TRIGR - Primary Prevention Study for Type 1 Diabetes in Children at Risk

Study Overview
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Brief Summary
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The Trial to Reduce IDDM in the Genetically at Risk (TRIGR) is an international effort to conduct a primary prevention nutrition trial for type 1 (insulin-dependent) diabetes. The TRIGR study was targeted at newborns who are at genetic risk for type 1 diabetes because their mother, father and/or full sibling has type 1 diabetes. All families were encouraged to breast feed their infants for as long as possible. Prior to birth, the child was randomly assigned to receive one of two infant formulas, should formula be required prior to 8 months of age. The study determined whether weaning to a possibly protective infant formula decreases these children's chances of developing diabetes - as it does in the animal models for diabetes.

Detailed Description
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The hypothesis for this study is that weaning to an extensively hydrolyzed infant formula will decrease the incidence of type 1 diabetes in subjects with risk-associated HLA genotypes and a first degree relative with type 1 diabetes, as it does in all relevant animal models for the disease. Specific Aims: I.a: To determine if weaning to a casein hydrolysate infant formula reduces the frequency of diabetes-predictive auto-antibodies in subjects with risk-associated HLA genotype and a first degree relative with type 1 diabetes (mother, father and/or full sibling). I-b: To determine if weaning to a casein hydrolysate infant formula reduces the frequency of clinical diabetes in subjects with risk-associated HLA genotype and an affected first degree relative. A secondary aim is to determine relationships between cow's milk antibodies, a measure of cow's milk exposure, and diabetes-associated auto-antibodies. The mother of the unborn child is recruited during pregnancy. Randomization to one of two infant formulas takes place before birth (after 35 weeks gestation) or immediately after birth. Experimental Arm: Use of extensively hydrolysed cow's milk based infant formula when needed in supplementation or substitution for breast milk through 6-8 months from birth. Control Arm: Use of non-hydrolysed cow's milk based infant formula when needed in supplementation or substitution for breast milk through 6-8 months from birth. All families were encouraged to breast feed their infants for as long as possible. The study infant formula was only used if exclusive breast feeding ceases before 8 months of age. Cord blood for genotyping was obtained at birth, or failing that from a heel prick by 7 days of age. Only subjects with genotypes indicating increased genetic risk for type 1 diabetes remained in the intervention trial. All other subjects were withdrawn from the study. All subjects were followed until the youngest subject turns age 10 years.

Official Title
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TRIGR - Trial to Reduce IDDM in the Genetically at Risk

Conditions
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Diabetes Mellitus, Type 1

Intervention / Treatment
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* Dietary Supplement: Hydrolysed infant formula
* Dietary Supplement: Nonhydrolysed infant formula


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Biological parent and/or full (not half) sibling of the newborn infant had type 1 diabetes as defined by the World Health Organization The infant's parent or legal guardians gave signed consent to participate Exclusion Criteria: An older sibling of the newborn infant had been included in the TRIGR intervention Multiple gestation The parents were unwilling or unable to feed the infant cow's milk based products for any reason (e.g., religious, cultural). The newborn infant had a recognizable severe illness such as those due to chromosomal abnormality, congenital malformation, respiratory failure needing assisted ventilation, enzyme deficiencies, etc. The gestational age of the newborn infant was less than 35 weeks. The infant was older than 7 days at randomization. Inability of the family to take part in the study (e.g. the family has no access to any of the Study Centers, the family has no telephone). The infant had received any infant formula other than Nutramigen prior to randomization. No HLA sample drawn before the age of 8 days.

Ages Eligible for Study
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Maximum Age: 7 Days

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Hydrolysed infant formula<br>Hydrolysed infant formula | Dietary Supplement: Hydrolysed infant formula<br>* Participants in the Hydrolysed infant formula -group received the test formula, casein hydrolysate (Nutramigen™, Mead Johnson Nutritionals), not containing antigenic CM protein, whenever breast milk is not available.<br>|
| Placebo Comparator: Nonhydrolysed infant formula<br>Nonhydrolysed cow's milk based infant formula | Dietary Supplement: Nonhydrolysed infant formula<br>* Participants in the Nonydrolysed infant formula -group received the CM protein containing control formula which has an addition (20 %) of Nutramigen, whenever breast milk is not available.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Type 1 Diabetes Mellitus | Number of participants with Type 1 diabetes mellitus assessed by (1) blood glucose and HbA1c at 12 and 18 months of age, and annually from age 2 to 10 years, and (2) oral glucose tolerance test at 6 and 10 years of age and in the final year of the study. | 12 and 18 months and annually from 2 years up to 14 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Diabetes Associated Autoantibodies | Diabetes associated autoantibodies (ICA, IAA, GADA, IA-2A) at 3, 6, 9, 12, and 18 months of age, and annually from age 2 to 10-14 years | 3, 6, 9, 12, 18 months and annually from 2 years up to 14 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diabetes Mellitus, Type 1, Genetic Predisposition to Disease, Infant Nutrition, Primary Prevention