GAD65 vaccination: 5 years of follow-up in a randomised dose-escalating study in adult-onset autoimmune diabetes
The aim of this study was to ascertain whether treatment of GAD65 autoantibody (GADA)-positive diabetic patients with alum-formulated recombinant GAD65 (GAD-alum) is safe and does not compromise beta cell function. This Phase 2, placebo-controlled, dose-escalation clinical trial, which was randomized through a central office, was performed in 47 GADA-positive type 2 diabetic patients, who received subcutaneous injections of GAD-alum (4 [n = 9], 20 [n = 8], 100 [n = 9] or 500 [n = 8] μg) or placebo (n = 13) at weeks 1 and 4 of the trial. Participants and caregivers were blinded to group assignments. The primary outcome was safety as assessed by neurological tests, medications and beta cell function evaluated over 5 years, representing the end of the trial. No severe study-related adverse events occurred during the 5 year follow-up. None of the dose groups was associated with an increased risk of starting insulin treatment compared with the placebo group. The use of oral hypoglycaemic agents did not differ between the dose groups. After 5 years, fasting C-peptide levels declined in the placebo group (−0.24; 95% CI −0.41 to −0.07 log10 nmol/l; p = 0.01) and the 500 µg dose group (−0.37; 95% CI −0.57 to −0.17 log10 nmol/l; p = 0.003), but not in the 4 µg (−0.10; 95% CI −0.28 to 0.07 log10 nmol/l; p = 0.20), 20 µg (0.04; 95% CI −0.12 to 0.19 log10 nmol/l; p = 0.58) and 100 µg (0.00; 95% CI −0.20 to −0.20 log10 nmol/l; p = 0.98) dose groups. The primary outcome of safety was achieved, since no severe study-related adverse events occurred. Because the study was initiated before 1 July 2005, the protocol was not registered in a registry. This trial was funded by the National Institutes of Health (grant numbers DK26190 and DK53004), the Swedish Research Council (grant number 72X-14064) and Diamyd Therapeutics (Stockholm, Sweden).