The Trial to Reduce Insulin Dependent Diabetes in the Genetically at Risk ('TRIGR') will determine whether weaning to a formula in which (foreign) proteins have been extensively hydrolysed, reduces disease risk for type 1 Diabetes (T1D) in genetically susceptible children, as it does in rodent models.
The Specific Aims are: I-a: To determine whether weaning to a hydrolysed casein formula (Nutramigen"""""""") reduces the frequency of diabetes-predictive autoantibodies, and I-b: To determine whether weaning to casein hydrolysate reduces the frequency of clinical diabetes. This double blind, randomized controlled trial in subjects with an affected first-degree relative and risk- associated HLA genotypes is currently in its 9th year. An international, multicenter consortium has been developed comprising 77 centers in 15 countries. Enrollment of 2160 eligible infants was completed successfully, providing a cushion above the required 2032 infants. The 6-8 month intervention designed to compare the effects of either hydrolyzed casein or standard cow milk based weaning formula was completed in 2007. Duration of breast-feeding at the mothers'discretion was similar to or above background populations All subjects are followed during and after the intervention period for at least 10 years with measurements of serological markers of intact cow milk exposure, diabetes predictive autoantibodies (the end point at age 6 years) and the clinical and/or metabolic indices of diabetes (the end point at age 10 years). Currently all planning parameters have been met and drop out rates are <2% with compliance at expected levels. A large, cross-linked repository of stored sera, DNA, T-cell data, and cryopreserved peripheral blood mononuclear cells allows independently funded ancillary and mechanistic studies related to the natural history of prediabetes and the hypothesis to be tested. This application covers years 11-15 for the International Coordinating Center and the Core Autoantibody Laboratory at the University of Helsinki and for the study centers in Europe and Australia for this 17 year study which is submitted in tandem with those of the US coordinating center and clinical centers and that of the Data Management Unit.

Public Health Relevance

Cow milk protein is the most common intact foreign weaning protein in humans. If our intervention is effective in delaying autoimmunity or ultimately its progression to clinical diabetes, this first ever primary prevention study of T1D, will have far-reaching impact for individuals and the global society.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project--Cooperative Agreements (U01)
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Pediatrics Subcommittee (CHHD)
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Grave, Gilman D
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University of Helsinki
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Writing Group for the TRIGR Study Group; Knip, Mikael; Åkerblom, Hans K et al. (2018) Effect of Hydrolyzed Infant Formula vs Conventional Formula on Risk of Type 1 Diabetes: The TRIGR Randomized Clinical Trial. JAMA 319:38-48
Nucci, Anita M; Virtanen, Suvi M; Sorkio, Susa et al. (2017) Regional differences in milk and complementary feeding patterns in infants participating in an international nutritional type 1 diabetes prevention trial. Matern Child Nutr 13:
Knip, Mikael; Åkerblom, Hans K; Becker, Dorothy et al. (2014) Hydrolyzed infant formula and early ?-cell autoimmunity: a randomized clinical trial. JAMA 311:2279-87
Hadley, David; Cheung, Roy K; Becker, Dorothy J et al. (2014) Large-scale prospective T cell function assays in shipped, unfrozen blood samples: experiences from the multicenter TRIGR trial. Clin Vaccine Immunol 21:203-11
Franciscus, Margaret; Nucci, Anita; Bradley, Brenda et al. (2014) Recruitment and retention of participants for an international type 1 diabetes prevention trial: a coordinators' perspective. Clin Trials 11:150-8
Lehtonen, Eveliina; Ormisson, Anne; Nucci, Anita et al. (2014) Use of vitamin D supplements during infancy in an international feeding trial. Public Health Nutr 17:810-22
Nucci, Anita M; Becker, Dorothy J; Virtanen, Suvi M et al. (2012) Growth differences between North American and European children at risk for type 1 diabetes. Pediatr Diabetes 13:425-31
Luopajärvi, Kristiina; Nieminen, Janne K; Ilonen, Jorma et al. (2012) Expansion of CD4+CD25+FOXP3+ regulatory T cells in infants of mothers with type 1 diabetes. Pediatr Diabetes 13:400-7
Vehik, Kendra; Cuthbertson, David; Boulware, David et al. (2012) Performance of HbA1c as an early diagnostic indicator of type 1 diabetes in children and youth. Diabetes Care 35:1821-5
Knip, Mikael; Virtanen, Suvi M; Becker, Dorothy et al. (2011) Early feeding and risk of type 1 diabetes: experiences from the Trial to Reduce Insulin-dependent diabetes mellitus in the Genetically at Risk (TRIGR). Am J Clin Nutr 94:1814S-1820S

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