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

Abstract

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 <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 < 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). HbA_1c 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 HbA_1c 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.

Trial registration: ClinicalTrials.gov NCT02215200.

Figure 1

Consort diagram. A total of 113 subjects were screened for eligibility, of whom 89 were randomized and 87 completed the primary outcome measure at 1 year. One subject was randomized but withdrew consent prior to receiving any study drug. All remaining participants received ATG/placebo infusions as specified in the protocol. This included two participants who received reduced doses per protocol specifications (one ATG and one placebo).

Figure 2

A–E: Effects of low-dose ATG and low-dose ATG/GCSF on C-peptide (A), mixed model predicted C-peptide (B), HbA_1c (C), insulin dose (D), and CD4/CD8 ratio (E). A and C–E show adjusted means and 95% CI at each time point. B shows the mixed model predicted population mean of the C-peptide AUC mean by treatment. In all figures, the placebo group is red, ATG/GCSF is green, and ATG alone is blue.