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

Research output: Contribution to journalArticle

308 Citations (Scopus)

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 - Jul 30 2011

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Type 1 Diabetes Mellitus
Placebos
C-Peptide
T-Lymphocytes
Area Under Curve
Abatacept
Intention to Treat Analysis
National Institutes of Health (U.S.)
Random Allocation
Neutropenia
Autoimmunity
Meals
Therapeutics
Randomized Controlled Trials
Research Personnel
Observation
Antigens

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Orban, T., Bundy, B., Becker, D. J., DiMeglio, L. A., Gitelman, S. E., Goland, R., ... Skyler, J. S. (2011). Co-stimulation modulation with abatacept in patients with recent-onset type 1 diabetes: A randomised, double-blind, placebo-controlled trial. The Lancet, 378(9789), 412-419. https://doi.org/10.1016/S0140-6736(11)60886-6

Co-stimulation modulation with abatacept in patients with recent-onset type 1 diabetes : A randomised, double-blind, placebo-controlled trial. / Orban, Tihamer; Bundy, Brian; Becker, Dorothy J.; DiMeglio, Linda A.; Gitelman, Stephen E.; Goland, Robin; Gottlieb, Peter A.; Greenbaum, Carla J.; Marks, Jennifer B.; Monzavi, Roshanak; Moran, Antoinette; Raskin, Philip; Rodriguez, Henry; Russell, William E.; Schatz, Desmond; Wherrett, Diane; Wilson, Darrell M.; Krischer, Jeffrey P.; Skyler, Jay S.

In: The Lancet, Vol. 378, No. 9789, 30.07.2011, p. 412-419.

Research output: Contribution to journalArticle

Orban, T, Bundy, B, Becker, DJ, DiMeglio, LA, Gitelman, SE, Goland, R, Gottlieb, PA, Greenbaum, CJ, Marks, JB, Monzavi, R, Moran, A, Raskin, P, Rodriguez, H, Russell, WE, Schatz, D, Wherrett, D, Wilson, DM, Krischer, JP & Skyler, JS 2011, 'Co-stimulation modulation with abatacept in patients with recent-onset type 1 diabetes: A randomised, double-blind, placebo-controlled trial', The Lancet, vol. 378, no. 9789, pp. 412-419. https://doi.org/10.1016/S0140-6736(11)60886-6
Orban, Tihamer ; Bundy, Brian ; Becker, Dorothy J. ; DiMeglio, Linda A. ; Gitelman, Stephen E. ; Goland, Robin ; Gottlieb, Peter A. ; Greenbaum, Carla J. ; Marks, Jennifer B. ; Monzavi, Roshanak ; Moran, Antoinette ; Raskin, Philip ; Rodriguez, Henry ; Russell, William E. ; Schatz, Desmond ; Wherrett, Diane ; Wilson, Darrell M. ; Krischer, Jeffrey P. ; Skyler, Jay S. / Co-stimulation modulation with abatacept in patients with recent-onset type 1 diabetes : A randomised, double-blind, placebo-controlled trial. In: The Lancet. 2011 ; Vol. 378, No. 9789. pp. 412-419.
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T1 - Co-stimulation modulation with abatacept in patients with recent-onset type 1 diabetes

T2 - A randomised, double-blind, placebo-controlled trial

AU - Orban, Tihamer

AU - Bundy, Brian

AU - Becker, Dorothy J.

AU - DiMeglio, Linda A.

AU - Gitelman, Stephen E.

AU - Goland, Robin

AU - Gottlieb, Peter A.

AU - Greenbaum, Carla J.

AU - Marks, Jennifer B.

AU - Monzavi, Roshanak

AU - Moran, Antoinette

AU - Raskin, Philip

AU - Rodriguez, Henry

AU - Russell, William E.

AU - Schatz, Desmond

AU - Wherrett, Diane

AU - Wilson, Darrell M.

AU - Krischer, Jeffrey P.

AU - Skyler, Jay S.

PY - 2011/7/30

Y1 - 2011/7/30

N2 - 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.

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