title: Co-stimulation modulation with abatacept in patients with recent-onset type 1 diabetes: a randomised, double-blind, placebo-controlled trial.
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.
  
  
  RESULTS
  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%]).
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  US National Institutes of Health.
authors: Joslin Diabetes Center, Boston, MA, USA.
authors: Tihamer
authors: T
authors: Orban
authors: Brian
authors: B
authors: Bundy
authors: Dorothy J
authors: DJ
authors: Becker
authors: Linda A
authors: LA
authors: DiMeglio
authors: Stephen E
authors: SE
authors: Gitelman
authors: Robin
authors: R
authors: Goland
authors: Peter A
authors: PA
authors: Gottlieb
authors: Carla J
authors: CJ
authors: Greenbaum
authors: Jennifer B
authors: JB
authors: Marks
authors: Roshanak
authors: R
authors: Monzavi
authors: Antoinette
authors: A
authors: Moran
authors: Philip
authors: P
authors: Raskin
authors: Henry
authors: H
authors: Rodriguez
authors: William E
authors: WE
authors: Russell
authors: Desmond
authors: D
authors: Schatz
authors: Diane
authors: D
authors: Wherrett
authors: Darrell M
authors: DM
authors: Wilson
authors: Jeffrey P
authors: JP
authors: Krischer
authors: Jay S
authors: JS
authors: Skyler
mesh_terms: D000069594:Abatacept; D000293:Adolescent; D000328:Adult; D015551:Autoimmunity; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D050417:Insulin-Secreting Cells / Q000502:physiology; D008297:Male; D016032:Randomized Controlled Trials as Topic; D013601:T-Lymphocytes / Q000276:immunology; D055815:Young Adult
chemical_list: D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D000069594:Abatacept