Human plasma‐derived alpha(1)‐proteinase inhibitor in patients with new‐onset type 1 diabetes mellitus: A randomized, placebo‐controlled proof‐of‐concept study

BACKGROUND: While circulating levels of alpha(1)‐proteinase inhibitor (alpha(1)‐PI) are typically normal, antiprotease activity appears to be compromised in patients with Type 1 diabetes mellitus (T1DM). Because alpha(1)‐PI [human] (alpha(1)‐PI[h]) therapy can inhibit pro‐inflammatory mediators associated with β‐cell destruction and reduced insulin production, it has been proposed for T1DM disease prevention. The aim of this study was to evaluate safety, tolerability, and efficacy of intravenous (IV) alpha(1)‐PI[h] in preserving C‐peptide production in newly diagnosed T1DM patients. PARTICIPANTS: Seventy‐six participants (aged 6–35 years) were randomized at 25 centers within 3 months of T1DM diagnosis. METHODS: A Phase II, multicenter, partially blinded, placebo‐controlled, proof‐of‐concept study evaluating four dosing regimens of alpha(1)‐PI[h] (NCT02093221, GTI1302): weekly IV infusions of either 90 or 180 mg/kg, each for either 13 or 26 weeks. Safety and efficacy were monitored over 52 weeks with an efficacy evaluation planned at 104 weeks. The primary efficacy endpoint was change from baseline in the 2‐h area‐under‐the‐curve C‐peptide level from a mixed‐meal tolerance test at 52 weeks. A battery of laboratory tests, including inflammatory biomarkers, constituted exploratory efficacy variables. RESULTS: Infusions were well tolerated with no new safety signals. All groups exhibited highly variable declines in the primary outcome measure at 52 weeks with no statistically significant difference from placebo. Interleukin‐6 (IL‐6) was reduced from baseline in all alpha(1)‐PI treatment groups but not the placebo group. CONCLUSION: Pharmacologic therapy with alpha(1)‐PI[h] is safe, well tolerated, and able to reduce IL‐6 levels; however, due to variability in the efficacy endpoint, its effects on preservation of C‐peptide production were inconclusive.