Interleukin-1 antagonism in type 1 diabetes of recent onset

Two multicentre, randomised, double-blind, placebo-controlled trials

Antoinette Moran, Brian Bundy, Dorothy J. Becker, Linda DiMeglio, Stephen E. Gitelman, Robin Goland, Carla J. Greenbaum, Kevan C. Herold, Jennifer B. Marks, Philip Raskin, Srinath Sanda, Desmond Schatz, Diane K. Wherrett, Darrell M. Wilson, Jeffrey P. Krischer, Jay S. Skyler, Linda Pickersgill, Eelco De Koning, Anette G. Ziegler, Bernhard Böehm & 11 others Klaus Badenhoop, Nanette Schloot, Jens Friis Bak, Paolo Pozzilli, Didac Mauricio, Marc Y. Donath, Luis Castaño, Ana Wägner, Hans Henrik Lervang, Hans Perrild, Thomas Mandrup-Poulsen

Research output: Contribution to journalArticle

177 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)1905-1915
Number of pages11
JournalThe Lancet
Volume381
Issue number9881
DOIs
StatePublished - Jun 1 2013

Fingerprint

Interleukin 1 Receptor Antagonist Protein
Type 1 Diabetes Mellitus
Interleukin-1
Placebos
C-Peptide
Area Under Curve
Meals
canakinumab
Randomized Controlled Trials
Intention to Treat Analysis
Interleukin-1 Receptors
Adaptive Immunity
Subcutaneous Injections
Random Allocation
Innate Immunity

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Interleukin-1 antagonism in type 1 diabetes of recent onset : Two multicentre, randomised, double-blind, placebo-controlled trials. / Moran, Antoinette; Bundy, Brian; Becker, Dorothy J.; DiMeglio, Linda; Gitelman, Stephen E.; Goland, Robin; Greenbaum, Carla J.; Herold, Kevan C.; Marks, Jennifer B.; Raskin, Philip; Sanda, Srinath; Schatz, Desmond; Wherrett, Diane K.; Wilson, Darrell M.; Krischer, Jeffrey P.; Skyler, Jay S.; Pickersgill, Linda; De Koning, Eelco; Ziegler, Anette G.; Böehm, Bernhard; Badenhoop, Klaus; Schloot, Nanette; Bak, Jens Friis; Pozzilli, Paolo; Mauricio, Didac; Donath, Marc Y.; Castaño, Luis; Wägner, Ana; Lervang, Hans Henrik; Perrild, Hans; Mandrup-Poulsen, Thomas.

In: The Lancet, Vol. 381, No. 9881, 01.06.2013, p. 1905-1915.

Research output: Contribution to journalArticle

Moran, A, Bundy, B, Becker, DJ, DiMeglio, L, Gitelman, SE, Goland, R, Greenbaum, CJ, Herold, KC, Marks, JB, Raskin, P, Sanda, S, Schatz, D, Wherrett, DK, Wilson, DM, Krischer, JP, Skyler, JS, Pickersgill, L, De Koning, E, Ziegler, AG, Böehm, B, Badenhoop, K, Schloot, N, Bak, JF, Pozzilli, P, Mauricio, D, Donath, MY, Castaño, L, Wägner, A, Lervang, HH, Perrild, H & Mandrup-Poulsen, T 2013, 'Interleukin-1 antagonism in type 1 diabetes of recent onset: Two multicentre, randomised, double-blind, placebo-controlled trials', The Lancet, vol. 381, no. 9881, pp. 1905-1915. https://doi.org/10.1016/S0140-6736(13)60023-9
Moran, Antoinette ; Bundy, Brian ; Becker, Dorothy J. ; DiMeglio, Linda ; Gitelman, Stephen E. ; Goland, Robin ; Greenbaum, Carla J. ; Herold, Kevan C. ; Marks, Jennifer B. ; Raskin, Philip ; Sanda, Srinath ; Schatz, Desmond ; Wherrett, Diane K. ; Wilson, Darrell M. ; Krischer, Jeffrey P. ; Skyler, Jay S. ; Pickersgill, Linda ; De Koning, Eelco ; Ziegler, Anette G. ; Böehm, Bernhard ; Badenhoop, Klaus ; Schloot, Nanette ; Bak, Jens Friis ; Pozzilli, Paolo ; Mauricio, Didac ; Donath, Marc Y. ; Castaño, Luis ; Wägner, Ana ; Lervang, Hans Henrik ; Perrild, Hans ; Mandrup-Poulsen, Thomas. / Interleukin-1 antagonism in type 1 diabetes of recent onset : Two multicentre, randomised, double-blind, placebo-controlled trials. In: The Lancet. 2013 ; Vol. 381, No. 9881. pp. 1905-1915.
@article{de5746ec701f497d9199e8154ba60abb,
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 {\^a}-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.",
author = "Antoinette Moran and Brian Bundy and Becker, {Dorothy J.} and Linda DiMeglio and Gitelman, {Stephen E.} and Robin Goland and Greenbaum, {Carla J.} and Herold, {Kevan C.} and Marks, {Jennifer B.} and Philip Raskin and Srinath Sanda and Desmond Schatz and Wherrett, {Diane K.} and Wilson, {Darrell M.} and Krischer, {Jeffrey P.} and Skyler, {Jay S.} and Linda Pickersgill and {De Koning}, Eelco and Ziegler, {Anette G.} and Bernhard B{\"o}ehm and Klaus Badenhoop and Nanette Schloot and Bak, {Jens Friis} and Paolo Pozzilli and Didac Mauricio and Donath, {Marc Y.} and Luis Casta{\~n}o and Ana W{\"a}gner and Lervang, {Hans Henrik} and Hans Perrild and Thomas Mandrup-Poulsen",
year = "2013",
month = "6",
day = "1",
doi = "10.1016/S0140-6736(13)60023-9",
language = "English",
volume = "381",
pages = "1905--1915",
journal = "The Lancet",
issn = "0140-6736",
publisher = "Elsevier Limited",
number = "9881",

}

TY - JOUR

T1 - Interleukin-1 antagonism in type 1 diabetes of recent onset

T2 - Two multicentre, randomised, double-blind, placebo-controlled trials

AU - Moran, Antoinette

AU - Bundy, Brian

AU - Becker, Dorothy J.

AU - DiMeglio, Linda

AU - Gitelman, Stephen E.

AU - Goland, Robin

AU - Greenbaum, Carla J.

AU - Herold, Kevan C.

AU - Marks, Jennifer B.

AU - Raskin, Philip

AU - Sanda, Srinath

AU - Schatz, Desmond

AU - Wherrett, Diane K.

AU - Wilson, Darrell M.

AU - Krischer, Jeffrey P.

AU - Skyler, Jay S.

AU - Pickersgill, Linda

AU - De Koning, Eelco

AU - Ziegler, Anette G.

AU - Böehm, Bernhard

AU - Badenhoop, Klaus

AU - Schloot, Nanette

AU - Bak, Jens Friis

AU - Pozzilli, Paolo

AU - Mauricio, Didac

AU - Donath, Marc Y.

AU - Castaño, Luis

AU - Wägner, Ana

AU - Lervang, Hans Henrik

AU - Perrild, Hans

AU - Mandrup-Poulsen, Thomas

PY - 2013/6/1

Y1 - 2013/6/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84878300647&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84878300647&partnerID=8YFLogxK

U2 - 10.1016/S0140-6736(13)60023-9

DO - 10.1016/S0140-6736(13)60023-9

M3 - Article

VL - 381

SP - 1905

EP - 1915

JO - The Lancet

JF - The Lancet

SN - 0140-6736

IS - 9881

ER -