Anette-Gabriele Ziegler, Ali Albeer, Stefanie Arnolds, Robin Assfalg, Melanie Bunk, Carolin Daniel, Anna Hofelich, Stefanie Jacobsen, Kerstin Kick, Jan Knoop, Mirjam Kohls, Olga Kordonouri, Claudia Matzke, Markus Pfirrmann, Claudia Ramminger, Katharina Sarcletti, Marlon Scholz, Katharina Schütte-Borkovec, Isabelle Serr, Marc Weigelt, Andreas Weiß, Christiane Winkler, Ezio Bonifacio, Peter Achenbach
OBJECTIVE: Oral administration of an antigen can induce immunological tolerance. Insulin is an autoantigen in childhood type 1 diabetes (T1D). We tested the effect of treatment with high-dose oral insulin on disease progression and immune response to insulin in children with stage 1 T1D. RESEARCH DESIGN AND METHODS: We conducted a phase 2 randomized placebo-controlled double-blind trial in children with stage 1 T1D who received daily oral insulin (7.5 mg/day for 3 months and 67.5 mg/day for 9 months; n = 110) or placebo (n = 110) for 12 months. The coprimary outcomes were 1) time from baseline to dysglycemia or clinical diabetes and 2) increased immune response to insulin within 12 months of treatment (assessed in the first 90 participants). RESULTS: Of 220 participants (112 girls; median age 4.8 years; interquartile range 3.6, 6.2), 179 completed the trial. Dysglycemia or diabetes developed in 87 participants (46 receiving oral insulin and 41 receiving placebo; hazard ratio 1.07; 95% CI 0.66-1.73; P = 0.74). The 5-year progression rate was 40% (95% CI 30-51%) in each group. A modest treatment interaction was found with the INS rs689 genotype (P = 0.03). Increased immune response to insulin was observed in 11 (25%) of 44 participants in the oral insulin group and 13 (31%) of 42 in the placebo group (P = 0.63). Oral insulin was well tolerated. No significant study-related adverse events occurred. CONCLUSIONS: In children with stage 1 T1D, 1 year of high-dose oral insulin did not alter progression to dysglycemia or diabetes or immune response to insulin.