期刊
LANCET
卷 378, 期 9789, 页码 412-419出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/S0140-6736(11)60886-6
关键词
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资金
- National Institutes of Health (NIH) through the National Institute of Diabetes and Digestive and Kidney Diseases
- National Institute of Allergy and Infectious Diseases
- Eunice Kennedy Shriver National Institute of Child Health and Human Development [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, HHSN267200800019C]
- National Center for Research Resources [UL1 RR024131, UL1 RR024139, UL1 RR024153, UL1 RR024975, UL1 RR024982, UL1 RR025744, UL1 RR025761, UL1 RR025780, UL1 RR029890, UL1 RR031986]
- General Clinical Research Center [M01 RR00400]
- Juvenile Diabetes Research Foundation International (JDRF)
- American Diabetes Association (ADA)
- Diamyd
- Tolerx
- Bayhill Therapeutics
- Macrogenics
- Omni Bio Therapeutics
- Aegera
- Andromeda Biotech
- Biodel
- Boehringer Ingelheim
- Calibra
- CPEX
- Generex
- Hoffman-LaRoche
- Mann Kind
- Novo-Nordisk
- Osiris Therapeutics
- Reata
- Eli Lilly
- Medtronic
- Halozyme
- Intuity
- Becton-Dickinson
- Merck
- Mann Kind Corporation
- GlaxoSmithKline
- Salutria Pharmaceuticals
- Veroscience
- Roche
- Exsulin
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 beta-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 beta-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.
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