2861-LB: Phase II Clinical Trial of BCG Immunotherapy for Latent Autoimmune Diabetes in Adults (LADA): Five-Year Analysis of HbA1c, Insulin Use, and Pancreatic C-Peptide Outcomes

Introduction and Objective: A Phase I clinical trial of 2 doses of bacillus Calmette-Guérin (BCG) in adults with juvenile-onset type 1 diabetes (T1D) demonstrated durable improvements in HbA1c, but a pilot trial in patients with LADA, who have older age of onset (AOO), slower decline in insulin production, and lack of lymphoid glycolysis defects vs juvenile-onset T1D, showed no HbA1c improvement with BCG. A Phase II, double-blind, placebo-controlled trial of BCG in 150 subjects with juvenile-onset T1D or LADA was undertaken with the primary endpoint of improved HbA1c (NCT02081326). Here we present 5-year data on subjects in the Phase II trial with LADA. Methods: Adults with LADA (AOO ≥ 21 y) were followed for 5 years and received 6 doses of intradermal (ID) Tokyo BCG (Japan BCG Laboratory, Japan) or placebo (n=68 BCG; n=27 placebo). The primary outcome was reduction in HbA1c. Secondary outcomes included insulin use, time spent in normoglycemia, autoantibody levels, and stimulated C-peptide secretion. Results: BCG was shown to be safe in LADA but did not statistically significantly improve HbA1c. However, insulin-dose adjusted A1c (IDAA1c) statistically significantly decreased with BCG (BCG P=0.044; placebo P=0.230), independent of weight but dependent on insulin use. Insulin use decreased by 2.89% in BCG-treated subjects, but increased by 22.08% in the placebo group (P=0.021). At enrollment, most subjects had remaining C-peptide and autoantibodies. BCG treatment led to preservation of C-peptide (P=0.01790), restoration of stimulated C-peptide (P=0.04) and a decrease in IA2 and GAD autoantibodies (P=0.0003). Conclusion: At Year 5, patients with LADA did not demonstrate significant HbA1c reduction with BCG, but did show improved insulin resistance, slowed C-peptide decay, restored stimulated peak C-peptide, and decreased diabetes-associated autoantibodies, suggesting diminished autoimmunity.