Low-Dose Anti-Thymocyte Globulin (ATG) Preserves β-Cell Function and Improves HbA1c in New-Onset Type 1 Diabetes
Authors: Haller Michael J. , Schatz Desmond A. , Skyler Jay S. , Krischer Jeffrey P. , Bundy Brian N. , Miller Jessica L. , Atkinson Mark A. , Becker Dorothy J. , Baidal David , DiMeglio Linda A. , Gitelman Stephen E. , Goland Robin , Gottlieb Peter A. , Herold Kevan C. , Marks Jennifer B. , Moran Antoinette , Rodriguez Henry , Russell William , Wilson Darrell M. , Greenbaum Carla J. ,   Type 1 Diabetes TrialNet ATG-GCSF Study Group, Greenbaum C. , Atkinson M. , Baidal D. , Battaglia M. , Becker D. , Bingley P. , Bosi E. , Buckner J. , Clements M. , Colman P. , DiMeglio L. , Evans-Molina C. , Gitelman S. , Goland R. , Gottlieb P. , Herold K. , Knip M. , Krischer J. , Lernmark A. , Moore W. , Moran A. , Muir A. , Palmer J. , Peakman M. , Philipson L. , Raskin P. , Redondo M. , Rodriguez H. , Russell W. , Spain L. , Schatz D.A. , Sosenko J. , Wherrett D. , Wilson D. , Winter W. , Ziegler A. , Anderson M. , Antinozzi P. , Benoist C. , Blum J. , Bourcier K. , Chase P. , Clare-Salzler M. , Clynes R. , Cowie C. , Eisenbarth G. , Fathman C.G. , Grave G. , Harrison L. , Hering B. , Insel R. , Jordan S. , Kaufman F. , Kay T. , Kenyon N. , Klines R. , Lachin J. , Leschek E. , Mahon J. , Marks J.B. , Monzavi R. , Nanto-Salonen K. , Nepom G. , Orban T. , Parkman R. , Pescovitz M. , Peyman J. , Pugliese A. , Ridge J. , Roep B. , Roncarolo M. , Savage P. , Simell O. , Sherwin R. , Siegelman M. , Skyler J.S. , Steck A. , Thomas J. , Trucco M. , Wagner J. , Bourcier Katarzyna , Greenbaum Carla J. , Krischer Jeffrey P. , Leschek Ellen , Rafkin Lisa , Spain Lisa , Cowie Catherine , Foulkes Mary , Insel Richard , Krause-Steinrauf Heidi , Lachin John M. , Malozowski Saul , Peyman John , Ridge John , Savage Peter , Skyler Jay S. , Zafonte Stephanie J. , Greenbaum Carla J. , Rafkin Lisa , Sosenko Jay M. , Skyler Jay S. , Kenyon Norma S. , Santiago Irene , Krischer Jeffrey P. , Bundy Brian , Abbondondolo Michael , Adams Timothy , Amado Darlene , Asif Ilma , Boonstra Matthew , Boulware David , Bundy Brian , Burroughs Cristina , Cuthbertson David , Eberhard Christopher , Fiske Steve , Ford Julie , Garmeson Jennifer , Guillette Heather , Geyer Susan , Hays Brian , Henderson Courtney , Henry Martha , Heyman Kathleen , Hsiao Belinda , Karges Christina , Kinderman Amanda , Lane Lindsay , Leinbach Ashley , Liu Shu , Lloyd Jennifer , Malloy Jamie , Maddox Kristin , Martin Julie , Miller Jessica , Moore Margaret , Muller Sarah , Nguyen Thuy , O’Donnell Ryan , Parker Melissa , Pereyra M.J. , Reed Nichole , Roberts Amy , Sadler Kelly , Stavros Tina , Tamura Roy , Wood Keith , Xu Ping , Young Kenneth , Alies Persida , Badias Franz , Baker Aaron , Bassi Monica , Beam Craig , Boulware David , Bounmananh London , Bream Susan , Deemer Mary , Freeman Doug , Gough Jessica , Ginem Jinin , Granger Moriah , Holloway Mary , Kieffer Michelle , Lane Page , Law Pat , Linton Cristin , Nallamshetty Lavanya , Oduah Vanessa , Parrimon Yazandra , Paulus Kate , Pilger Jennifer , Ramiro Joy , Luvon AQesha , Ritzie Archana , Sharma Audrey , Shor Xiaohong , Song Amanda , Terry Jeanne , Weinberger Margaret , Wootten Judith , Fradkin Ellen , Leschek Lisa , Spain Catherine , Cowie Saul , Malozowski Peter , Savage Gerald , Beck Emily , Blumberg Rose , Gubitosi-Klug Lori , Laffel Robert , Veatch Dennis , Wallace Jonathan , Braun David , Brillon Ake , Lernmark Bernard , Lo Herman , Mitchell Ali , Naji Jorn , Nerup Trevor , Orchard Michael , Steffes Anastasios , Tsiatis Bernard , Zinman Brett , Loechelt Lindsey , Baden Michael , Green Adriana , Weinberg Santica , Marcovina Jerry P. , Palmer Adriana , Weinberg Liping , Yu William , Winter George S. , Eisenbarth Annie , Shultz Emily , Batts Kristin , Fitzpatrick Mary , Ramey Randy , Guerra Christopher , Webb Melita , Romasco Carla , Greenbaum Sandra , Lord Dana , VanBuecken Wei , Hao Marli , McCulloch Deborah , Hefty Kim , Varner Robin , Goland Ellen , Greenberg Sarah , Pollack Bryce , Nelson Lisa , Looper Linda , DiMeglio Maria , Spall Carmella , Evans-Molina Manasa , Mantravadi Juan , Sanchez Maureen , Mullen Vanessa , Patrick Stephanie , Woerner Darrell M. , Wilson Tandy , Aye Trudy , Esrey Karen , Barahona Bonita , Baker Hiyam , Bitar Catherine , Ghodrat Martha , Hamilton Stephen E. , Gitelman Christine T. , Ferrara Srinath , Sanda Rebecca , Wesch Christine , Torok Peter , Gottlieb Jordan , Lykens Carrie , Brill Aaron , Michels Allison , Schauwecker Michael J. , Haller Desmond A. , Schatz Mark A. , Atkinson Laura M. , Jacobsen Miriam , Cintron Todd M. , Brusko Clive H. , Wasserfall Clay E. , Mathews Jay S. , Skyler Jennifer M. , Marks David , Baidal Carlos , Blaschke Della , Matheson Antoinette , Moran Brandon , Nathan Anne , Street Janice , Leschyshyn Beth , Pappenfus Brittney , Nelson Nancy , Flaherty Dorothy , Becker Kelly , Delallo David , Groscost Karen , Riley Henry , Rodriguez Danielle , Henson Emily , Eyth William , Russell Anne , Brown Faith , Brendall Kevan , Herold  , Feldman Laurie 
Published: July 2018

OBJECTIVE
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 &lt;100 days).

RESEARCH DESIGN AND METHODS
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 &lt; 0.025.

RESULTS
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.

CONCLUSIONS
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.