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. 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 A1c (HbA1c) and insulin dose, and safety. Analysis included all randomised patients with known measurements. This trial is registered with ClinicalTrials.gov, number NCT00529399. 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. HbA1c, insulin use, and the occurrence and severity of adverse events did not differ between groups. 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. US National Institutes of Health.
Bibliographical noteFunding Information:
The trial was undertaken under the auspices of the Type 1 Diabetes TrialNet Study Group. TrialNet was responsible for the study design, data collection, data analysis, data interpretation, and writing of the report. TrialNet is funded by the US National Institutes of Health (NIH), with all members listed in the webappendix . As noted in the webappendix , some NIH staff members participated in several aspects of TrialNet, including study design. However, NIH staff did not participate in data collection, data analysis, data interpretation, or writing of the report. The writing committee (DKW, JSS, BB and JPK) had full access to all study data, and made the decision to publish the paper.
DKW reports receiving lecture fees from Eli Lilly and Medtronic. DJB reports receiving a grant from Diamyd. SEG reports serving on an advisory board for Genentech. RG reports receiving grants from Diamyd and Tolerx. PAG reports serving on advisory boards for Genentech, Eli Lilly, Sanofi-Aventis, and Tolerx; and reports receiving grants from Bayhill Therapeutics, Diamyd, Macrogenics, Omni BioTherapeutics, and Tolerx. CJG reports receiving grants from Bayhill Therapeutics, Diamyd, and Tolerx. JBM reports serving on an advisory board for Amgen. AM reports serving on an advisory board for Pfizer; and receiving grants from Tolerx, Merck, and Osiris Therapeutics. TO reports serving on the data safety monitoring board for Osiris Therapeutics, and being a founder of Orban Biotech. JPP reports being a consultant and receiving research grants and leading studies for Diamyd. PR reports serving on advisory boards for Amgen, AstraZeneca, MannKind, and Novo-Nordisk; serving on speakers bureaus for Merck and Novo-Nordisk; and receiving grants from Aegera, Andromeda Biotech, Bayhill Therapeutics, Biodel, Boehringer Ingelheim, Calibra, CPEX, Generex, Hoffman-LaRoche, MannKind, Novo-Nordisk, Osiris Therapeutics, and Reata. HR reports serving on an advisory board for Marcadia Biotech; serving as a consultant to Eli Lilly, Genentech, Bayer, EMD Serono, and Merck; being on the speakers bureau of Eli Lilly and Novo-Nordisk; and receiving grant support from Macrogenics and Eli Lilly. DS reports serving on advisory boards for Andromeda, Eli Lilly, GlaxoSmithKline, and Roche; giving a lecture supported by Pfizer; and receiving a grant from Diamyd. DMW reports serving on an advisory boards for DexCom and Genentech; and receiving grants support from Genentech, Diamyd, and Osiris Therapeutics. JSS reports serving on boards for Amylin Pharmaceuticals, DexCom, and Sanofi-Aventis; receiving grants from Bayhill Therapeutics, Halozyme, Intuity, and Osiris Therapeutics; receiving consultancy fees from Becton-Dickinson, Merck, MannKind Corporation, GlaxoSmithKline, Salutria Pharmaceuticals, Veroscience, Roche, and Exsulin; and receiving speakers' fees and payment for development of an educational presentation from Novo-Nordisk; and holds stock in Amylin Pharmaceuticals and Dexcom. BB, LAD, KCH, RM, and JPK declare that they have no conflicts of interest.
The sponsor of the trial was the Type 1 Diabetes TrialNet Study Group. The Type 1 Diabetes TrialNet Study Group is a clinical trials network funded by NIH through the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Allergy and Infectious Diseases, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, via cooperative agreements (U01 DK061010, U01 DK061016, U01 DK061034, U01 DK061036, U01 DK061040, U01 DK061041, U01 DK061042, U01 DK061055, U01 DK061058, U01 DK084565, U01 DK085453, U01 DK085461, U01 DK085463, U01 DK085466, U01 DK085499, U01 DK085505, and U01 DK085509) and a contract (HHSN267200800019C) ; and through the National Center for Research Resources, via clinical translational science awards (UL1 RR024131, UL1 RR024139, UL1 RR024153, UL1 RR024975, UL1 RR024982, UL1 RR025744, UL1 RR025761, UL1 RR025780, UL1 RR029890, and UL1 RR031986) and a general clinical research center award (M01 RR00400) . TrialNet also receives non-financial support from the Juvenile Diabetes Research Foundation International (JDRF) and the American Diabetes Association (ADA). The contents of this paper are solely the responsibility of the authors and do not necessarily represent the official views of NIH, JDRF, or ADA. Diamyd Medical (Stockholm, Sweden) provided GAD-alum and placebo (alum), but had no involvement with the final study design, study conduct or management, data collection, data analysis, data interpretation, or writing of the report. There are no agreements concerning confidentiality of the data between Diamyd and the authors or the institutions named in the credit lines. The authors did provide Diamyd Medical a copy of the original report before submission. Roche Diagnostics (Indianapolis, IN, USA) provided blood glucose monitoring metres and strips to research patients. No funds were paid for preparation of this report.