Alpha-1 Antitrypsin Therapy in Recent-Onset Type 1 Diabetes

Previous phase I studies demonstrated that alpha-1 antitrypsin (AAT) was safe and well tolerated in type 1 diabetes (T1D) patients. This multicenter, randomized, placebo-controlled phase II trial was designed to test whether AAT could preserve C-peptide secretion in new-onset T1D patients aged 8-25 years. Seventy patients (37 males; mean age 13.1 ± 4.1 years) were randomized (1:1:1) to treatment with 22 IV infusions − 60 mg/kg AAT, 120 mg/kg AAT or placebo administered over 1 year. The primary end point of the study was the change in C-peptide area under the curve (AUC) from a 2-h mixed-meal tolerance test (MMTT) after 1 year. Secondary endpoints were HbA1c and safety parameters. Post-hoc sub-group analysis by age was performed. At 1 year, the decrease in C-peptide AUC was not different in AAT vs. placebo groups (P = 0.66 and 0.96, for 60 and 120 mg/kg AAT). Within 12-18 years subgroup (n=35), C-peptide AUC in placebo-treated and 60 mg/kg AAT-treated patients decreased significantly from baseline (-0.34 and -0.55 pmol/mL, respectively, P < 0.01) while no significant decrease was observed in the 120 mg/kg AAT-treated patients (-0.18 pmol/mL, P = 0.20). At 1 year, mean HbA1c levels were higher in placebo-treated patients and 60 mg/kg AAT-treated patients vs. 120 mg/kg AAT-treated patients (8.24 ± 1.42% and 7.85% ± 1.67% vs. 6.66% ± 1.01%, respectively, P = 0.for 120 mg/kg AAT vs. placebo); a lower percentage of patients attained HbA1c ≤ 7% in the placebo and 60 mg/kg AAT groups compared to 120 mg/kg AAT (25% and 28.6% vs. 70%, P = 0.07). The infusions were well tolerated with a similar safety profile in the AAT and placebo groups. Two patients in the 60 mg/kg treatment group had allergic reactions after 4 and 17 infusions. Although AAT intervention shows promise with a favorable safety profile, the efficacy of AAT in T1D patients is inconclusive. Further studies should be undertaken with appropriate patient stratification pre-randomization and implementation of biomarkers to determine whether AAT has a beneficial effect on beta cell preservation.