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, Type 1 Diabetes TrialNet Abatacept Study Group, Jay S Skyler, Mark Anderson, Katarzyna Bourcier, Dorothy Becker, Penelope Bingley, Janice Blum, Emanuele Bosi, Jane Buckner, H Peter Chase, Michael Clare-Salzler, Peter Colman, Linda DiMeglio, George S Eisenbarth, C Garrison Fathman, Stephen Gitelman, Robin Goland, Peter Gottlieb, Gilman Grave, Carla Greenbaum, Leonard Harrison, Kevan Herold, Richard Insel, Jeffrey P Krischer, Jeffrey Mahon, Jennifer Marks, Antoinette Moran, Jerry P Palmer, Mark Peakman, Alberto Pugliese, Philip Raskin, Maria Grazia Roncarolo, William Russell, Peter Savage, Desmond Schatz, Robert Sherwin, Mark Siegelman, Olli Simell, James Thomas, Massimo Trucco, John Wagner, Diane Wherrett, Darrell M Wilson, William Winter, Judith Fradkin, Ellen Leschek, Lisa Spain, Christophe Benoist, Jeffrey Bluestone, David Brown, Catherine Cowie, Bernard Hering, Stanley Jordan, Francine R Kaufman, John M Lachin, Kirsti Nanto-Salonen, Gerald Nepom, Tihamer Orban, Robertson Parkman, Mark Pescovitz, John Peyman, John Ridge, Henry Rodriguez, Anette Ziegler, Jay S Skyler, Katarzyna Bourcier, Carla J Greenbaum, Jeffrey P Krischer, Ellen Leschek, Lisa Rafkin, Peter Savage, Lisa Spain, Catherine Cowie, Mary Foulkes, Heidi Krause-Steinrauf, John M Lachin, Saul Malozowski, John Peyman, John Ridge, Stephanie J Zafonte, Jay S Skyler, Carla J Greenbaum, Norma S Kenyon, Lisa Rafkin, Irene Santiago, Jay M Sosenko, Jeffrey P Krischer, Aqesha Luvon Ritzie, Brian Bundy, Michael Abbondondolo, Timothy Adams, Persida Alies, Franz Badias, Craig Beam, Matthew Boonstra, David Boulware, David Cuthbertson, Christopher Eberhard, Julie Ford, Jinin Ginem, Heather Guillette, Brian Hays, Martha Henry, Pat Law, Cristin Linton, Shu Liu, Jennifer Lloyd, Sarah Muller, Ryan O'Donnell, Yazandra Parrimon, Kate Paulus, Jennifer Pilger, Joy Ramiro, Amy Roberts, Kelly Sadler, Amanda Terry, Margaret Wootten, Ping Xu, Kenneth Young, Monica Bassi, Doug Freeman, Moriah Granger, Michelle Kieffer, Lavanya Nallamshetty, Audrey Shor, John M Lachin, Mary Foulkes, Pamela Harding, Heidi Krause-Steinrauf, Susan McDonough, Paula F McGee, Kimberly Owens Hess, Donna Phoebus, Scott Quinlan, Erica Raiden, Judith Fradkin, Ellen Leschek, Peter Savage, Lisa Spain, Emily Blumberg, Jonathan Braun, Lori Laffel, Ali Naji, Jorn Nerup, Trevor Orchard, Anastasios Tsiatis, Robert Veatch, Dennis Wallace, Ake Lernmark, Bernard Lo, Herman Mitchell, Michael Steffes, Bernard Zinman, Brett Loechelt, Lindsey Baden, Michael Green, Adriana Weinberg, Sunanda Babu, George S Eisenbarth, Santica Marcovina, Jerry P Palmer, Adriana Weinberg, William Winter, Liping Yu, Tihamer Orban, Peter Gottlieb, Carla Greenbaum, Heidi Krause-Steinrauf, John M Lachin, Ellen Leschek, Brett Loechelt, Robertson Parkman, Lisa Rafkin, Alison Rigby, Jay S Skyler, Lisa Spain, John Wagner, Carla Greenbaum, Jennifer Bollyky, Srinath Sanda, David Tridgell, Marli McCulloch-Olson, Heather Vendettuoli, Deborah Hefty, Mary Ramey, Christine Webber, Kristen Kuhns, Nicole Hilderman, Angela Dove, Marissa Hammond, Jani Klein, Emily Batts, Roshanak Monzavi, Mary Halvorson, Meredith Bock, Lynda Fisher, Debra Jeandron, Jamie Wood, Francine R Kaufman, Robin Goland, Ellen Greenberg, Mary Pat Gallagher, Jeniece Trast, Mary Chan, Henry Rodriguez, Mark Pescovitz, Linda DiMeglio, Lyla Christner, Maria Nicholson, Martha Mendez, Tihamer Orban, Christophe Benoist, Joseph Wolfsdorf, Alyne Ricker, Heyam Jalahej, Debbie Conboy, Klara Farkas, Janos Kis, Hui Zhang, Steve Fay, Darrell M Wilson, Bruce A Buckingham, Tandy Aye, Trudy Esrey, Adriana Soto, Jennifer Perry, Bonita Baker, Alison Rigby, Barbara Berry, Stephen E Gitelman, Stephen M Rosenthal, Mark Anderson, Saleh Adi, Kathleen Breen, Celia Hamilton, Peter Gottlieb, H Peter Chase, Aaron Michels, Whitney Kastelic, Laurie Weiner, Desmond Schatz, Michael Haller, Michael Clare-Salzler, Roberta Cook, Diane Mancini, Annie Abraham, Elena Hicks, Gloria Cole, Jennifer B Marks, Alberto Pugliese, Della Matheson, Carlos Blaschke, Luz Arazo, Mario Cisneros, Brenda Acosta, Antoinette Moran, Brandon Nathan, John Wagner, Mary Ann Boes, Carrie Gibson, Lois Finney, Theresa Albright-Fischer, Jennifer Smith, Dorothy Becker, Frederico Toledo, Ingrid Libman, Karen Riley, Kelli Delallo, Kym Smith, Diane Gwynn, Gyna Wohlers, Philip Raskin, Perrin White, Bryan Dickson, Soumya Adhikari, Mark Siegelman, Marilyn Alford, Nenita Torres, Tauri Harden, Lourdes Pruneda, Erica Cordova, Renee Davis, Stefani Fernandez, Jamie Arthur, Diane Wherrett, Lesley A Eisel, Brenda Ahenkorah, Natasha Razack, Mithula Sriskandarajah, William E Russell, James W Thomas, Daniel J Moore, Anne Brown, Margo Black, Eric Pittel, Faith Brendle, 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, Type 1 Diabetes TrialNet Abatacept Study Group, Jay S Skyler, Mark Anderson, Katarzyna Bourcier, Dorothy Becker, Penelope Bingley, Janice Blum, Emanuele Bosi, Jane Buckner, H Peter Chase, Michael Clare-Salzler, Peter Colman, Linda DiMeglio, George S Eisenbarth, C Garrison Fathman, Stephen Gitelman, Robin Goland, Peter Gottlieb, Gilman Grave, Carla Greenbaum, Leonard Harrison, Kevan Herold, Richard Insel, Jeffrey P Krischer, Jeffrey Mahon, Jennifer Marks, Antoinette Moran, Jerry P Palmer, Mark Peakman, Alberto Pugliese, Philip Raskin, Maria Grazia Roncarolo, William Russell, Peter Savage, Desmond Schatz, Robert Sherwin, Mark Siegelman, Olli Simell, James Thomas, Massimo Trucco, John Wagner, Diane Wherrett, Darrell M Wilson, William Winter, Judith Fradkin, Ellen Leschek, Lisa Spain, Christophe Benoist, Jeffrey Bluestone, David Brown, Catherine Cowie, Bernard Hering, Stanley Jordan, Francine R Kaufman, John M Lachin, Kirsti Nanto-Salonen, Gerald Nepom, Tihamer Orban, Robertson Parkman, Mark Pescovitz, John Peyman, John Ridge, Henry Rodriguez, Anette Ziegler, Jay S Skyler, Katarzyna Bourcier, Carla J Greenbaum, Jeffrey P Krischer, Ellen Leschek, Lisa Rafkin, Peter Savage, Lisa Spain, Catherine Cowie, Mary Foulkes, Heidi Krause-Steinrauf, John M Lachin, Saul Malozowski, John Peyman, John Ridge, Stephanie J Zafonte, Jay S Skyler, Carla J Greenbaum, Norma S Kenyon, Lisa Rafkin, Irene Santiago, Jay M Sosenko, Jeffrey P Krischer, Aqesha Luvon Ritzie, Brian Bundy, Michael Abbondondolo, Timothy Adams, Persida Alies, Franz Badias, Craig Beam, Matthew Boonstra, David Boulware, David Cuthbertson, Christopher Eberhard, Julie Ford, Jinin Ginem, Heather Guillette, Brian Hays, Martha Henry, Pat Law, Cristin Linton, Shu Liu, Jennifer Lloyd, Sarah Muller, Ryan O'Donnell, Yazandra Parrimon, Kate Paulus, Jennifer Pilger, Joy Ramiro, Amy Roberts, Kelly Sadler, Amanda Terry, Margaret Wootten, Ping Xu, Kenneth Young, Monica Bassi, Doug Freeman, Moriah Granger, Michelle Kieffer, Lavanya Nallamshetty, Audrey Shor, John M Lachin, Mary Foulkes, Pamela Harding, Heidi Krause-Steinrauf, Susan McDonough, Paula F McGee, Kimberly Owens Hess, Donna Phoebus, Scott Quinlan, Erica Raiden, Judith Fradkin, Ellen Leschek, Peter Savage, Lisa Spain, Emily Blumberg, Jonathan Braun, Lori Laffel, Ali Naji, Jorn Nerup, Trevor Orchard, Anastasios Tsiatis, Robert Veatch, Dennis Wallace, Ake Lernmark, Bernard Lo, Herman Mitchell, Michael Steffes, Bernard Zinman, Brett Loechelt, Lindsey Baden, Michael Green, Adriana Weinberg, Sunanda Babu, George S Eisenbarth, Santica Marcovina, Jerry P Palmer, Adriana Weinberg, William Winter, Liping Yu, Tihamer Orban, Peter Gottlieb, Carla Greenbaum, Heidi Krause-Steinrauf, John M Lachin, Ellen Leschek, Brett Loechelt, Robertson Parkman, Lisa Rafkin, Alison Rigby, Jay S Skyler, Lisa Spain, John Wagner, Carla Greenbaum, Jennifer Bollyky, Srinath Sanda, David Tridgell, Marli McCulloch-Olson, Heather Vendettuoli, Deborah Hefty, Mary Ramey, Christine Webber, Kristen Kuhns, Nicole Hilderman, Angela Dove, Marissa Hammond, Jani Klein, Emily Batts, Roshanak Monzavi, Mary Halvorson, Meredith Bock, Lynda Fisher, Debra Jeandron, Jamie Wood, Francine R Kaufman, Robin Goland, Ellen Greenberg, Mary Pat Gallagher, Jeniece Trast, Mary Chan, Henry Rodriguez, Mark Pescovitz, Linda DiMeglio, Lyla Christner, Maria Nicholson, Martha Mendez, Tihamer Orban, Christophe Benoist, Joseph Wolfsdorf, Alyne Ricker, Heyam Jalahej, Debbie Conboy, Klara Farkas, Janos Kis, Hui Zhang, Steve Fay, Darrell M Wilson, Bruce A Buckingham, Tandy Aye, Trudy Esrey, Adriana Soto, Jennifer Perry, Bonita Baker, Alison Rigby, Barbara Berry, Stephen E Gitelman, Stephen M Rosenthal, Mark Anderson, Saleh Adi, Kathleen Breen, Celia Hamilton, Peter Gottlieb, H Peter Chase, Aaron Michels, Whitney Kastelic, Laurie Weiner, Desmond Schatz, Michael Haller, Michael Clare-Salzler, Roberta Cook, Diane Mancini, Annie Abraham, Elena Hicks, Gloria Cole, Jennifer B Marks, Alberto Pugliese, Della Matheson, Carlos Blaschke, Luz Arazo, Mario Cisneros, Brenda Acosta, Antoinette Moran, Brandon Nathan, John Wagner, Mary Ann Boes, Carrie Gibson, Lois Finney, Theresa Albright-Fischer, Jennifer Smith, Dorothy Becker, Frederico Toledo, Ingrid Libman, Karen Riley, Kelli Delallo, Kym Smith, Diane Gwynn, Gyna Wohlers, Philip Raskin, Perrin White, Bryan Dickson, Soumya Adhikari, Mark Siegelman, Marilyn Alford, Nenita Torres, Tauri Harden, Lourdes Pruneda, Erica Cordova, Renee Davis, Stefani Fernandez, Jamie Arthur, Diane Wherrett, Lesley A Eisel, Brenda Ahenkorah, Natasha Razack, Mithula Sriskandarajah, William E Russell, James W Thomas, Daniel J Moore, Anne Brown, Margo Black, Eric Pittel, Faith Brendle

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.

Conflict of interest statement

Dualities:

Dr. Orban reports serving on the Data Safety Monitoring Board for Osiris Therapeutics, and being a founder of Orban Biotech LLC; Dr. Becker reports receiving a grant from Diamyd; Dr. Gitelman reports serving on an advisory board for Genentech; Dr. Golaand reports receiving grants from Diamyd and Tolerx; Dr. Gottlieb reports serving on advisory boards for Genentech, Eli Lilly, Sanofi-Aventis, and Tolerx, and reports receiving grants from Bayhill Therapeutics, Diamyd, Macrogenics, Omni BioTherapeutics, and Tolerx; Dr. Greenbaum reports receiving grants from Bayhill Therapeutics, Diamyd, and Tolerx; Dr. Marks reports serving on an advisory board for Amgen; Dr. Moran reports serving on an advisory board for Pfizer, and receiving grants from Tolerx, Merck, and Osiris Therapeutics; Dr. Raskin reports serving on advisory boards for Amgen, AstraZeneca, MannKind, and Novo-Nordisk, serving on speakers bureaus for Merck and Novo-Nordisk, and receiving grants from Aegera, Andromeda Biotech, Bayhill Therapeutics, Biodel, Boehringer Ingelheim, Calibra, CPEX, Generex, Hoffman-LaRoche, MannKind, Novo-Nordisk, Osiris Therapeutics, and Reata; Dr. Rodriguez reports serving on an advisory board for Marcadia Biotech, serving as a consultant to Eli Lilly, Genentech, Bayer, EMD Serono, and Merck, being on the speakers bureau of Eli Lilly and Novo-Nordisk, and receiving grant support from Macrogenics and Eli Lilly; Dr. Schatz reports serving on advisory boards for Eli Lilly and GlaxoSmithKline, and receiving a grant from Diamyd; Dr. Wherrett reports receiving lecture fees from Eli Lilly and Medtronic; Dr. Wilson reports serving on an advisory boards for DexCom and Genentech, and receiving grants support from Genentech, Diamyd, and Osiris Therapeutics; Dr. Skyler reports serving on boards for Amylin Pharmaceuticals, DexCom, and Sanofi-Aventis, and reports receiving grants from Bayhill Therapeutics, Halozyme, Intuity, and Osiris Therapeutics. No other potential conflict of interest relevant to this article was reported.