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.

Summary

In this adaptive, double-blind RCT (n=117), both 2.5 mg/kg and 0.5 mg/kg ATG preserved stimulated C-peptide at 12 months versus placebo, with baseline-adjusted differences in ln(AUC C-peptide+1) of 0.124 and 0.102, respectively. Cytokine release syndrome and serum sickness were common at 2.5 mg/kg but substantially less frequent at 0.5 mg/kg, identifying 0.5 mg/kg as a minimum effective, better-tolerated dose.

Key Findings

• Both 2.5 mg/kg and 0.5 mg/kg ATG improved 12-month stimulated C-peptide versus placebo (mean baseline-adjusted differences in ln(AUC C-peptide+1): 0.124 and 0.102; p=0.0028 and p=0.014).
• Adverse events were dose-related: cytokine release syndrome in 33% (2.5 mg/kg) vs 24% (0.5 mg/kg); serum sickness in 82% vs 32%, respectively; none in placebo.
• 0.5 mg/kg was identified as a minimum effective dose with improved tolerability in patients aged 5–25 years within 3–9 weeks of diagnosis.

Clinical Implications

Low-dose ATG (0.5 mg/kg) emerges as a promising, more tolerable disease-modifying strategy for recent-onset type 1 diabetes and merits phase 3 evaluation, with attention to early treatment windows and AE mitigation.

Limitations

• Modest sample size (n=117) and 12-month follow-up limit detection of long-term clinical outcomes
• Not powered for hard clinical endpoints (e.g., insulin independence, severe hypoglycemia)

Future Directions

Proceed to phase 3 trials testing 0.5 mg/kg ATG with longer follow-up, patient-centered outcomes, and benefit–risk profiling by age and autoantibody status.