Low-Dose Anti-Thymocyte Globulin (ATG) Preserves β-Cell Function and Improves HbA1c in New-Onset Type 1 Diabetes

Michael J. Haller, Desmond A. Schatz, Jay S. Skyler, Jeffrey P. Krischer, Brian N. Bundy, Jessica L. Miller, Mark A. Atkinson, Dorothy J. Becker, David Baidal, Linda A. DiMeglio, Stephen E. Gitelman, Robin Goland, Peter A. Gottlieb, Kevan C. Herold, Jennifer B. Marks, Antoinette Moran, Henry Rodriguez, William Russell, Darrell M. Wilson, Carla J. Greenbaum, C. Greenbaum, M. Atkinson, D. Baidal, M. Battaglia, D. Becker, P. Bingley, E. Bosi, J. Buckner, M. Clements, P. Colman, L. DiMeglio, C. Evans-Molina, S. Gitelman, R. Goland, P. Gottlieb, K. Herold, M. Knip, J. Krischer, A. Lernmark, W. Moore, A. Moran, A. Muir, J. Palmer, M. Peakman, L. Philipson, P. Raskin, M. Redondo, H. Rodriguez, W. Russell, L. Spain, D.A. Schatz, J. Sosenko, D. Wherrett, D. Wilson, W. Winter, A. Ziegler, M. Anderson, P. Antinozzi, C. Benoist, J. Blum, K. Bourcier, P. Chase, M. Clare-Salzler, R. Clynes, C. Cowie, G. Eisenbarth, C.G. Fathman, G. Grave, L. Harrison, B. Hering, R. Insel, S. Jordan, F. Kaufman, T. Kay, N. Kenyon, R. Klines, J. Lachin, E. Leschek, J. Mahon, J.B. Marks, R. Monzavi, K. Nanto-Salonen, G. Nepom, T. Orban, R. Parkman, M. Pescovitz, J. Peyman, A. Pugliese, J. Ridge, B. Roep, M. Roncarolo, P. Savage, O. Simell, R. Sherwin, M. Siegelman, J.S. Skyler, A. Steck, J. Thomas, M. Trucco, J. Wagner, Katarzyna Bourcier, Carla J. Greenbaum, Jeffrey P. Krischer, Ellen Leschek, Lisa Rafkin, Lisa Spain, Catherine Cowie, Mary Foulkes, Richard Insel, Heidi Krause-Steinrauf, John M. Lachin, Saul Malozowski, John Peyman, John Ridge, Peter Savage, Jay S. Skyler, Stephanie J. Zafonte, Carla J. Greenbaum, Lisa Rafkin, Jay M. Sosenko, Jay S. Skyler, Norma S. Kenyon, Irene Santiago, Jeffrey P. Krischer, Brian Bundy, Michael Abbondondolo, Timothy Adams, Darlene Amado, Ilma Asif, Matthew Boonstra, David Boulware, Brian Bundy, Cristina Burroughs, David Cuthbertson, Christopher Eberhard, Steve Fiske, Julie Ford, Jennifer Garmeson, Heather Guillette, Susan Geyer, Brian Hays, Courtney Henderson, Martha Henry, Kathleen Heyman, Belinda Hsiao, Christina Karges, Amanda Kinderman, Lindsay Lane, Ashley Leinbach, Shu Liu, Jennifer Lloyd, Jamie Malloy, Kristin Maddox, Julie Martin, Jessica Miller, Margaret Moore, Sarah Muller, Thuy Nguyen, Ryan O’Donnell, Melissa Parker, M.J. Pereyra, Nichole Reed, Amy Roberts, Kelly Sadler, Tina Stavros, Roy Tamura, Keith Wood, Ping Xu, Kenneth Young, Persida Alies, Franz Badias, Aaron Baker, Monica Bassi, Craig Beam, David Boulware, London Bounmananh, Susan Bream, Mary Deemer, Doug Freeman, Jessica Gough, Jinin Ginem, Moriah Granger, Mary Holloway, Michelle Kieffer, Page Lane, Pat Law, Cristin Linton, Lavanya Nallamshetty, Vanessa Oduah, Yazandra Parrimon, Kate Paulus, Jennifer Pilger, Joy Ramiro, AQesha Luvon, Archana Ritzie, Audrey Sharma, Xiaohong Shor, Amanda Song, Jeanne Terry, Margaret Weinberger, Judith Wootten, Ellen Fradkin, Lisa Leschek, Catherine Spain, Saul Cowie, Peter Malozowski, Gerald Savage, Emily Beck, Rose Blumberg, Lori Gubitosi-Klug, Robert Laffel, Dennis Veatch, Jonathan Wallace, David Braun, Ake Brillon, Bernard Lernmark, Herman Lo, Ali Mitchell, Jorn Naji, Trevor Nerup, Michael Orchard, Anastasios Steffes, Bernard Tsiatis, Brett Zinman, Lindsey Loechelt, Michael Baden, Adriana Green, Santica Weinberg, Jerry P. Marcovina, Adriana Palmer, Liping Weinberg, William Yu, George S. Winter, Annie Eisenbarth, Emily Shultz, Kristin Batts, Mary Fitzpatrick, Randy Ramey, Christopher Guerra, Melita Webb, Carla Romasco, Sandra Greenbaum, Dana Lord, Wei VanBuecken, Marli Hao, Deborah McCulloch, Kim Hefty, Robin Varner, Ellen Goland, Sarah Greenberg, Bryce Pollack, Lisa Nelson, Linda Looper, Maria DiMeglio, Carmella Spall, Manasa Evans-Molina, Juan Mantravadi, Maureen Sanchez, Vanessa Mullen, Stephanie Patrick, Darrell M. Woerner, Tandy Wilson, Trudy Aye, Karen Esrey, Bonita Barahona, Hiyam Baker, Catherine Bitar, Martha Ghodrat, Stephen E. Hamilton, Christine T. Gitelman, Srinath Ferrara, Rebecca Sanda, Christine Wesch, Peter Torok, Jordan Gottlieb, Carrie Lykens, Aaron Brill, Allison Michels, Michael J. Schauwecker, Desmond A. Haller, Mark A. Schatz, Laura M. Atkinson, Miriam Jacobsen, Todd M. Cintron, Clive H. Brusko, Clay E. Wasserfall, Jay S. Mathews, Jennifer M. Skyler, David Marks, Carlos Baidal, Della Blaschke, Antoinette Matheson, Brandon Moran, Anne Nathan, Janice Street, Beth Leschyshyn, Brittney Pappenfus, Nancy Nelson, Dorothy Flaherty, Kelly Becker, David Delallo, Karen Groscost, Henry Riley, Danielle Rodriguez, Emily Henson, William Eyth, Anne Russell, Faith Brown, Kevan Brendall, Herold, Laurie Feldman

A pilot study suggested that combination therapy with low-dose anti-thymocyte globulin (ATG) and pegylated granulocyte colony-stimulating factor (GCSF) preserves C-peptide in established type 1 diabetes (T1D) (duration 4 months to 2 years). We hypothesized that 1) low-dose ATG/GCSF or 2) low-dose ATG alone would slow the decline of β-cell function in patients with new-onset T1D (duration <100 days). A three-arm, randomized, double-masked, placebo-controlled trial was performed by the Type 1 Diabetes TrialNet Study Group in 89 subjects: 29 subjects randomized to ATG (2.5 mg/kg intravenously) followed by pegylated GCSF (6 mg subcutaneously every 2 weeks for 6 doses), 29 to ATG alone (2.5 mg/kg), and 31 to placebo. The primary end point was mean area under the curve (AUC) C-peptide during a 2-h mixed-meal tolerance test 1 year after initiation of therapy. Significance was defined as one-sided P value < 0.025. The 1-year mean AUC C-peptide was significantly higher in subjects treated with ATG (0.646 nmol/L) versus placebo (0.406 nmol/L) (P = 0.0003) but not in those treated with ATG/GCSF (0.528 nmol/L) versus placebo (P = 0.031). HbA1c was significantly reduced at 1 year in subjects treated with ATG and ATG/GCSF, P = 0.002 and 0.011, respectively. Low-dose ATG slowed decline of C-peptide and reduced HbA1c in new-onset T1D. Addition of GCSF did not enhance C-peptide preservation afforded by low-dose ATG. Future studies should be considered to determine whether low-dose ATG alone or in combination with other agents may prevent or delay the onset of the disease.