TRIGR - Primary Prevention Study for Type 1 Diabetes in Children at Risk
NCT ID: NCT00179777
Last Updated: 2021-07-30
Study Results
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View full resultsBasic Information
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COMPLETED
NA
5156 participants
INTERVENTIONAL
2002-05-06
2017-09-30
Brief Summary
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Detailed Description
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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 All other subjects were withdrawn from the study.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.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
PREVENTION
QUADRUPLE
Study Groups
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Hydrolysed infant formula
Hydrolysed infant formula
Hydrolysed infant formula
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.
Nonhydrolysed infant formula
Nonhydrolysed cow's milk based infant formula
Nonhydrolysed infant formula
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.
Interventions
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Hydrolysed infant formula
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.
Nonhydrolysed infant formula
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.
Eligibility Criteria
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Inclusion Criteria
* The infant's parent or legal guardians gave signed consent to participate
Exclusion Criteria
* 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.
7 Days
ALL
No
Sponsors
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United States Congress
FED
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
NIH
Canadian Institutes of Health Research (CIHR)
OTHER_GOV
Juvenile Diabetes Research Foundation
OTHER
European Community (EC)
OTHER_GOV
European Foundation for the Study of Diabetes
OTHER
Mead Johnson Nutrition
INDUSTRY
Academy of Finland
OTHER
Diabetes Research Foundation, Finland
OTHER
Dutch Diabetes Research Foundation
OTHER
University of Helsinki
OTHER
Responsible Party
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Mikael Knip
Professor, Principal Investigator
Principal Investigators
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Mikael Knip, MD
Role: PRINCIPAL_INVESTIGATOR
University of Helsinki
Locations
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The University of South Florida
Tampa, Florida, United States
University of Pittsburgh
Pittsburgh, Pennsylvania, United States
Children's Hospital at Westmead
Westmead, New South Wales, Australia
Robarts Research Institute
London, Ontario, Canada
3rd Faculty of Medicine, Charles University, University Hospital Vinohrady
Prague, , Czechia
Tartu University Children's Hospital
Tartu, , Estonia
University of Helsinki
Helsinki, , Finland
Kinderkrankenhaus auf der Bult
Hanover, , Germany
Semmelweis Medical University
Budapest, , Hungary
St. Michele Hospital
Cagliari, Sardinia, Italy
University Campus Bio-Medico of Rome
Rome, , Italy
Centre Hospitalier de Luxembourg
Luxembourg, , Luxembourg
Sophia Children's Hospital
Rotterdam, , Netherlands
Medical University of Wroclaw
Wroclaw, , Poland
Hospital de Cruces
Barakaldo, Vizcaya, Spain
Hospital Clinico San Carlos
Madrid, , Spain
University of Linkoping
Linköping, , Sweden
University Children's Hospital
Zurich, , Switzerland
Countries
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References
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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.
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.
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.
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.
Niinisto S, Cuthbertson D, Miettinen ME, Hakola L, Nucci A, Korhonen TE, Hyoty H, Krischer JP, Vaarala O, Knip M, Savilahti E, Virtanen SM; TRIGR Investigators. High Concentrations of Immunoglobulin G Against Cow Milk Proteins and Frequency of Cow Milk Consumption Are Associated With the Development of Islet Autoimmunity and Type 1 Diabetes-The Trial to Reduce Insulin-dependent Diabetes Mellitus (IDDM) in the Genetically at Risk (TRIGR) Study. J Nutr. 2024 Aug;154(8):2493-2500. doi: 10.1016/j.tjnut.2024.06.005. Epub 2024 Jun 19.
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.
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.
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.
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.
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.
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.
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.
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.
Provided Documents
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Document Type: Study Protocol and Statistical Analysis Plan
Related Links
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TRIGR International website - Click here for more information on this study - www.TRIGR.org
TRIGR North America website - Click here for more information on this study - www.trigrnorthamerica.org
Other Identifiers
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