Low-Dose Anti-Thymocyte Globulin Preserves C-Peptide, Reduces HbA1c, and Increases Regulatory to Conventional T-Cell Ratios in New-Onset Type 1 Diabetes: Two-Year Clinical Trial Data
Authors: Haller Michael J. , Long S. Alice , Blanchfield J. Lori , Schatz Desmond A. , Skyler Jay S. , Krischer Jeffrey P. , Bundy Brian N. , Geyer Susan M. , Warnock Megan V. , Miller Jessica L. , Atkinson Mark A. , Becker Dorothy J. , Baidal David A. , DiMeglio Linda A. , Gitelman Stephen E. , Goland Robin , Gottlieb Peter A. , Herold Kevan C. , Marks Jennifer B. , Moran Antoinette , Rodriguez Henry , Russell William E. , Wilson Darrell M. , Greenbaum Carla J. ,   Type 1 Diabetes TrialNet ATG-GCSF Study Group, Greenbaum Carla J. , Atkinson Mark A. , Baidal David A. , Battaglia Manuela , Becker Dorothy , Bingley Penelope , Bosi Emanuele , Buckner Jane , Clements Mark , Colman Peter G. , DiMeglio Linda , Evans-Molina Carmella , Gitelman Stephen E. , Goland Robin , Gottlieb Peter , Herold Kevan , Knip Mikael , Krischer Jeffrey P. , Lernmark Ake , Moore Wayne , Moran Antoinette , Muir Andrew , Palmer Jerry , Peakman Mark , Philipson Louis , Raskin Philip , Redondo Maria , Rodriguez Henry , Russell William , Schatz Desmond A. , Sosenko Jay M. , Spain Lisa , Wentworth John , Wherrett Diane , Wilson Darrell M. , Winter William , Ziegler Anette , Anderson Mark , Antinozzi Peter , Insel Richard , Kay Thomas , Marks Jennifer B. , Pugliese Alberto , Roep Bart , Skyler Jay S. , Toppari Jorma , Greenbaum Carla J. , Krischer Jeffrey P. , Leschek Ellen , Spain Lisa , Bourcier Katarzyna , Insel Richard , Ridge John , Skyler Jay S. , Greenbaum Carla J. , Rafkin Lisa , Sosenko Jay M. , Skyler Jay S. , Santiago Irene , Krischer Jeffrey P. , Bundy Brian , Abbondondolo Michael , Adams Timothy , Asif Ilma , Bjellquist Jenna , Boonstra Matthew , Burroughs Cristina , Cleves Mario , Cuthbertson David , DeSalvatore Meagan , Eberhard Christopher , Fiske Steve , Ford Julie , Garmeson Jennifer , Geyer Susan , Hays Brian , Henderson Courtney , Henry Martha , Heyman Kathleen , Hsiao Belinda , Karges Christina , Koziol Beata-Gabriela , Lane Lindsay , Liu Shu , Lloyd Jennifer , Maddox Kristin , Malloy Jamie , Martin Julie , McNeill Cameron , Moore Margaret , Muller Sarah , Nguyen Thuy , Nunez Jodie , O’Donnell Ryan , Parker Melissa , Pereyra M.J. , Roberts Amy , Sadler Kelly , Sullivan Christine , Tamura Roy , Walker-Veras Elon , Warnock Megan V. , Wood Keith , Wood Rebecca , Xu Ping , Yanek Vanessa , Young Kenneth , Amado Darlene , Kinderman Amanda , Leinbach Ashley , Miller Jessica , Reed Nichole , Stavros Tina , Leschek Ellen , Spain Lisa , Blumberg Emily , Aas Sean , Beck Gerald , Gubitosi-Klug Rose , Laffel Lori , Vigersky Robert , Wallace Dennis , Brillon David , Veatch Robert , Loechelt Brett , Baden Lindsey , Gottlieb Peter , Green Michael , Leschek Ellen , Weinberg Adriana , Marcovina Santica , Palmer Jerry P. , Tischfield Jay , Weinberg Adriana , Winter William , Yu Liping , Shultz Annie , Batts Emily , Pagryzinski Arielle , Ramey Mary , Tobin Meghan , Fitzpatrick Kristin , Guerra Randy , Romasco Melita , Webb Christopher , Gottlieb Peter , Barr Maya , Drye Mary , Lykens Jordan , Michels Aaron , Schauwecker Allison , Steck Andrea , Wadwa Paul , Greenbaum Carla J. , Buckner Jane , Hao Wei , Lord Sandra , McCulloch-Olson Marli , Ramey Mary , Sachter Elaine , Snavely Jenna , Tobin Meghan , Tordillos Corinna , VanBuecken Dana , Goland Robin , Alvarez Analia , Bogun Magdalena , Gandica Rachelle , Leibel Natasha , Pollak Sarah , Softness Barney , Williams Kristen , Nelson Bryce , Amrhein James , Looper Lisa , Moreland Elaine , Smith Andrew , Weir Beth , Wise Lori , DiMeglio Linda , Evans-Molina Carmella , Mantravadi Manasa , Mullen Maureen , Patrick Vanessa , Spall Maria , Woerner Stephanie , Wilson Darrell M. , Arrizon-Ruiz Nora , Aye Tandy , Bachrach Laura , Barahona Karen , Esrey Trudy , Nally Laura , Gitelman Stephen E. , Anderson Mark , Auerback Glenna , Buchanan Jeanne , Ferrara Christine T. , Ko Karen , Sanda Srinath , Torok Christine , Wesch Rebecca , Haller Michael J. , Albanese-O'Neill Anastasia , Brusko Todd , Cintron Miriam , Hosford Jennifer , Jacobsen Laura M. , Rohrs Henry , Schatz Desmond A. , Silverstein Janet , Towe Paula , Baidal David A. , Blaschke Carlos , Matheson Della , Sanchez Janine , Sanders-Branca Natalia , Skyler Jay S. , Sosenko Jay M. , Moran Antoinette , Leschyshyn Janice , McVean Jennifer , Nathan Brandon , Nelson Brittney , Pappenfus Beth , Ruedy Jessica , Street Anne , Sunni Muna , Weingartner Darcy , Becker Dorothy , DeLallo Kelli , Diaz Ana , Groscost David , Beth Klein Mary , Libman Ingrid , Riley Karen , Rodriguez Henry , Bollepalli Sureka , Brownstein Rachel , Eyth Emily , Henson Danielle , Laine Michele , Shulman Dorothy , Russell William , Brendle Faith , Brown Anne , Dixon Brenna , Gregory Justin , Moore Dan , Thomas James , Herold Kevan , Feldman Laurie , Tamborlane William 
Published: April 2019

A three-arm, randomized, double-masked, placebo-controlled phase 2b trial performed by the Type 1 Diabetes TrialNet Study Group previously demonstrated that low-dose anti-thymocyte globulin (ATG) (2.5 mg/kg) preserved β-cell function and reduced HbA1c for 1 year in new-onset type 1 diabetes. Subjects (N = 89) were randomized to 1) ATG and pegylated granulocyte colony-stimulating factor (GCSF), 2) ATG alone, or 3) placebo. Herein, we report 2-year area under the curve (AUC) C-peptide and HbA1c, prespecified secondary end points, and potential immunologic correlates. The 2-year mean mixed-meal tolerance test–stimulated AUC C-peptide, analyzed by ANCOVA adjusting for baseline C-peptide, age, and sex (n = 82) with significance defined as one-sided P &lt; 0.025, was significantly higher in subjects treated with ATG versus placebo (P = 0.00005) but not ATG/GCSF versus placebo (P = 0.032). HbA1c was significantly reduced at 2 years in subjects treated with ATG (P = 0.011) and ATG/GCSF (P = 0.022) versus placebo. Flow cytometry analyses demonstrated reduced circulating CD4:CD8 ratio, increased regulatory T-cell:conventional CD4 T-cell ratios, and increased PD-1+CD4+ T cells following low-dose ATG and ATG/GCSF. Low-dose ATG partially preserved β-cell function and reduced HbA1c 2 years after therapy in new-onset type 1 diabetes. Future studies should determine whether low-dose ATG might prevent or delay the onset of type 1 diabetes.