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Author Notes:

William E. Russell, bill.russell@vumc.org

W.E.R., C.J.G., and K.C.H. conceived of the study, obtained funding, collected data, and wrote the manuscript. B.N.B. and K.C.H. performed the data analysis and wrote the manuscript. M.S.A., L.A.C., R.S.G., P.A.G., M.J.H., I.M.L., P.S.L., S.A.L., S.M.L., D.J.M., W.V.M, A.M.M., A.B.M., P.R., J.M.W., D.K.W., D.M.W., and A.-G.Z. collected data and edited the manuscript. S.E.G., J.M.W., and K.C.H. collected data and wrote the manuscript. J.P.K. obtained funding, conceived of the study, performed the data analysis and edited the manuscript. J.S.S. conceived of the study, obtained funding, and edited the manuscript. W.E.R. is the TN18 Study Chair. K.C.H. is the TrialNet Chair. W.E.R. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and accuracy of the data analysis.

The authors thank members of the Human Immunophenotyping Core at Benaroya Research Institute: Alice Wiedeman, Anna Kus, and Sheila Scheiding, who designed the flow panel, acquired flow data, and performed hierarchical analyses, and to Dr. Erin M. Witkop, at Benaroya Research Institute, for data analysis. We also thank Drs. Lisa Spain, Ellen Leschek, and Judy Fradkin, of the NIDDK, for their guidance and support, and Sarah Muller and Drs. Adriana Weinberg, Michael Green, and Brett Loechelt for analysis of clinical and laboratory data. Finally, the authors thank to Darlene Amado, Colleen Maguire, Jessica Conaty, and Sarah Muller of the TrialNet Coordinating Center for data collection, study management, and assistance with preparation of the manuscript.

S.E.G. served as a consultant or speaker or received grants or contracts from Janssen, Provention Bio, Tolerion, and Intrexon Actobiotics and served on the DSMB or advisory board or received consulting fees from Avotres Therapeutics Diamyd, SAB Biotherapeutics, and Abata Therapeutics. P.A.G. served as a speaker or received grants or contracts from Intrexon, Provention Bio, Nova Pharmaceuticals, and Dompe and served on the DSMB or advisory board or received consulting fees from Immunomolecular Therapeutics, Inc., and Provention Bio. C.J.G. has served as a speaker or received grants or contracts from Bristol-Myers Squib, Janssen, Intrexon, Provention Bio, and Pfizer. M.J.H. served on the DSMB or advisory board or received consulting fees from Sanofi and SAbBiotherapeutics and has stock in SAbBiothereapeutics. P.S.L. served on the DSMB or advisory board or received consulting fees from Bristol-Myers Squibb. D.J.M. served on the DSMB or advisory board or received consulting fees from Provention Bio. A.M.M. served as a speaker or received grants or contracts from Intrexon, Provention Bio, and Caladrius and served on the DSMB or advisory board or received consulting fees from Dompe, Provention Bio, Caladrius, Novo Nordisk, and Abbott Laboratories. W.E.R. received grants or contracts from Provention Bio. J.S.S. served as a speaker or received grants or contracts from Novo Nordisk, Precigen, Sanofi, and Viacyte and served on the DSMB or advisory board or received consulting fees from Imcyse, Provention Bio, Avotres, and IM Therapeutics. D.M.W. served on the DSMB or advisory board or received consulting fees from Precigen Actobio. A.G.Z. served as a speaker or received grants or contracts from Janssen, Provention Bio, Tolerion, and Intrexon Actobiotics and served on the DSMB or advisory board for Diamyd and on the advisory board for Avotres Therapeutics, Provention Bio, SAB Biotherapeutics, Abata Therapeutics, Biolojic, and Toleron. K.C.H. has been a consultant for Provention Bio and has received a contract from Intrexon. No other potential conflicts of interest relevant to this article were reported.

Subject:

Research Funding:

The Type 1 Diabetes TrialNet Study Group is a clinical trials network currently funded by the National Institutes of Health through the National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) through the cooperative agreements U01 DK060782, U01 DK060916, U01 DK060987, U01 DK061010, U01 DK061016, U01 DK061029, U01 DK061030, U01 DK061034, U01 DK061035, U01 DK061036, U01 DK061037, U01 DK061040, U01 DK061041, U01 DK061042, U01 DK061055, U01 DK061058, U01 DK084565, U01 DK085453, U01 DK085461, U01 DK085463, U01 DK085465, UC4 DK085466, U01 DK085476, U01 DK085499, U01 DK085504, U01 DK085505, U01 DK085509, U01 DK097835, U01 DK103153, U01 DK103180, U01 DK103266, U01 DK103282, U01 DK106984, UC4 DK106993, U01 DK106994, U01 DK107013, U01 DK107014, and contract HHSN267200800019C, the National Center for Research Resources, through Clinical Translational Science Awards UL1 RR024131, UL1 RR024139, UL1 RR024153, UL1 RR024975, UL1 RR024982, UL1 RR025744, UL1 RR025761, UL1 RR025780, UL1 RR029890, UL1 RR031986, and UL1 TR001872, and General Clinical Research Center Award M01 RR00400.

The Immune Tolerance Network-funded portion of the research came from the National Institute of Allergy and Infection Diseases under award number UM1AI109565. JDRF International supported this study through grants 3-SRA-2015-27-Q-R, 2-SRA-2018-609-Q-R, 2-SRA-2020-900-S-B, 82-2013-652, and 1-SRA-2020-900-M-X. BMS, Lawrenceville, NJ, provided abatacept and matching placebo.

BMS reviewed the manuscript before submission but was not involved in the conduct or the trial or the data analysis. Representatives from the NIDDK participated in the design and conduct of the trial, interpretation of the data, preparation, review, and approval of the manuscript for submission, and the decision to submit the manuscript for publication. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Keywords:

  • Humans
  • Abatacept
  • Diabetes Mellitus, Type 1
  • Immunosuppressive Agents
  • T-Lymphocytes, Regulatory
  • Glucose

Abatacept for Delay of Type 1 Diabetes Progression in Stage 1 Relatives at Risk: A Randomized, Double-Masked, Controlled Trial

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Journal Title:

Diabetes Care

Volume:

Volume 46, Number 5

Publisher:

, Pages 1005-1013

Type of Work:

Article | Final Publisher PDF

Abstract:

OBJECTIVE Previous studies showed that inhibiting lymphocyte costimulation reduces declining b-cell function in individuals newly diagnosed with type 1 diabetes. We tested whether abatacept would delay or prevent progression of type 1 diabetes from nor-mal glucose tolerance (NGT) to abnormal glucose tolerance (AGT) or to diabetes and the effects of treatment on immune and metabolic responses. RESEARCH DESIGN AND METHODS We conducted a phase 2, randomized, placebo-controlled, double-masked trial of abatacept in antibody-positive participants with NGT who received monthly abatacept/placebo infusions for 12 months. The end point was AGT or diabetes, assessed by oral glucose tolerance tests. RESULTS A total of 101 participants received abatacept and 111 placebo. Of these, 81 (35 abatacept and 46 placebo) met the end point of AGT or type 1 diabetes diagnosis (hazard ratio 0.702; 95% CI 0.452, 1.09; P = 0.11) The C-peptide responses to oral glucose tolerance tests were higher in the abatacept arm (P < 0.03). Abatacept reduced the frequency of inducible T-cell costimulatory (ICOS)+ PD1+ T-follicular helper (Tfh) cells during treatment (P < 0.0001), increased naive CD4+ T cells, and also reduced the frequency of CD4+ regulatory T cells (Tregs) from the baseline (P = 0.0067). Twelve months after treatment, the frequency of ICOS+ Tfh, naive CD4+ T cells, and Tregs returned to baseline. CONCLUSIONS Although abatacept treatment for 1 year did not significantly delay progression to glucose intolerance in at-risk individuals, it impacted immune cell subsets and preserved insulin secretion, suggesting that costimulation blockade may modify progression of type 1 diabetes.

Copyright information:

© 2023 by the American Diabetes Association

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/).
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