title: Antigen-based therapy with glutamic acid decarboxylase (GAD) vaccine in patients with recent-onset type 1 diabetes: a randomised double-blind trial.
abstract: BACKGROUND
  Glutamic acid decarboxylase (GAD) is a major target of the autoimmune response that occurs in type 1 diabetes mellitus. In animal models of autoimmunity, treatment with a target antigen can modulate aggressive autoimmunity. We aimed to assess whether immunisation with GAD formulated with aluminum hydroxide (GAD-alum) would preserve insulin production in recent-onset type 1 diabetes.
  
  
  METHODS
  Patients aged 3-45 years who had been diagnosed with type 1 diabetes for less than 100 days were enrolled from 15 sites in the USA and Canada, and randomly assigned to receive one of three treatments: three injections of 20 μg GAD-alum, two injections of 20 μg GAD-alum and one of alum, or 3 injections of alum. Injections were given subcutaneously at baseline, 4 weeks later, and 8 weeks after the second injection. The randomisation sequence was computer generated at the TrialNet coordinating centre. Patients and study personnel were masked to treatment assignment. The primary outcome was the baseline-adjusted geometric mean area under the curve (AUC) of serum C-peptide during the first 2 h of a 4-h mixed meal tolerance test at 1 year. Secondary outcomes included changes in glycated haemoglobin A(1c) (HbA(1c)) and insulin dose, and safety. Analysis included all randomised patients with known measurements. This trial is registered with ClinicalTrials.gov, number NCT00529399.
  
  
  RESULTS
  145 patients were enrolled and treated with GAD-alum (n=48), GAD-alum plus alum (n=49), or alum (n=48). At 1 year, the 2-h AUC of C-peptide, adjusted for age, sex, and baseline C-peptide value, was 0·412 nmol/L (95% CI 0·349-0·478) in the GAD-alum group, 0·382 nmol/L (0·322-0·446) in the GAD-alum plus alum group, and 0·413 nmol/L (0·351-0·477) in the alum group. The ratio of the population mean of the adjusted geometric mean 2-h AUC of C-peptide was 0·998 (95% CI 0·779-1·22; p=0·98) for GAD-alum versus alum, and 0·926 (0·720-1·13; p=0·50) for GAD-alum plus alum versus alum. HbA(1c), insulin use, and the occurrence and severity of adverse events did not differ between groups.
  
  
  CONCLUSIONS
  Antigen-based immunotherapy therapy with two or three doses of subcutaneous GAD-alum across 4-12 weeks does not alter the course of loss of insulin secretion during 1 year in patients with recently diagnosed type 1 diabetes. Although antigen-based therapy is a highly desirable treatment and is effective in animal models, translation to human autoimmune disease remains a challenge.
  
  
  BACKGROUND
  US National Institutes of Health.
authors.affiliation: Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
authors.forename: Diane K
authors.initials: DK
authors.lastname: Wherrett
authors.forename: Brian
authors.initials: B
authors.lastname: Bundy
authors.forename: Dorothy J
authors.initials: DJ
authors.lastname: Becker
authors.forename: Linda A
authors.initials: LA
authors.lastname: DiMeglio
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Gitelman
authors.forename: Robin
authors.initials: R
authors.lastname: Goland
authors.forename: Peter A
authors.initials: PA
authors.lastname: Gottlieb
authors.forename: Carla J
authors.initials: CJ
authors.lastname: Greenbaum
authors.forename: Kevan C
authors.initials: KC
authors.lastname: Herold
authors.forename: Jennifer B
authors.initials: JB
authors.lastname: Marks
authors.forename: Roshanak
authors.initials: R
authors.lastname: Monzavi
authors.forename: Antoinette
authors.initials: A
authors.lastname: Moran
authors.forename: Tihamer
authors.initials: T
authors.lastname: Orban
authors.forename: Jerry P
authors.initials: JP
authors.lastname: Palmer
authors.forename: Philip
authors.initials: P
authors.lastname: Raskin
authors.forename: Henry
authors.initials: H
authors.lastname: Rodriguez
authors.forename: Desmond
authors.initials: D
authors.lastname: Schatz
authors.forename: Darrell M
authors.initials: DM
authors.lastname: Wilson
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Krischer
authors.forename: Jay S
authors.initials: JS
authors.lastname: Skyler
mesh_terms: D000293:Adolescent; D000941:Antigens / Q000276:immunology / Q000627:therapeutic use; D001327:Autoimmune Diseases / Q000276:immunology / Q000628:therapy*; D002170:Canada; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000628:therapy*; D004311:Double-Blind Method; D005260:Female; D005968:Glutamate Decarboxylase / Q000276:immunology / Q000627:therapeutic use*; D006801:Humans; D016233:Immunotherapy, Active; D008297:Male; D008875:Middle Aged; D014481:United States; D055815:Young Adult
chemical_list: D000941:Antigens; D005968:Glutamate Decarboxylase