Antigen Therapy for Type 1 Diabetes

The onset of type 1 diabetes is manifested by the effects of inadequate insulin secretion due to the immunologic destruction of pancreatic-islet beta-cells. Even modest preservation of insulin secretion appears to reduce short- and long-term complications (mortality and morbidity) of type 1 diabetes. Autoantigens have been proposed as an alternative approach to the treatment of type 1 diabetes, to induce immunologic tolerance. In a previous study, investigators found that the 65-kD isoform of glutamic acid decarboxylase (GAD65) formulated with alum (GAD-alum) was associated with a preserved fasting C-peptide level at 30 months after treatment and a preserved stimulated C-peptide level at 15 months. In this study [N Engl J Med. 2012;366(5):433-442], the investigators conducted a phase 3 trial of GAD-alum treatment initiated within 3 months after diagnosis of type 1 diabetes. The study was a multicenter, randomized, double-blind trial performed at 63 clinics in 9 European countries. Patients with recent-onset type 1 diabetes who were 10 to 20 years of age were screened between August 2008 and November 2009. Inclusion in the trial required detectable serum GAD65 autoantibodies, a fasting C-peptide level >0.3 ng/mL (0.1 nmol/L), and a duration of type 1 diabetes of <3 months. The primary outcome was the change in the stimulated serum C-peptide level (mean area under the curve over the 2-hour period after a mixed-meal tolerance test) between the baseline visit and the 15-month visit. Secondary outcomes included the changes in the mean daily insulin dose, glycated hemoglobin level, and fasting C-peptide level; the incidences of any hypoglycemic event and of severe hypoglycemic events (hypoglycemia with unconsciousness, convulsions, or both); changes in the stimulated C-peptide level between baseline and 30, 60, 90, and 120 minutes during the mixed-meal tolerance test; the proportions of patients with a maximum stimulated C-peptide level >0.6 ng/mL (0.2 nmol/L); and the proportion of patients with a glycated hemoglobin value <7%. Three regimens were administered: subcutaneous injections of 20 mcg of GAD-alum on days 1, 30, 90, and 270 (4-dose regimen); subcutaneous injections of GAD-alum on days 1 and 30 and of placebo on days 90 and 270 (2-dose regimen); and injections of placebo on days 1, 30, 90, and 270. Of the 469 patients assessed for eligibility, 334 underwent randomization. There were 327 patients in the modified intent-to-treat population; 109 received 4 doses of GAD-alum (4-dose regimen), 107 received 2 doses of GAD-alum (2-dose regimen), and 111 received placebo. Stimulated C-peptide levels showed a progressive decline from baseline to month 15 in all 3 study groups. At 15 months, the treatment effect of the 4- and 2-dose regimens combined was not significantly larger than the effect of placebo. At 15 months, there were no significant differences between the 4- and 2-dose groups, compared in combination or individually with placebo, in the treatment effect on the mean daily insulin dose, glycated hemoglobin value, or any other secondary outcome. There was a significant effect of GAD-alum therapy in 4 subgroups. In the subgroup of 173 male patients, estimated treatment ratios for the combined 4- and 2-dose groups, the 4-dose group alone, and the 2-dose group alone versus placebo were 1.41, 1.42, and 1.41, with P values of 0.009, 0.02, and 0.03, respectively. Among the 110 patients with a baseline Tanner pubertal stage of 2 or 3, the estimated treatment ratio for the 4-dose regimen versus placebo was 1.52 (P=.04). The 110 patients with a baseline daily insulin dose of 0.398 to 0.605 IU/kg of body weight had estimated treatment ratios of 1.33 for the 4- and 2-dose regimens combined (P=.049 for comparison with placebo) and 1.56 for the 4-dose regimen alone (P=.008 for comparison with placebo). GAD-alum treatment resulted in a rapid rise in GAD65 autoantibody levels in both active-treatment groups at 3 months, followed by a decline at the 9-month visit; at 15 months, there was an increase in the levels in the 4-dose group but a continued decline in the 2-dose group. GAD65 autoantibody levels in the placebo group remained stable throughout the trial.