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


METHODS
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] microg) 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.


RESULTS
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 log(10) nmol/l; p = 0.01) and the 500 microg dose group (-0.37; 95% CI -0.57 to -0.17 log(10) nmol/l; p = 0.003), but not in the 4 microg (-0.10; 95% CI -0.28 to 0.07 log(10) nmol/l; p = 0.20), 20 microg (0.04; 95% CI -0.12 to 0.19 log(10) nmol/l; p = 0.58) and 100 microg (0.00; 95% CI -0.20 to -0.20 log(10) nmol/l; p = 0.98) dose groups.


CONCLUSIONS
The primary outcome of safety was achieved, since no severe study-related adverse events occurred.


BACKGROUND
Because the study was initiated before 1 July 2005, the protocol was not registered in a registry.
Agardh
C-D
CD
Department of Endocrinology, University Hospital MAS, Malmö, Sweden. carl-david.agardh@med.lu.se
Lynch
K F
KF
Palmér
M
M
Link
K
K
Lernmark
A
A
D000284:Administration, Oral; D000534:Alum Compounds / Q000008:administration & dosage; D001323:Autoantibodies / Q000097:blood; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000276:immunology; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000276:immunology*; D004305:Dose-Response Relationship, Drug; D005500:Follow-Up Studies; D005968:Glutamate Decarboxylase / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology*; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage; D007279:Injections, Subcutaneous; D007328:Insulin / Q000008:administration & dosage; D050417:Insulin-Secreting Cells / Q000276:immunology; D014614:Vaccines, Synthetic / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology
D000534:Alum Compounds; D001323:Autoantibodies; D007004:Hypoglycemic Agents; D007328:Insulin; D014614:Vaccines, Synthetic; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2