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

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

The Lancet (British edition), 2011, Vol.378 (9789), p.412-419 [Periódico revisado por pares]

Kidlington: Elsevier Ltd

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Co-stimulation modulation with abatacept in patients with recent-onset type 1 diabetes: a randomised, double-blind, placebo-controlled trial
Autor: 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
Assuntos: Abatacept ; Adolescent ; Adult ; Autoimmunity ; Biological and medical sciences ; blood serum ; c-peptide ; Child ; Clinical trials ; Diabetes ; Diabetes Mellitus, Type 1 - drug therapy ; Diabetes Mellitus, Type 1 - immunology ; Diabetes Mellitus, Type 1 - physiopathology ; Diabetes. Impaired glucose tolerance ; Double-Blind Method ; Embargoes & blockades ; Endocrine pancreas. Apud cells (diseases) ; Endocrinopathies ; Etiopathogenesis. Screening. Investigations. Target tissue resistance ; Female ; General aspects ; Hepatitis ; human resources ; Humans ; Immunoconjugates - adverse effects ; Immunoconjugates - immunology ; Immunoconjugates - therapeutic use ; Immunosuppressive Agents - adverse effects ; Immunosuppressive Agents - therapeutic use ; insulin-dependent diabetes mellitus ; Insulin-Secreting Cells - physiology ; Internal Medicine ; intravenous injection ; Male ; Medical sciences ; National Institutes of Health ; neutropenia ; patients ; Peptides ; randomized clinical trials ; Randomized Controlled Trials as Topic ; Rheumatoid arthritis ; T-lymphocytes ; T-Lymphocytes - immunology ; Young Adult
É parte de: The Lancet (British edition), 2011, Vol.378 (9789), p.412-419
Notas: http://dx.doi.org/10.1016/S0140-6736(11)60886-6
Descrição: 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.
Editor: Kidlington: Elsevier Ltd
Idioma: Inglês

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

Kidlington: Elsevier Ltd

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