New research presented at this year’s Annual Meeting of the European Association for the Study of Diabetes (EASD) in Vienna, Austria (15-19 September) and published simultaneously inThe Lancetshows that a much lower dose than previously thought of the old immunomodulatory drug anti-thymocyte globulin (ATG) is safe and effective in preventing progression oftype 1 diabetes(T1D) in young people. The authors, led by EASD President Professor Chantal Mathieu, Department of Endocrinology, UZ Leuven, Belgium, say that the trial findings open up the potential use of this affordable, repurposed agent, ATG, in a low and safe dose, as a disease-modifying agent in children and adolescents with newly diagnosed clinical T1D. T1D is a chronic disease affecting approximately 9·5 million people worldwide. T1D affects both adults and children, but particularly in children and adolescents incidence rates have been rising by more than 2% per year in the last 20 years. Growing insight into T1D pathogenesis as anautoimmune diseasewhere destruction of pancreatic insulin-producing beta-cells leads toinsulindependence, has allowed identification of promising disease-modifying interventions. Several interventions have been tested in people with recent-onset clinical T1D (stage 3), and demonstrated relative therapeutic success, with preservation of stimulated C-peptide (a biomarker of beta cell viability) in the first year after diagnosis. ATG is a well-known drug in transplantation immunology with over 35 years of use. It is an immunomodulatory drug made of antibodies that target T lymphocytes, which are cells of the immune system that can attack the body's own tissues (as happens in T1D). It is produced by immunising rabbits with human T cells and then collecting and purifying the antibodies from the animals' blood. In the present study ATG was given intravenously over 2 consecutive days in a double-blind manner, with a randomised design, placebo controlled. Participants aged between 5-25 years diagnosed with clinical, stage 3 T1D between 3-9 weeks before treatment, having random C-peptide levels 0.2 nmol/L or above and at least one diabetes-related autoantibody (GADA, IA-2A or ZnT8) (confirming presence of T1D) were recruited in 14 hospitals, in 8 European countries*. All study centres were part of the INNODIA IHI consortium (grant number 115797), funded by the Innovative Initiative 2 Joint Undertaking and the trial was sponsored by UZ Leuven, under the guidance of Professor Mathieu. A novel, adaptive trial design was used, to allow testing of multiple doses of ATG in a single trial. The primary outcome of the trial was each patient’s C-peptide level (and thus beta cell function) during a 2-hour mixed meal tolerance test, conducted 12 months after treatment, assessed by a statistical method called area under the curve (AUC). Participants were mainly European Caucasian, had a median age of 13·0 years, a median duration of diabetes of 51 days, a mean HbA1c (glycated haemoglobin) of 7.79 % and a median AUC of the stimulated C-peptide of 0·82 nmol/L/min. They were treated with placebo (n=30 of whom 10 females), 2·5mg/kg (n=33 of whom 20 females), and 0·5mg/kg (n=34 of whom 22 females) ATG, with progressive dropping of 0·1mg/kg (n=6 of whom 3 females) and 1·5mg/kg (n=11 of whom 7 females) ATG according to the adaptive trial design. The difference between the AUC result for placebo and the 2.5mg/kg dose was similar to that for the 0.5mg/kg dose, showing that the lower dose was similarly effective. However, previously documented side effects were more common with the higher dose - cytokine release syndrome occurred in 11 (33%) and 8 (24%) participants, and serum sickness in 27 (82%) and 11 (32%) participants treated with 2·5mg/kg or 0·5mg/kg ATG, respectively, versus none in placebo-treated participants. The authors say: “The MELD-ATG trial showed that an adaptive trial design for testing an intervention aiming to arrest the loss of functional beta-cell mass in young people with recent-onset clinical, stage 3 T1D successfully identified a minimum effective dose of 0·5mg/kg ATG. In addition, it allowed confirmation of previous efficacy and safety findings of 2·5mg/kg ATG, including in children as young as 5 years of age. Low dose ATG is a safe and effective intervention for arresting or at least delaying progression of T1D… This adaptive trial design can be considered for further exploration of novel therapies in T1D, and even for other fields.” The authors add that the MELD-ATG results underscore the need to perform immune modulatory intervention studies directly in young individuals with T1D, in contrast to current drug development strategies that, driven by regulatory guidance, typically target adults first. They add: “Especially in the youngest age group, the 0·5mg/kg dose was effective with a good safety profile and would be the recommended dose for treatment. Of interest, being able to limit the administration of ATG to 0·5mg/kg would also mean only needing one infusion on one day, instead of the two days of infusion with the previously studied 2·5mg/kg.” Professor Mathieu also adds: “It should be noted that the ATG therapy at 0.5mg/kg as a single day infusion is available in most countries worldwide at very affordable prices.” Mathieu, ChantalMathieu, Chantal et al., Minimum effective low dose of antithymocyte globulin in people aged 5–25 years with recent-onset stage 3 type 1 diabetes (MELD-ATG): a phase 2, multicentre, double-blind, randomised, placebo-controlled, adaptive dose-ranging trial,The Lancet.