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 b-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 < 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 b-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.
Bibliographical noteFunding Information:
Funding. The sponsor of the trial was the Type 1 Diabetes TrialNet Study Group. The Type 1 Diabetes TrialNet Study Group is a clinical trials network funded by the National Institutes of Health (NIH) through the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Allergy and Infectious Diseases, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development through the cooperative agreements U01-DK-061010, U01-DK-061034, U01-DK-061042, U01-DK-061058, U01-DK-085465, U01-DK-085461, UC4-DK-085466, U01-DK-085476, U01-DK-085499, U01-DK-085509, U01-DK-097835, U01-DK-103266, U01-DK-103282, U01-DK-106984, U01-DK-107014, and UC4-DK-106993; the National Center for Research Resources through Clinical Translational Science Awards UL1-TR-001085, UL1-TR-001427, UL1-TR-001863, UL1-TR-001082, UL1-TR-000114, UL1-TR-001857, UL1-TR-000445, UL1-TR-002529, UL1-TR-001872, UL1-TR-002243, and PO1-NIH-AI-42288; the JDRF; and the American Diabetes Association. The flow cytometry was supported by the Immune Tolerance Network and sponsored by the National Institute of Allergy and Infectious Diseases under award number UM1-AI-109565. Additional funding sources for this study were provided by The Leona M. and Harry B. Helmsley Charitable Trust.