A groundbreaking phase 2 trial has demonstrated that a significantly lower dose of antithymocyte globulin (ATG) can effectively preserve beta-cell function in young people with newly diagnosed type 1 diabetes while substantially reducing adverse events. The MELD-ATG study, presented at the European Association for the Study of Diabetes annual meeting and published simultaneously in The Lancet, found that 0.5 mg/kg ATG achieved similar therapeutic benefits to the standard 2.5 mg/kg dose with improved safety outcomes.
Study Design and Methodology
The MELD-ATG trial employed an innovative adaptive design across 14 hospitals in eight European countries, enrolling 117 children and young adults aged 5 to 25 years. Participants were diagnosed with stage 3 type 1 diabetes 3 to 9 weeks before treatment, had random C-peptide levels of 0.2 nmol/L or more at baseline, and tested positive for at least one diabetes-related autoantibody.
"We wanted to identify the minimum effective dose that was able to preserve beta-cell function over 12 months in people with newly diagnosed type 1 diabetes," said Professor Chantal Mathieu, chair of endocrinology at University Hospital Gasthuisberg Leuven and president of the European Association for the Study of Diabetes.
The adaptive trial design allowed researchers to drop ineffective dose groups during the study, with participants ultimately randomized to receive 0.5 mg/kg ATG (n=35), 2.5 mg/kg ATG (n=33), or placebo (n=31). The rabbit ATG (Sanofi) was administered intravenously over two consecutive days, with participants followed for one year.
Primary Efficacy Outcomes
At one year, both ATG doses demonstrated significant preservation of beta-cell function compared to placebo. The area under the curve of stimulated C-peptide concentration showed a mean difference of 0.124 nmol/L/min for the 2.5 mg/kg dose (95% CI, 0.043-0.205; P = .0028) and 0.102 nmol/L/min for the 0.5 mg/kg dose (95% CI, 0.021-0.183; P = .014) versus placebo.
Notably, participants receiving 0.5 mg/kg ATG achieved significantly lower HbA1c levels at one year compared to placebo (mean difference, −0.5 percentage points; 95% CI, −0.93 to −0.07; P = .024), while no difference was observed between the 2.5 mg/kg group and placebo. Daily insulin requirements remained similar across all groups.
Safety Profile Improvements
The lower dose demonstrated a markedly improved safety profile. Grade 2 adverse events occurred in 82.4% of patients receiving 0.5 mg/kg ATG compared to 93.9% in the 2.5 mg/kg group. Grade 3 adverse events were reported in 8.8% versus 12.1% of patients, respectively.
Most significantly, cytokine release syndrome occurred in 24% of patients receiving the lower dose compared to 33% with the higher dose. Serum sickness, a major concern with ATG therapy, was dramatically reduced from 82% in the 2.5 mg/kg group to just 32% in the 0.5 mg/kg cohort.
"The reason why we wanted to find an even lower dose than the 2.5 mg/kg was side effects," Mathieu explained. "Side effects are there if you treat individuals with ATG. Even at the low doses, you can see the [high proportion] of grade 2 and grade 3 side effects."
Clinical Implications and Future Directions
The findings have significant implications for type 1 diabetes treatment, particularly in pediatric populations. The 0.5 mg/kg dose offers several practical advantages, including the ability to complete treatment in a single day rather than requiring two-day infusions.
"Especially in the youngest age group, the 0.5 mg/kg dose was effective with a good safety profile and would be the recommended dose for treatment," the researchers noted. The study successfully included children as young as 5 years old, addressing a critical gap in pediatric diabetes research.
In a related commentary published in The Lancet, Dr. Cate Speake from the Benaroya Research Institute praised the adaptive trial design and pediatric inclusion, writing that "this study firmly maintains ATG as part of the existing list of plausible options" for type 1 diabetes treatment.
Regulatory and Commercial Considerations
The affordability of ATG presents a significant advantage for global implementation. "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 emphasized.
A phase 3 trial could proceed if Sanofi pursues regulatory approval for this new indication. Mathieu suggested that future developments in humanized ATG could enable repeat dosing and potentially extend therapeutic effects, opening possibilities for treatment in earlier disease stages.
The MELD-ATG trial represents the first adaptive trial design used in type 1 diabetes research, potentially serving as a model for future intervention studies in the field. The results underscore the importance of conducting immune modulatory studies directly in young patients rather than following traditional adult-first development strategies.
