Antigen-based therapy with glutamic acid decarboxylase (GAD) vaccine in patients with recent-onset type 1 diabetes: a randomised double-blind trial

Diane K Wherrett, Brian Bundy, Dorothy J Becker, Linda A DiMeglio, Stephen E Gitelman, Robin Goland, Peter A Gottlieb, Carla J Greenbaum, Kevan C Herold, Jennifer B Marks, Roshanak Monzavi, Antoinette Moran, Tihamer Orban, Jerry P Palmer, Philip Raskin, Henry Rodriguez, Desmond Schatz, Darrell M Wilson, Jeffrey P Krischer, Jay S Skyler, Type 1 Diabetes TrialNet GAD 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, Brian Bundy, Joy Ramiro, 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, Aqesha Luvon Ritzie, Sarah Muller, Ryan O'Donnell, Yazandra Parrimon, Kate Paulus, Jennifer Pilger, 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, Diane Wherett, Penelope Bingley, Roberta Cook, Jeffrey Mahon, Jerry Palmer, Carla Greenbaum, Jeffrey Krischer, Ellen Leschek, Brett Loechelt, Lisa Rafkin, Jay S Skyler, Audrey Shor, Lisa Spain, John M Lachin, Heidi Krause-Steinrauf, Paula F McGee, 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, Robin Goland, Ellen Greenberg, Mary Pat Gallagher, Jeniece Trast, Mary Chan, Kelly Smith, Henry Rodriguez, Mark Pescovitz, Linda DiMeglio, Sheryl Lynch, Maria Nicholson, Martha Mendez, Jennifer Terrell, Tihamer Orban, Joseph Wolfsdorf, Alyne Ricker, Heyam Jalahej, Debbie Conboy, Hui Zhang, Steve Fay, Darrell M Wilson, Bruce A Buckingham, Tandy Aye, Trudy Esrey, Adriana Soto, Jennifer Perry, Bonita Baker, Barbara Berry, Stephen E Gitelman, Stephen M Rosenthal, Mark Anderson, Saleh Adi, Kathleen Breen, Celia Hamilton, Peter Gottlieb, Aaron Michaels, H Peter Chase, Susan Ulmer, Sandy Barry, Lisa Meyers, Debbie Lehr, Libbie Tuthill, 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, Theresa Albright-Fischer, Jennifer Smith, Anne Street, Janice Leschyshyn, Chris Kwong, Dorothy Becker, Frederico Toledo, Ingrid Libman, Karen Riley, Kelli Delallo, Kym Smith, Diane Gwynn, Gyna Wohlers, Nursen Gurtunca, 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, Roze Kovalakovska, Lesley A Eisel, Brenda Ahenkorah, Mithula Sriskandarajah, Mary-Jo Ricci, Kevan C Herold, Laurie Feldman, Robert Sherwin, Diane K Wherrett, Brian Bundy, Dorothy J Becker, Linda A DiMeglio, Stephen E Gitelman, Robin Goland, Peter A Gottlieb, Carla J Greenbaum, Kevan C Herold, Jennifer B Marks, Roshanak Monzavi, Antoinette Moran, Tihamer Orban, Jerry P Palmer, Philip Raskin, Henry Rodriguez, Desmond Schatz, Darrell M Wilson, Jeffrey P Krischer, Jay S Skyler, Type 1 Diabetes TrialNet GAD 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, Brian Bundy, Joy Ramiro, 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, Aqesha Luvon Ritzie, Sarah Muller, Ryan O'Donnell, Yazandra Parrimon, Kate Paulus, Jennifer Pilger, 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, Diane Wherett, Penelope Bingley, Roberta Cook, Jeffrey Mahon, Jerry Palmer, Carla Greenbaum, Jeffrey Krischer, Ellen Leschek, Brett Loechelt, Lisa Rafkin, Jay S Skyler, Audrey Shor, Lisa Spain, John M Lachin, Heidi Krause-Steinrauf, Paula F McGee, 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, Robin Goland, Ellen Greenberg, Mary Pat Gallagher, Jeniece Trast, Mary Chan, Kelly Smith, Henry Rodriguez, Mark Pescovitz, Linda DiMeglio, Sheryl Lynch, Maria Nicholson, Martha Mendez, Jennifer Terrell, Tihamer Orban, Joseph Wolfsdorf, Alyne Ricker, Heyam Jalahej, Debbie Conboy, Hui Zhang, Steve Fay, Darrell M Wilson, Bruce A Buckingham, Tandy Aye, Trudy Esrey, Adriana Soto, Jennifer Perry, Bonita Baker, Barbara Berry, Stephen E Gitelman, Stephen M Rosenthal, Mark Anderson, Saleh Adi, Kathleen Breen, Celia Hamilton, Peter Gottlieb, Aaron Michaels, H Peter Chase, Susan Ulmer, Sandy Barry, Lisa Meyers, Debbie Lehr, Libbie Tuthill, 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, Theresa Albright-Fischer, Jennifer Smith, Anne Street, Janice Leschyshyn, Chris Kwong, Dorothy Becker, Frederico Toledo, Ingrid Libman, Karen Riley, Kelli Delallo, Kym Smith, Diane Gwynn, Gyna Wohlers, Nursen Gurtunca, 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, Roze Kovalakovska, Lesley A Eisel, Brenda Ahenkorah, Mithula Sriskandarajah, Mary-Jo Ricci, Kevan C Herold, Laurie Feldman, Robert Sherwin

Abstract

Background: Glutamic acid decarboxylase (GAD) is a major target of the autoimmune response that occurs in type 1 diabetes mellitus. In animal models of autoimmunity, treatment with a target antigen can modulate aggressive autoimmunity. We aimed to assess whether immunisation with GAD formulated with aluminum hydroxide (GAD-alum) would preserve insulin production in recent-onset type 1 diabetes.

Methods: Patients aged 3-45 years who had been diagnosed with type 1 diabetes for less than 100 days were enrolled from 15 sites in the USA and Canada, and randomly assigned to receive one of three treatments: three injections of 20 μg GAD-alum, two injections of 20 μg GAD-alum and one of alum, or 3 injections of alum. Injections were given subcutaneously at baseline, 4 weeks later, and 8 weeks after the second injection. The randomisation sequence was computer generated at the TrialNet coordinating centre. Patients and study personnel were masked to treatment assignment. The primary outcome was the baseline-adjusted geometric mean area under the curve (AUC) of serum C-peptide during the first 2 h of a 4-h mixed meal tolerance test at 1 year. Secondary outcomes included changes in glycated haemoglobin A(1c) (HbA(1c)) and insulin dose, and safety. Analysis included all randomised patients with known measurements. This trial is registered with ClinicalTrials.gov, number NCT00529399.

Findings: 145 patients were enrolled and treated with GAD-alum (n=48), GAD-alum plus alum (n=49), or alum (n=48). At 1 year, the 2-h AUC of C-peptide, adjusted for age, sex, and baseline C-peptide value, was 0·412 nmol/L (95% CI 0·349-0·478) in the GAD-alum group, 0·382 nmol/L (0·322-0·446) in the GAD-alum plus alum group, and 0·413 nmol/L (0·351-0·477) in the alum group. The ratio of the population mean of the adjusted geometric mean 2-h AUC of C-peptide was 0·998 (95% CI 0·779-1·22; p=0·98) for GAD-alum versus alum, and 0·926 (0·720-1·13; p=0·50) for GAD-alum plus alum versus alum. HbA(1c), insulin use, and the occurrence and severity of adverse events did not differ between groups.

Interpretation: Antigen-based immunotherapy therapy with two or three doses of subcutaneous GAD-alum across 4-12 weeks does not alter the course of loss of insulin secretion during 1 year in patients with recently diagnosed type 1 diabetes. Although antigen-based therapy is a highly desirable treatment and is effective in animal models, translation to human autoimmune disease remains a challenge.

Funding: US National Institutes of Health.

Copyright © 2011 Elsevier Ltd. All rights reserved.

Figures

Figure 1
Figure 1
(A): Enrollment, Randomization, and Follow-up of Study Participants. (B): Rate of enrollment over time. Indicated is the point at which approval was granted to change the lower age for eligibility of enrollment from 16 years to 3 years.
Figure 1
Figure 1
(A): Enrollment, Randomization, and Follow-up of Study Participants. (B): Rate of enrollment over time. Indicated is the point at which approval was granted to change the lower age for eligibility of enrollment from 16 years to 3 years.
Figure 2
Figure 2
(A): The population mean (and 95% confidence intervals) of stimulated C-peptide 2-hour AUC mean (expressed as nmol/L) over time for each treatment group. The estimates are from the analysis of covariance model adjusting for age, gender, baseline value of C-peptide, and treatment assignment. Y-axis is on a log(y + 1) scale. (B): The fitted line representing the population mean of stimulated C-peptide 2-hour AUC mean over time for each treatment group. The estimates are from the analysis of mixed effects model adjusting for age, gender, baseline value of C-peptide, and treatment assignment, and including a fixed effect for time as a linear line on the log(y + 1) scale. (C): The proportion of subjects with 2 hour peak C-peptide remaining at or above 0.2 nmol/L over time for each treatment group.
Figure 2
Figure 2
(A): The population mean (and 95% confidence intervals) of stimulated C-peptide 2-hour AUC mean (expressed as nmol/L) over time for each treatment group. The estimates are from the analysis of covariance model adjusting for age, gender, baseline value of C-peptide, and treatment assignment. Y-axis is on a log(y + 1) scale. (B): The fitted line representing the population mean of stimulated C-peptide 2-hour AUC mean over time for each treatment group. The estimates are from the analysis of mixed effects model adjusting for age, gender, baseline value of C-peptide, and treatment assignment, and including a fixed effect for time as a linear line on the log(y + 1) scale. (C): The proportion of subjects with 2 hour peak C-peptide remaining at or above 0.2 nmol/L over time for each treatment group.
Figure 3
Figure 3
(A): The population mean of HbA1c over time for each treatment group. The estimates are from the analysis of covariance model adjusting for age, gender, baseline value of HbA1c, and treatment assignment. (B): The population mean of insulin use per kilogram of body weight over time (in 3 month interval) for each treatment group. The estimates are from the analysis of covariance model adjusting for age, gender, baseline value of HbA1c, and treatment assignment.
Figure 4
Figure 4
(A): The ratio (GAD-alum ×3 to alum ×3) of treatment effect on 1 year stimulated C-peptide AUC mean within categories of pre-specified baseline factors. The estimates are from the analysis of covariance modeling log of C-peptide adjusting for age, gender, baseline value of C-peptide, the indicated categorized factor, treatment assignment, and treatment interaction terms. The homogeneity test of treatment effect was significant for DR3 allele status (p = 0.04). (B): The ratio (GAD-alum ×2 to alum ×3) of treatment effect on 1 year stimulated C-peptide AUC mean within categories of pre-specified baseline factors. The estimates are from the analysis of covariance modeling log of C-peptide adjusting for age, gender, baseline value of C-peptide, the indicated categorized factor, treatment assignment, and treatment interaction terms.

Source: PubMed

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