Co-stimulation modulation with abatacept in patients with recent-onset type 1 diabetes: A randomised, double-blind, placebo-controlled trial

Tihamer Orban, Brian Bundy, Dorothy J. Becker, Linda A. DiMeglio, Stephen E. Gitelman, Robin Goland, Peter A. Gottlieb, Carla J. Greenbaum, Jennifer B. Marks, Roshanak Monzavi, Antoinette Moran, Philip Raskin, Henry Rodriguez, William E. Russell, Desmond Schatz, Diane Wherrett, Darrell M. Wilson, Jeffrey P. Krischer, Jay S. Skyler

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407 Scopus citations

Abstract

Background: The immunopathogenesis of type 1 diabetes mellitus is associated with T-cell autoimmunity. To be fully active, immune T cells need a co-stimulatory signal in addition to the main antigen-driven signal. Abatacept modulates co-stimulation and prevents full T-cell activation. We evaluated the effect of abatacept in recent-onset type 1 diabetes. Methods: In this multicentre, double-blind, randomised controlled trial, patients aged 6-45 years recently diagnosed with type 1 diabetes were randomly assigned (2:1) to receive abatacept (10 mg/kg, maximum 1000 mg per dose) or placebo infusions intravenously on days 1, 14, 28, and monthly for a total of 27 infusions over 2 years. Computer-generated permuted block randomisation was used, with a block size of 3 and stratified by participating site. Neither patients nor research personnel were aware of treatment assignments. The primary outcome was baseline-adjusted geometric mean 2-h area-under-the-curve (AUC) serum C-peptide concentration after a mixed-meal tolerance test at 2 years' follow-up. Analysis was by intention to treat for all patients for whom data were available. This trial is registered at ClinicalTrials.gov, NCT00505375. Findings: 112 patients were assigned to treatment groups (77 abatacept, 35 placebo). Adjusted C-peptide AUC was 59% (95% CI 6.1-112) higher at 2 years with abatacept (n=73, 0.378 nmol/L) than with placebo (n=30, 0.238 nmol/L; p=0.0029). The difference between groups was present throughout the trial, with an estimated 9.6 months' delay (95% CI 3.47-15.6) in C-peptide reduction with abatacept. There were few infusion-related adverse events (36 reactions occurred in 17 [22%] patients on abatacept and 11 reactions in six [17%] on placebo). There was no increase in infections (32 [42%] patients on abatacept vs 15 [43%] on placebo) or neutropenia (seven [9%] vs five [14%]). Interpretation: Co-stimulation modulation with abatacept slowed reduction in β-cell function over 2 years. The beneficial effect suggests that T-cell activation still occurs around the time of clinical diagnosis of type 1 diabetes. Yet, despite continued administration of abatacept over 24 months, the decrease in β-cell function with abatacept was parallel to that with placebo after 6 months of treatment, causing us to speculate that T-cell activation lessens with time. Further observation will establish whether the beneficial effect continues after cessation of abatacept infusions. Funding: US National Institutes of Health.

Original languageEnglish (US)
Pages (from-to)412-419
Number of pages8
JournalThe Lancet
Volume378
Issue number9789
DOIs
StatePublished - 2011

Bibliographical note

Funding Information:
The sponsor of the trial was the Type 1 Diabetes TrialNet Study Group. 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 a 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 Juvenile Diabetes Research Foundation International (JDRF); and the American Diabetes Association (ADA). 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 ADA. Bristol-Myers Squibb provided abatacept. Lifescan Division of Johnson and Johnson provided blood glucose monitoring meters and strips to participants.

Funding Information:
TO reports serving on a data safety monitoring board for Osiris Therapeutics and being a founder of Orban Biotech LLC. DJB reports receiving a grant from Diamyd. SEG reports serving on an advisory board for Genentech. RG reports receiving grants from Diamyd and Tolerx. PAG reports serving on advisory boards for Genentech, Eli Lilly, Sanofi-Aventis, and Tolerx, and reports receiving grants from Bayhill Therapeutics, Diamyd, Macrogenics, Omni BioTherapeutics, and Tolerx. CJG reports receiving grants from Bayhill Therapeutics, Diamyd, and Tolerx. JBM reports serving on an advisory board for Amgen. AM reports serving on an advisory board for Pfizer and receiving grants from Tolerx, Merck, and Osiris Therapeutics. PR reports serving on advisory boards for Amgen, AstraZeneca, MannKind, and Novo-Nordisk, serving on speakers bureaus for Merck and Novo-Nordisk, and receiving grants from Aegera, Andromeda Biotech, Bayhill Therapeutics, Biodel, Boehringer Ingelheim, Calibra, CPEX, Generex, Hoffman-LaRoche, MannKind, Novo-Nordisk, Osiris Therapeutics, and Reata. HR reports serving on an advisory board for Marcadia Biotech, serving as a consultant to Eli Lilly, Genentech, Bayer, EMD Serono, and Merck, being on the speakers bureau of Eli Lilly and Novo-Nordisk, and receiving grant support from Macrogenics and Eli Lilly. DS reports serving on advisory boards for Eli Lilly and GlaxoSmithKline and receiving a grant from Diamyd. DW reports receiving lecture fees from Eli Lilly and Medtronic. DMW reports serving on an advisory boards for DexCom and Genentech and receiving grants support from Genentech, Diamyd, and Osiris Therapeutics. JSS reports serving on boards for Amylin Pharmaceuticals, DexCom, and Sanofi-Aventis, receiving grants from Bayhill Therapeutics, Halozyme, Intuity, and Osiris Therapeutics, receiving consultancy fees from Becton-Dickinson, Merck, MannKind Corporation, GlaxoSmithKline, Salutria Pharmaceuticals, Veroscience, Roche, and Exsulin, and receiving speakers' fees and payment for development of an educational presentation from Novo-Nordisk and holds stock in Amylin Pharmaceuticals and Dexcom. BB, LADM, RM, WER, and JPK declare that they have no conflicts of interest.

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