Clinical trial NCT00179777: TRIGR - Primary Prevention Study for Type 1 Diabetes in Children at Risk
Official title: TRIGR - Trial to Reduce IDDM in the Genetically at Risk
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Diabetes Mellitus, Type 1
Keywords: Diabetes Mellitus, Type 1
Genetic Predisposition to Disease
Infant Nutrition
Primary Prevention
Lead sponsor: University of Helsinki
Sponsor class: OTHER
Collaborators: name: United States Congress
name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
name: Canadian Institutes of Health Research (CIHR)
name: Juvenile Diabetes Research Foundation
name: European Community (EC)
name: European Foundation for the Study of Diabetes
name: Mead Johnson Nutrition
name: Academy of Finland
name: Diabetes Research Foundation, Finland
name: Dutch Diabetes Research Foundation
First posted: 2005-09-16
Enrollment: 5156
Sex: ALL
Maximum age (years): 7
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Number of Participants With Type 1 Diabetes Mellitus
timeFrame: 12 and 18 months and annually from 2 years up to 14 years
Secondary outcomes:
measure: Number of Participants With Diabetes Associated Autoantibodies
timeFrame: 3, 6, 9, 12, 18 months and annually from 2 years up to 14 years
Other outcomes:
Locations:
city: Tampa
country: United States
facility: The University of South Florida
state: Florida
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
city: Westmead
country: Australia
facility: Children's Hospital at Westmead
state: New South Wales
city: London
country: Canada
facility: Robarts Research Institute
state: Ontario
city: Prague
country: Czechia
facility: 3rd Faculty of Medicine, Charles University, University Hospital Vinohrady
city: Tartu
country: Estonia
facility: Tartu University Children's Hospital
city: Helsinki
country: Finland
facility: University of Helsinki
city: Hannover
country: Germany
facility: Kinderkrankenhaus auf der Bult
city: Budapest
country: Hungary
facility: Semmelweis Medical University
city: Cagliari
country: Italy
facility: St. Michele Hospital
state: Sardinia
city: Rome
country: Italy
facility: University Campus Bio-Medico of Rome
city: Luxembourg
country: Luxembourg
facility: Centre Hospitalier de Luxembourg
city: Rotterdam
country: Netherlands
facility: Sophia Children's Hospital
city: Wroclaw
country: Poland
facility: Medical University of Wroclaw
city: Barakaldo
country: Spain
facility: Hospital de Cruces
state: Vizcaya
city: Madrid
country: Spain
facility: Hospital Clinico San Carlos
city: Linkoping
country: Sweden
facility: University of Linkoping
city: Zurich
country: Switzerland
facility: University Children's Hospital
Study officials:
affiliation: University of Helsinki
name: Mikael Knip, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Akerblom HK, Virtanen SM, Ilonen J, Savilahti E, Vaarala O, Reunanen A, Teramo K, Hamalainen AM, Paronen J, Riikjarv MA, Ormisson A, Ludvigsson J, Dosch HM, Hakulinen T, Knip M; National TRIGR Study Groups. Dietary manipulation of beta cell autoimmunity in infants at increased risk of type 1 diabetes: a pilot study. Diabetologia. 2005 May;48(5):829-37. doi: 10.1007/s00125-005-1733-3. Epub 2005 Apr 19.
citation: TRIGR Study Group. Study design of the Trial to Reduce IDDM in the Genetically at Risk (TRIGR). Pediatr Diabetes. 2007 Jun;8(3):117-37. doi: 10.1111/j.1399-5448.2007.00239.x.
citation: Åkerblom HK, Knip M, Becker D, Dosch H-M, Dupré J, Ilonen J, Krischer JP and the TRIGR Study Group. The TRIGR Trial: Testing the Potential Link between Weaning Diet and Type 1 Diabetes. Immun, Endoc, Metab Agents in Med Chem 7:251-263, 2007.
citation: Writing Group for the TRIGR Study Group; Knip M, Akerblom HK, Al Taji E, Becker D, Bruining J, Castano L, Danne T, de Beaufort C, Dosch HM, Dupre J, Fraser WD, Howard N, Ilonen J, Konrad D, Kordonouri O, Krischer JP, Lawson ML, Ludvigsson J, Madacsy L, Mahon JL, Ormisson A, Palmer JP, Pozzilli P, Savilahti E, Serrano-Rios M, Songini M, Taback S, Vaarala O, White NH, Virtanen SM, Wasikowa R. Effect of Hydrolyzed Infant Formula vs Conventional Formula on Risk of Type 1 Diabetes: The TRIGR Randomized Clinical Trial. JAMA. 2018 Jan 2;319(1):38-48. doi: 10.1001/jama.2017.19826.
citation: Niinisto S, Miettinen ME, Cuthbertson D, Honkanen J, Hakola L, Autio R, Erlund I, Arohonka P, Vuorela A, Harkonen T, Hyoty H, Krischer JP, Vaarala O, Knip M, Virtanen SM; TRIGR Investigators. Associations Between Serum Fatty Acids and Immunological Markers in Children Developing Islet Autoimmunity-The TRIGR Nested Case-Control Study. Front Immunol. 2022 May 25;13:858875. doi: 10.3389/fimmu.2022.858875. eCollection 2022.
citation: Nucci AM, Virtanen SM, Cuthbertson D, Ludvigsson J, Einberg U, Huot C, Castano L, Aschemeier B, Becker DJ, Knip M, Krischer JP; TRIGR Investigators. Growth and development of islet autoimmunity and type 1 diabetes in children genetically at risk. Diabetologia. 2021 Apr;64(4):826-835. doi: 10.1007/s00125-020-05358-3. Epub 2021 Jan 21.
citation: Pacaud D, Nucci AM, Cuthbertson D, Becker DJ, Virtanen SM, Ludvigsson J, Ilonen J, Knip M; TRIGR investigators. Association between family history, early growth and the risk of beta cell autoimmunity in children at risk for type 1 diabetes. Diabetologia. 2021 Jan;64(1):119-128. doi: 10.1007/s00125-020-05287-1. Epub 2020 Oct 7.
citation: Krischer JP, Cuthbertson D, Couluris M, Knip M, Virtanen SM. Association of diabetes-related autoantibodies with the incidence of asthma, eczema and allergic rhinitis in the TRIGR randomised clinical trial. Diabetologia. 2020 Sep;63(9):1796-1807. doi: 10.1007/s00125-020-05188-3. Epub 2020 Jun 17.
citation: Miettinen ME, Niinisto S, Erlund I, Cuthbertson D, Nucci AM, Honkanen J, Vaarala O, Hyoty H, Krischer JP, Knip M, Virtanen SM; TRIGR Investigators. Serum 25-hydroxyvitamin D concentration in childhood and risk of islet autoimmunity and type 1 diabetes: the TRIGR nested case-control ancillary study. Diabetologia. 2020 Apr;63(4):780-787. doi: 10.1007/s00125-019-05077-4. Epub 2020 Jan 7.
citation: Knip M, Akerblom HK, Becker D, Dosch HM, Dupre J, Fraser W, Howard N, Ilonen J, Krischer JP, Kordonouri O, Lawson ML, Palmer JP, Savilahti E, Vaarala O, Virtanen SM; TRIGR Study Group. Hydrolyzed infant formula and early beta-cell autoimmunity: a randomized clinical trial. JAMA. 2014 Jun 11;311(22):2279-87. doi: 10.1001/jama.2014.5610.
citation: Franciscus M, Nucci A, Bradley B, Suomalainen H, Greenberg E, Laforte D, Kleemola P, Hyytinen M, Salonen M, Martin MJ, Catte D, Catteau J; TRIGR Investigators. Recruitment and retention of participants for an international type 1 diabetes prevention trial: a coordinators' perspective. Clin Trials. 2014 Apr;11(2):150-8. doi: 10.1177/1740774513510070. Epub 2013 Nov 11.
citation: TRIGR Study Group; Akerblom HK, Krischer J, Virtanen SM, Berseth C, Becker D, Dupre J, Ilonen J, Trucco M, Savilahti E, Koski K, Pajakkala E, Fransiscus M, Lough G, Bradley B, Koski M, Knip M. The Trial to Reduce IDDM in the Genetically at Risk (TRIGR) study: recruitment, intervention and follow-up. Diabetologia. 2011 Mar;54(3):627-33. doi: 10.1007/s00125-010-1964-9. Epub 2010 Dec 12.