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

Type 1 Diabetes TrialNet ATG-GCSF Study Group

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)1267-1276
Number of pages10
JournalDiabetes
Volume68
Issue number6
DOIs
StatePublished - Jun 1 2019

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Antilymphocyte Serum
C-Peptide
Type 1 Diabetes Mellitus
Clinical Trials
T-Lymphocytes
Placebos
Granulocyte Colony-Stimulating Factor
Area Under Curve
CD4-CD8 Ratio
Regulatory T-Lymphocytes
Granulocyte-Macrophage Colony-Stimulating Factor
Meals
Flow Cytometry

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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. / Type 1 Diabetes TrialNet ATG-GCSF Study Group.

In: Diabetes, Vol. 68, No. 6, 01.06.2019, p. 1267-1276.

Research output: Contribution to journalArticle

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title = "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",
abstract = "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.",
author = "{Type 1 Diabetes TrialNet ATG-GCSF Study Group} and Haller, {Michael J.} and {Alice Long}, S. and {Lori Blanchfield}, J. and Schatz, {Desmond A.} and Skyler, {Jay S.} and Krischer, {Jeffrey P.} and Bundy, {Brian N.} and Geyer, {Susan M.} and Warnock, {Megan V.} and Miller, {Jessica L.} and Atkinson, {Mark A.} and Becker, {Dorothy J.} and Baidal, {David A.} and DiMeglio, {Linda A.} and Gitelman, {Stephen E.} and Robin Goland and Gottlieb, {Peter A.} and Herold, {Kevan C.} and Marks, {Jennifer B.} and Antoinette Moran and Henry Rodriguez and Russell, {William E.} and Wilson, {Darrell M.} and Greenbaum, {Carla J.}",
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AU - Type 1 Diabetes TrialNet ATG-GCSF Study Group

AU - Haller, Michael J.

AU - Alice Long, S.

AU - Lori Blanchfield, J.

AU - Schatz, Desmond A.

AU - Skyler, Jay S.

AU - Krischer, Jeffrey P.

AU - Bundy, Brian N.

AU - Geyer, Susan M.

AU - Warnock, Megan V.

AU - Miller, Jessica L.

AU - Atkinson, Mark A.

AU - Becker, Dorothy J.

AU - Baidal, David A.

AU - DiMeglio, Linda A.

AU - Gitelman, Stephen E.

AU - Goland, Robin

AU - Gottlieb, Peter A.

AU - Herold, Kevan C.

AU - Marks, Jennifer B.

AU - Moran, Antoinette

AU - Rodriguez, Henry

AU - Russell, William E.

AU - Wilson, Darrell M.

AU - Greenbaum, Carla J.

PY - 2019/6/1

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N2 - 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.

AB - 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.

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