TRIGR

Project objectives

The TRIGR Project is an international, multicenter, randomized, double-blind study enrolling 2800 newborns worldwide (approximately 60 in Italy, half of whom are in Sardinia). The project is based on the hypothesis that cow's milk administered in the first months of life is diabetogenic. It is a randomized, double-blind, primary prevention study aimed at analyzing the differences between the group normally exposed to cow's milk proteins and the group treated with protein hydrolysate, in terms of the onset of type 1 diabetes or the development of anti-islet cell antibodies. Both groups will consist of newborns genetically at high risk of developing type 1 diabetes (first-degree relatives of diabetics with specific high-risk HLA haplotypes). The first group of infants is expected to have a reduced onset of antibodies associated with type 1 diabetes compared to the control group. The second hypothesis is that the group weaned on casein hydrolysate has a reduced incidence of type 1 diabetes. If this hypothesis is correct, preventing a portion of type 1 diabetes cases and the consequent reduction in morbidity, mortality, and related costs would be a feasible objective that could then be easily applied to the general population, which accounts for 90% of type 1 diabetes cases. More specifically, it predicts:

• Elimination of cow's milk proteins in the first 6-8 months of life prevents the onset of type 1 diabetes or anti-islet cell antibodies (surrogate markers) in infants at high genetic risk

• Within the time frame proposed in this protocol, it is unlikely that a satisfactory response will be possible in terms of diabetes development in the study cohort. However, evidence regarding the role played by antibody markers suggests that any intervention that prevents beta-cell destruction must inevitably prevent the autoimmune attack and therefore the formation of autoantibodies, which constitute an important surrogate marker of damage. For this reason, it is justified to consider reducing the appearance of anti-islet cell autoantibodies as the study's goal.

Ancillary or secondary goals: In general, these goals include understanding the natural history of type 1 diabetes, starting from the prediabetes phase, and determining the relationship between anti-beta-cell autoimmunity and the immune response to cow's milk proteins. Specifically:

• To assess which pancreatic beta-cell antigen is predominant in triggering the autoimmune response

• To assess which anti-beta-cell antibody appears first in the prediabetes phase

• To evaluate the relationship between humoral and cellular responses in the various phases of prediabetes

• To evaluate the effect of dietary intervention on the development of antibodies and T cells reactive against cow's milk proteins.

• To evaluate the relationship between the immune response against beta cells and against cow's milk proteins

This is the first primary prevention study for type 1 diabetes ever proposed. Indeed, all diabetes prevention trials to date have been conducted on subjects at risk because they have antibodies against beta cells, and therefore are already in an advanced stage of the autoimmune attack on these cells. The failure of the preventive strategy in these studies would be attributed precisely to the late timing of intervention. In the present study, however, the hypothetical preventive strategy is applied to subjects with a high genetic risk of developing diabetes (first-degree relatives with high-risk HLA haplotypes) but who have not yet developed autoimmune insulitis.

Start and end date

2001 - 2017

Project Manager

Prof. Paolo Pozzilli, Diabetology and Endocrinology Research Unit - Scientific Coordinator of the Research Program for Italy

Coordinating institution of the project

University of Helsinki - Finland

Other Institutions involved

• Australia

• Canada

• Czech Republic

• Estonia

• Finland

• Germany

• Hungary

• Italy

• Luxembourg

• The Netherlands

• poland

• Spain

• Sweden

• Switzerland

• USA

Funding source(s).

• Grant Numbers HD040364, HD042444 and HD051997 from the National Institute of Child Health and Human Development and National Institute of Diabetes and Digestive and Kidney Diseases

• National Institutes of Health, Canadian Institutes of HealthResearch

• The Juvenile Diabetes Research Foundation International

• The Commission of the European Communities (specific RTD program “Quality of Life and management of Living Resources”, contract number QLK1-2002-00372 "Diabetes Prevention"

• The EFSD/JDRF/Novo Nordisk Focused Research Grant

• The study formulas were provided free of charge by Mead Johnson Nutrition