Antigen therapy with glutamic acid decarboxylase 65 formulated with alum failed to induce immunologic tolerance and stem the loss of stimulated serum C-peptide in a phase III clinical trial of new-onset type 1 diabetes, according to a report in the Feb. 2 issue of the New England Journal of Medicine.
The treatment also failed to improve clinical outcomes during the 15-month study, said Dr. Johnny L. Ludvigsson of the department of clinical and experimental medicine, division of pediatrics, Linkoping (Sweden) University, and his associates.
Dr. Johnny L. Ludvigsson
In a previous phase II study, treatment with the 65-kD isoform of glutamic acid decarboxylase (GAD65) formulated with alum (GAD-alum) had preserved stimulated C-peptide levels and fasting C-peptide levels for 4 years in a subgroup of patients who were treated immediately after diagnosis (Diabetologia 2011;54:634-40). However, a more recent phase II trial of GAD-alum did not show any clinical benefit, the investigators noted.
Dr. Ludvigsson and his colleagues performed their phase III clinical trial at 63 clinics in Finland, France, Germany, Italy, the Netherlands, Slovenia, Spain, Sweden, and the United Kingdom. The 327 study subjects were aged 10-20 years and had been diagnosed as having type 1 diabetes within the preceding 3 months.
The patients were randomly assigned in double-blind fashion to receive one of three regimens of subcutaneous injections: four doses of GAD-alum (on days 1, 30, 90, and 270), two doses of GAD-alum (on days 1 and 30), or four doses of placebo.
The primary outcome was preservation of the stimulated serum C-peptide level after 15 months. Stimulated C-peptide levels showed progressive declines in all three groups throughout the study. The declines were not significantly different among the three groups at any time point, including at the conclusion of the study, the investigators said (N. Engl. J. Med. 2012;366:433-42).
Moreover, there were no differences among the three groups in mean daily insulin dose, glycated hemoglobin levels, or several other clinical outcomes.
The rates of adverse events also were similar among the three study groups.
"Much as treatments for diseases such as childhood cancer and immunotherapy of allergy have developed in a stepwise, gradual manner through the combination of existing therapies, treatment for type 1 diabetes will most likely be based on the knowledge gained from this and other studies, as well as future studies, of single agents or combination therapies for both intervention and prevention," Dr. Ludvigsson and his associates said.
They added that patients who develop stiff person syndrome have been shown in previous studies to carry elevated levels of GAD65 autoantibodies. In this study, all the subjects underwent periodic neurologic assessments, and no symptoms suggestive of stiff person syndrome were seen.
This study was supported by Diamyd Medical and the Swedish Child Diabetes Foundation. Dr. Ludvigsson reported ties to Johnson & Johnson, GlaxoSmithKline, Sanofi-Aventis, and Novo Nordisk; his associates reported ties to Merck Sharp and Dohme, Bristol-Myers Squibb, Eli Lilly, Medtronic, Tolerx, and Andromeda Biotech.