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 hydrolysed 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 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 Data Management Unit for this 17 year study which is submitted in tandem with those of the European coordinating and clinical centers and those of the US coordinating and clinical centers.

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)
Project #
Application #
Study Section
Pediatrics Subcommittee (CHHD)
Program Officer
Grave, Gilman D
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of South Florida
Schools of Medicine
United States
Zip Code
Writing Group for the TRIGR Study Group; Knip, Mikael; Ã…kerblom, 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; Ã…kerblom, 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
Kingery, Suzanne E; Wu, Yee Ling; Zhou, Bi et al. (2012) Gene CNVs and protein levels of complement C4A and C4B as novel biomarkers for partial disease remissions in new-onset type 1 diabetes patients. Pediatr Diabetes 13:408-18
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
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
TRIGR Study Group; Akerblom, H K; Krischer, J et al. (2011) The Trial to Reduce IDDM in the Genetically at Risk (TRIGR) study: recruitment, intervention and follow-up. Diabetologia 54:627-33

Showing the most recent 10 out of 12 publications