GAD65 antigen therapy in recently diagnosed type 1 diabetes mellitus.

Abstract

BACKGROUND:

The 65-kD isoform of glutamic acid decarboxylase (GAD65) is a major autoantigen in type 1 diabetes. We hypothesized that alum-formulated GAD65 (GAD-alum) can preserve beta-cell function in patients with recent-onset type 1 diabetes.

METHODS:

We studied 334 patients, 10 to 20 years of age, with type 1 diabetes, fasting C-peptide levels of more than 0.3 ng per milliliter (0.1 nmol per liter), and detectable serum GAD65 autoantibodies. Within 3 months after diagnosis, patients were randomly assigned to receive one of three study treatments: four doses of GAD-alum, two doses of GAD-alum followed by two doses of placebo, or four doses of placebo. The primary outcome was the change in the stimulated serum C-peptide level (after a mixed-meal tolerance test) between the baseline visit and the 15-month visit. Secondary outcomes included the glycated hemoglobin level, mean daily insulin dose, rate of hypoglycemia, and fasting and maximum stimulated C-peptide levels.

RESULTS:

The stimulated C-peptide level declined to a similar degree in all study groups, and the primary outcome at 15 months did not differ significantly between the combined active-drug groups and the placebo group (P=0.10). The use of GAD-alum as compared with placebo did not affect the insulin dose, glycated hemoglobin level, or hypoglycemia rate. Adverse events were infrequent and mild in the three groups, with no significant differences.

CONCLUSIONS:

Treatment with GAD-alum did not significantly reduce the loss of stimulated C peptide or improve clinical outcomes over a 15-month period. (Funded by Diamyd Medical and the Swedish Child Diabetes Foundation; ClinicalTrials.gov number, NCT00723411.).

• Authors: Johnny Ludvigsson, David Krisky, Rosaura Casas, Tadej Battelino, Luis Castaño, James Greening, Olga Kordonouri, Timo Otonkoski, Paolo Pozzilli, Jean-Jacques Robert, Henk J Veeze, Jerry Palmer, Ulf Samuelsson, Helena Elding Larsson, Jan Åman, Gunilla Kärdell, Jan Neiderud Helsingborg, Göran Lundström, Eva Albinsson, Annelie Carlsson, Maria Nordvall, Hans Fors, Carl-Göran Arvidsson, Stig Edvardson, Ragnar Hanås, Karin Larsson, Björn Rathsman, Henrik Forsgren, Helena Desaix, Gun Forsander, Nils-Östen Nilsson, Carl-Göran Åkesson, Päivi Keskinen, Riitta Veijola, Timo Talvitie, Klemens Raile, Thomas Kapellen, Walter Burger, Andreas Neu, Ilse Engelsberger, Bettina Heidtmann, Suzanne Bechtold, David Leslie, Francesco Chiarelli, Alesandro Cicognani, Giuseppe Chiumello, Franco Cerutti, Gian Vincenzo Zuccotti, Ana Gomez Gila, Itxaso Rica, Raquel Barrio, Maria Clemente, Maria José López Garcia, Mercedes Rodriguez, Isabel Gonzalez, Juan Pedro Lopez, Mirentxu Oyarzabal, H M Reeser, Roos Nuboer, Pauline Stouthart, Natasa Bratina, Nina Bratanic, Marc de Kerdanet, Jacques Weill, Nicole Ser, Pascal Barat, Anne Marie Bertrand, Jean-Claude Carel, Rachel Reynaud, Regis Coutant, Sabine Baron
• Journal: The New England journal of medicine (N Engl J Med) Vol. 366 Issue 5 Pg. 433-42 (Feb 02 2012) ISSN: 1533-4406 [Electronic] United States
• PMID: 22296077 (Publication Type: Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Autoantibodies
• C-Peptide
• Protein Isoforms
• Glutamate Decarboxylase
• glutamate decarboxylase 2

Topics

• Adolescent
• Autoantibodies (blood)
• C-Peptide (blood)
• Child
• Diabetes Mellitus, Type 1 (blood, drug therapy, immunology)
• Female
• Glutamate Decarboxylase (adverse effects, immunology, therapeutic use)
• Humans
• Male
• Protein Isoforms
• Young Adult