Antithymocyte globulin therapy for patients with recent-onset type 1 diabetes: 2 year results of a randomised trial

Abstract

Aims/hypothesis: Type 1 diabetes results from T cell mediated destruction of beta cells. We conducted a trial of antithymocyte globulin (ATG) in new-onset type 1 diabetes (the Study of Thymoglobulin to ARrest T1D [START] trial). Our goal was to evaluate the longer-term safety and efficacy of ATG in preserving islet function at 2 years.

Methods: A multicentre, randomised, double-blind, placebo-controlled trial of 6.5 mg/kg ATG (Thymoglobulin) vs placebo in patients with new-onset type 1 diabetes was conducted at seven university medical centres and one Children's Hospital in the USA. The site-stratified randomisation scheme was computer generated at the data coordinating centre using permuted-blocks of size 3 or 6. Eligible participants were between the ages of 12 and 35, and enrolled within 100 days from diagnosis. Subjects were randomised to 6.5 mg/kg ATG (thymoglobulin) vs placebo in a 2:1 ratio. Participants were blinded, and the study design included two sequential patient-care teams: an unblinded study-drug administration team (for the first 8 weeks), and a blinded diabetes management team (for the remainder of the study). Endpoints assessed at 24 months included meal-stimulated C-peptide AUC, safety and immunological responses.

Results: Fifty-eight patients were enrolled; at 2 years, 35 assigned to ATG and 16 to placebo completed the study. The pre-specified endpoints were not met. In post hoc analyses, older patients (age 22-35 years) in the ATG group had significantly greater C-peptide AUCs at 24 months than placebo patients. Using complete preservation of baseline C-peptide at 24 months as threshold, nine of 35 ATG-treated participants (vs 2/16 placebo participants) were classified as responders; nine of 11 responders (67%) were older. All participants reported at least one adverse event (AE), with 1,148 events in the 38 ATG participants vs 415 in the 20 placebo participants; a comparable number of infections were noted in the ATG and placebo groups, with no opportunistic infections nor difficulty clearing infections in either group. Circulating T cell subsets depleted by ATG partially reconstituted, but regulatory, naive and central memory subsets remained significantly depleted at 24 months. Beta cell autoantibodies did not change over the 24 months in the ATG-treated or placebo participants. At 12 months, ATG-treated participants had similar humoral immune responses to tetanus and HepA vaccines as placebo-treated participants, and no increased infections.

Conclusions/interpretation: A brief course of ATG substantially depleted T cell subsets, including regulatory cells, but did not preserve islet function 24 months later in the majority of patients with new-onset type 1 diabetes. ATG preserved C-peptide secretion in older participants, which may warrant further study.

Trial registration: ClinicalTrials.gov NCT00515099 PUBLIC DATA REPOSITORY: START datasets are available in TrialShare www.itntrialshare.org

Funding: National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH). The trial was conducted by the Immune Tolerance Network (ITN).

Keywords: ATG; Beta cells; C-peptide; START trial; T cells; Thymoglobulin; Tregs; Type 1 diabetes.

Figures

Fig. 1

Change in C-peptide AUC from baseline to 24 months in participants assigned to ATG and placebo in the ITT sample. (a) Change in 2 h C-peptide AUC in all participants. The number of evaluable participants (n) at each time point is shown in ESM Fig. 1. (b) Change in 2 h C-peptide AUC in participants aged 12–21 years. (ATG, n = 26; placebo, n = 12). (c) Change in 2 h C-peptide AUC in participants aged 22–35 years (ATG, n = 12; placebo, n = 8). Black, ATG; grey, placebo. Data were analysed by fitting ANCOVA models with adjustment for baseline levels and plotted as unadjusted means ± 95% CI; p values are two-sided; *p < 0.05

Fig. 2

Responder analysis based on preservation of baseline C-peptide secretion at 2 years. The % change in 2 h C-peptide AUC from baseline to 2 years was plotted for each participant as a function of age (black circles, younger participants [12–21 years]; white circles, older participants [22–35 years]); (a) ATG arm; (b) placebo arm. Participants to the right of the dotted line (>0% change) are denoted ‘responders’

Fig. 3

Changes in T cell subsets from baseline to 24 months. (a) Absolute counts of total CD4+ T cells. (b) Absolute counts of total CD8+ T cells. (c) Percentage change from baseline of naive CD4+ T cells (Tn; CD4+CD45RA+CD45RO−CD62Lhi); central memory CD4+ T cells (Tcm; CD4+CD45RA−CD45RO+CD62Lhi); and regulatory CD4+ T cells (Treg; CD4+CD127−/loCD25hi). (d) Percentage change from baseline of CD8+ Tn cells (CD8+CD45RA+CD45RO−CD62Lhi) and CD8+ Tcm cells (CD8+CD45RA−CD45RO+CD62Lhi). Black circles, ATG; grey circles, placebo in (a) and (b); diamonds, Tcm; inverted triangles, Treg; squares, Tn in (c) and (d). All data are mean values ± SEM. Data were log2-transformed and analysed using one-sided paired t tests to test whether the absolute cell counts at month 24 were significantly lower than baseline within the ATG group. ***p < 0.001, **p < 0.01