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

William E. Russell; Brian N. Bundy; Mark S. Anderson; Laura A. Cooney; Stephen E. Gitelman; Robin S. Goland; Peter A. Gottlieb; Carla J. Greenbaum; Michael J. Haller; Jeffrey P. Krischer; Ingrid M. Libman; Peter S. Linsley; S. Alice Long; Sandra M. Lord; Daniel J. Moore; Wayne V. Moore; Antoinette M. Moran; Andrew B. Muir; Philip Raskin; Jay S. Skyler; John M. Wentworth; Diane K. Wherrett; Darrell M. Wilson; Anette Gabriele Ziegler; Kevan C. Herold

doi:10.2337/dc22-2200

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

William E. Russell, Brian N. Bundy, Mark S. Anderson, Laura A. Cooney, Stephen E. Gitelman, Robin S. Goland, Peter A. Gottlieb, Carla J. Greenbaum, Michael J. Haller, Jeffrey P. Krischer, Ingrid M. Libman, Peter S. Linsley, S. Alice Long, Sandra M. Lord, Daniel J. Moore, Wayne V. Moore, Antoinette M. Moran, Andrew B. Muir, Philip Raskin, Jay S. SkylerJohn M. Wentworth, Diane K. Wherrett, Darrell M. Wilson, Anette Gabriele Ziegler, Kevan C. Herold

Pediatric Endocrinology

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1005-1013
Number of pages	9
Journal	Diabetes care
Volume	46
Issue number	5
DOIs	https://doi.org/10.2337/dc22-2200
State	Published - May 2023

Bibliographical note

Funding Information:
Acknowledgments. The authors thank mem bers 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 Le-schek, 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. 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.

Publisher Copyright:
© 2023 by the American Diabetes Association.

PubMed: MeSH publication types

Randomized Controlled Trial
Clinical Trial, Phase II
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.2337/dc22-2200

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Russell, W. E., Bundy, B. N., Anderson, M. S., Cooney, L. A., Gitelman, S. E., Goland, R. S., Gottlieb, P. A., Greenbaum, C. J., Haller, M. J., Krischer, J. P., Libman, I. M., Linsley, P. S., Long, S. A., Lord, S. M., Moore, D. J., Moore, W. V., Moran, A. M., Muir, A. B., Raskin, P., ... Herold, K. C. (2023). Abatacept for Delay of Type 1 Diabetes Progression in Stage 1 Relatives at Risk: A Randomized, Double-Masked, Controlled Trial. Diabetes care, 46(5), 1005-1013. https://doi.org/10.2337/dc22-2200

Russell, WE, Bundy, BN, Anderson, MS, Cooney, LA, Gitelman, SE, Goland, RS, Gottlieb, PA, Greenbaum, CJ, Haller, MJ, Krischer, JP, Libman, IM, Linsley, PS, Long, SA, Lord, SM, Moore, DJ, Moore, WV, Moran, AM, Muir, AB, Raskin, P, Skyler, JS, Wentworth, JM, Wherrett, DK, Wilson, DM, Ziegler, AG & Herold, KC 2023, 'Abatacept for Delay of Type 1 Diabetes Progression in Stage 1 Relatives at Risk: A Randomized, Double-Masked, Controlled Trial', Diabetes care, vol. 46, no. 5, pp. 1005-1013. https://doi.org/10.2337/dc22-2200

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

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.",

author = "Russell, {William E.} and Bundy, {Brian N.} and Anderson, {Mark S.} and Cooney, {Laura A.} and Gitelman, {Stephen E.} and Goland, {Robin S.} and Gottlieb, {Peter A.} and Greenbaum, {Carla J.} and Haller, {Michael J.} and Krischer, {Jeffrey P.} and Libman, {Ingrid M.} and Linsley, {Peter S.} and Long, {S. Alice} and Lord, {Sandra M.} and Moore, {Daniel J.} and Moore, {Wayne V.} and Moran, {Antoinette M.} and Muir, {Andrew B.} and Philip Raskin and Skyler, {Jay S.} and Wentworth, {John M.} and Wherrett, {Diane K.} and Wilson, {Darrell M.} and Ziegler, {Anette Gabriele} and Herold, {Kevan C.}",

note = "Funding Information: Acknowledgments. The authors thank mem bers 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 Le-schek, 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. 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. Publisher Copyright: {\textcopyright} 2023 by the American Diabetes Association.",

year = "2023",

month = may,

doi = "10.2337/dc22-2200",

language = "English (US)",

volume = "46",

pages = "1005--1013",

journal = "Diabetes care",

issn = "0149-5992",

publisher = "American Diabetes Association Inc.",

number = "5",

}

TY - JOUR

T1 - Abatacept for Delay of Type 1 Diabetes Progression in Stage 1 Relatives at Risk

T2 - A Randomized, Double-Masked, Controlled Trial

AU - Russell, William E.

AU - Bundy, Brian N.

AU - Anderson, Mark S.

AU - Cooney, Laura A.

AU - Gitelman, Stephen E.

AU - Goland, Robin S.

AU - Gottlieb, Peter A.

AU - Greenbaum, Carla J.

AU - Haller, Michael J.

AU - Krischer, Jeffrey P.

AU - Libman, Ingrid M.

AU - Linsley, Peter S.

AU - Long, S. Alice

AU - Lord, Sandra M.

AU - Moore, Daniel J.

AU - Moore, Wayne V.

AU - Moran, Antoinette M.

AU - Muir, Andrew B.

AU - Raskin, Philip

AU - Skyler, Jay S.

AU - Wentworth, John M.

AU - Wherrett, Diane K.

AU - Wilson, Darrell M.

AU - Ziegler, Anette Gabriele

AU - Herold, Kevan C.

N1 - Funding Information: Acknowledgments. The authors thank mem bers 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 Le-schek, 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. 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. Publisher Copyright: © 2023 by the American Diabetes Association.

PY - 2023/5

Y1 - 2023/5

N2 - 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.

AB - 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.

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ER -

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

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UN SDGs

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