Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• The Lancet (British edition), 2011, Vol.378 (9789), p.412-419

Ort / Verlag

Kidlington: Elsevier Ltd

Erscheinungsjahr

2011

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• Summary 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.