Extended evaluation of the safety and efficacy of GAD treatment of children and adolescents with recent-onset type 1 diabetes: a randomised controlled trial

Abstract

Aims/hypothesis The aim of this study was to investigate the safety and efficacy of alum formulated glutamic acid decarboxylase GAD 65 (GAD-alum) treatment of children and adolescents with type 1 diabetes after 4 years of follow-up. Methods Seventy children and adolescents aged 10-18 years with recent onset type 1 diabetes participated in a phase II, double-blind, randomised placebo-controlled clinical trial. Patients identified as possible participants attended one of eight clinics in Sweden to receive information about the study and for an eligibility check, including a medical history. Participants were randomised to one of the two treatment groups and received either a subcutaneous injection of 20 μg of GAD-alum or placebo at baseline and 1 month later. The study was blinded to participants and investigators until month 30. The study was unblinded at 15 months to the sponsor and statistician in order to evaluate the data. At follow-up after 30 months there was a significant preservation of residual insulin secretion, as measured by C-peptide, in the group receiving GAD-alum compared with placebo. This was particularly evident in patients with <6 months disease duration at baseline. There were no treatment-related serious adverse events. We have now followed these patients for 4 years. Overall, 59 patients, 29 who had been treated with GAD-alum and 30 who had received placebo, gave their informed consent. Results One patient in each treatment group experienced an episode of keto-acidosis between months 30 and 48. There were no treatment-related adverse events. The primary efficacy endpoint was the change in fasting C-peptide concentration from baseline to 15 months after the prime injection for all participants per protocol set. In the GADalum group fasting C-peptide was 0.332±0.032 nmol/l at day 1 and 0.215 ± 0.031 nmol/l at month 15. The corresponding figures for the placebo group were 0.354± 0.039 and 0.184±0.033 nmol/l, respectively. The decline in fasting C-peptide levels between day 1 and month 1, was smaller in the GAD-alum group than the placebo group. The difference between the treatment groups was not statistically significant. In those patients who were treated within 6 months of diabetes diagnosis, fasting C-peptide had decreased significantly less in the GADalum group than in the placebo-treated group after 4 years.

Antigen-based vs. systemic immunomodulation in type 1 diabetes

“…Nevertheless, at 30 mo post-trial initiation, this parameter was stable and significantly increased for a period up to 4 y. 129 Also the stimulated C-peptide secretion was significantly higher than the placebo group at both 15 and 30 mo. However, these differences were only seen in a subpopulation of patients treated within 6 mo of diagnosis.…”

“…107 Again no treatment-related SAE or AE could be determined, not even after 4 y of follow up. 129 However the primary endpoint, a change in fasting C-peptide after 15 mo in comparison to placebo, was not achieved. Nevertheless, at 30 mo post-trial initiation, this parameter was stable and significantly increased for a period up to 4 y.…”

Regin in Blood Immune Regulation in Type 1 Diabetes

“…shorter disease duration at inclusion, and no serious treatment-related adverse events were reported [243]. [234].…”

Stem Cell Therapies for Type I Diabetes

“…For this reason, therapies that modulate the immune response to cells and cell antigens also exist, and their safety and efficacy have been or are currently being tested in clinical trials (Bluestone, Herold et al 2010;WaldronLynch and Herold 2011). GAD65 specific-antigen-based immunotherapy with alum adjuvant demonstrated preservation of C-peptide fasting levels in younger new-onset patients four years after treatment (Ludvigsson, Hjorth et al 2011), but this was not supported in the larger Phase III trial (Ludvigsson, Krisky et al 2012). Humanized anti-CD3 antibody (in which human Fc immunoglobulin domains are engineered to mouse CD3-binding portions of the antibody) therapy given in a single dose reduced the decline of insulin production and the amount of exogenous insulin required in the patients (Herold, Gitelman et al 2009).…”