GAD65 vaccination: 5 years of follow-up in a randomised dose-escalating study in adult-onset autoimmune diabetes

Agardh, Carl‐David; Lynch, Kristian; Palmér, Mats; Link, Katarina; Lernmark, Åke

doi:10.1007/s00125-009-1371-2

Cited by 84 publications

(60 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A dose-finding study in patients with latent autoimmune diabetes in adults (LADA) indicated that a prime and boost injection of 20 μg GAD-alum (recombinant human GAD 65 in a standard vaccine formulation with alum) might preserve residual insulin secretion [28]. This treatment was easy to perform and well tolerated by the patients, and at a follow-up after 5 years there were no treatment-related adverse events and potential efficacy was reported in one of the subgroups [29].…”

Section: Introductionmentioning

confidence: 97%

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

et al. 2010

View full text Add to dashboard Cite

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.

show abstract

Section: Introductionmentioning

confidence: 97%

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

et al. 2010

View full text Add to dashboard Cite

show abstract

“…In NOD mice, administration of GAD 65 prevented type 1 diabetes and also protected transplanted islets after onset of the disease [11; 12]. A dose-finding study in Latent Autoimmune Diabetes in Adults (LADA) patients supported the clinical effect and safety of subcutaneous administration of 20 µg alum-formulated recombinant human GAD 65 (GADalum) [13], and the 5-year follow up suggests a persistent effect [14]. We have conducted a phase II clinical trial, where we showed that two injections of 20 µg GAD-alum contributes to the preservation of residual insulin secretion in children with recent onset type 1 diabetes [15].…”

Section: Introductionmentioning

confidence: 99%

GAD-alum treatment in patients with type 1 diabetes and the subsequent effect on GADA IgG subclass distribution, GAD65 enzyme activity and humoral response

Chéramy

Skoglund

Johansson

et al. 2010

Clinical Immunology

View full text Add to dashboard Cite

, GAD-alum treatment in patients with type 1 diabetes and the subsequent effect on GADA IgG subclass distribution, GAD (65) AbstractWe have previously shown that two injections of 20 μg GAD-alum to recent onset type 1 diabetic children induced GADA levels in parallel to preservation of insulin secretion. Here we investigated if boosted GADA induced changes in IgG1, 2, 3 and 4 subclass distributions or affected GAD 65 enzyme activity. We further studied the specific effect of GAD-alum through analyses of IA-2A, tetanus toxoid and total IgE antibodies. Serum from children receiving GAD-alum or placebo was collected pre-treatment and after 3, 9, 15 and 21 months.At 3 month a reduced percentage of IgG1 and increased IgG3/IgG4 were detected in GADalum treated. Further, IA-2A, IgE and tetanus toxoid antibodies, as well as GAD 65 enzyme activity, were unaffected confirming the specific effect of treatment. In the GAD-alum group, higher pre-treatment GADA were associated to more pronounced C-peptide preservation. The induced IgG3/IgG4 and reduced IgG1 suggest a Th2 deviation of the immune response.

show abstract

“…While insulin autoimmunity is affecting the young, GAD65 autoimmunity is less sensitive to age. Alum-formulated recombinant human GAD65 tested in Phase II and III clinical trials were found to be safe [38][39][40] . The immunomodulating effect seemed to include the induction of Treg cells 16,38 and the residual beta-cell function in newly diagnosed T1D patients.…”

Section: Glutamic Acid Decarboxylase (Gad65)mentioning

confidence: 99%

“…GAD-alum tested in Phase II clinical trials with some effect on preserving residual cpeptide 39,40 was tested in an additional phase II trial with a dose-regiment that differed from previous trials 53 . Two or three doses of subcutaneous GAD-alum across 4-12 weeks did not alter the c-peptide disappearance rate during 12 month in newly diagnosed T1D patients (NCT00529399).…”

Section: Gad-alummentioning

confidence: 99%

Immune therapy in type 1 diabetes mellitus

Lernmark

Larsson

2013

Nat Rev Endocrinol

View full text Add to dashboard Cite

(200 words) Type 1 diabetes mellitus (T1D) is an autoimmune disorder directed against the pancreatic islet β cells. The genetic risk for the disease is linked to HLA-DQ genotypes and unknown environmental triggers. In most countries, only 10-15% of newly diagnosed T1D children or young adults have a first degree relative with the disease. Autoantibodies against insulin, GAD65, IA-2 or ZnT8 transporter mark islet autoimmunity. These islet autoantibodies may develop already at 1-2 years of age. Immune therapy in T1D is approached at three stages. Primary prevention is treatment of subjects at increased genetic risk. The TRIGR trial is testing if hydrolyzed casein milk formula may reduce T1D in genetically predisposed infants. Secondary prevention is in subjects with persistent islet autoantibodies. On-going trials are either non-autoantigen (BCG, CD3 monoclonal antibodies) or autoantigen (oral and nasal insulin or Alum-formulated GAD65) specific. Intervention at diabetes onset include non-autoantigen (CD3 monoclonal antibodies, IL-2 receptor antibodies, Il-1b receptor inhibitor, Il-1b antibodies, BCG, ATG, DiaPep277) and autoantigen (proinsulin peptides) specific therapy. Although preserved beta-cell function long term has been difficult to achieve in many prior studies, considerable progress is being made through controlled clinical trials and animal investigations to uncover mechanisms of beta-cell destruction. Novel therapies that would prevent islet autoimmunity or halt progressive beta-cell destruction need to be designed.

show abstract

GAD65 vaccination: 5 years of follow-up in a randomised dose-escalating study in adult-onset autoimmune diabetes

Abstract: Because the study was initiated before 1 July 2005, the protocol was not registered in a registry.

Cited by 84 publications

References 16 publications

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

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

GAD-alum treatment in patients with type 1 diabetes and the subsequent effect on GADA IgG subclass distribution, GAD65 enzyme activity and humoral response

Immune therapy in type 1 diabetes mellitus

Contact Info

Product

Resources

About