311860
references.citation: N Engl J Med. 2002 May 30;346(22):1692-8
references.pmid: 12037148
references.citation: N Engl J Med. 2005 Jun 23;352(25):2598-608
references.pmid: 15972866
references.citation: Nat Rev Drug Discov. 2012 Aug;11(8):633-52
references.pmid: 22850787
references.citation: Pediatr Diabetes. 2011 Nov;12(7):656-67
references.pmid: 21518168
references.citation: Diabetologia. 2010 Apr;53(4):614-23
references.pmid: 20225393
references.citation: Clin Immunol. 2009 Aug;132(2):166-73
references.pmid: 19443276
references.citation: Endocrinology. 1987 Oct;121(4):1424-31
references.pmid: 3308437