- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT00179777
TRIGR - Primary Prevention Study for Type 1 Diabetes in Children at Risk (TRIGR)
TRIGR - Trial to Reduce IDDM in the Genetically at Risk
Study Overview
Status
Conditions
Intervention / Treatment
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 All other subjects were withdrawn from the study.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.
Study Type
Enrollment (Actual)
Phase
- Not Applicable
Contacts and Locations
Study Locations
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New South Wales
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Westmead, New South Wales, Australia, 2145
- Children's Hospital at Westmead
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Ontario
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London, Ontario, Canada, N6A 5K8
- Robarts Research Institute
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Prague, Czechia, 10
- 3rd Faculty of Medicine, Charles University, University Hospital Vinohrady
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Tartu, Estonia, 51014
- Tartu University Children's Hospital
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Helsinki, Finland, 00029HUS
- University of Helsinki
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Hannover, Germany, 30173
- Kinderkrankenhaus auf der Bult
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Budapest, Hungary, 1083
- Semmelweis Medical University
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Rome, Italy, 00155
- University Campus Bio-Medico of Rome
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Sardinia
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Cagliari, Sardinia, Italy, 09134
- St. Michele Hospital
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Luxembourg, Luxembourg, 1210
- Centre Hospitalier de Luxembourg
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Rotterdam, Netherlands, 3015 GJ
- Sophia Children's Hospital
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Wroclaw, Poland, 50-376
- Medical University of Wroclaw
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Madrid, Spain, 28040
- Hospital Clinico San Carlos
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Vizcaya
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Barakaldo, Vizcaya, Spain, 48903
- Hospital De Cruces
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Linkoping, Sweden, S-58185
- University of Linköping
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Zurich, Switzerland, CH-8032
- University Children's Hospital
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Florida
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Tampa, Florida, United States, 33620
- The University of South Florida
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Pennsylvania
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Pittsburgh, Pennsylvania, United States, 15213-2583
- University of Pittsburgh
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: PREVENTION
- Allocation: RANDOMIZED
- Interventional Model: PARALLEL
- Masking: QUADRUPLE
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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EXPERIMENTAL: Hydrolysed infant formula
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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.
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PLACEBO_COMPARATOR: Nonhydrolysed infant formula
Nonhydrolysed cow's milk based infant formula
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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.
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
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Number of Participants With Type 1 Diabetes Mellitus
Time Frame: 12 and 18 months and annually from 2 years up to 14 years
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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.
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12 and 18 months and annually from 2 years up to 14 years
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
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Number of Participants With Diabetes Associated Autoantibodies
Time Frame: 3, 6, 9, 12, 18 months and annually from 2 years up to 14 years
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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
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3, 6, 9, 12, 18 months and annually from 2 years up to 14 years
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Collaborators and Investigators
Sponsor
Collaborators
Publications and helpful links
General Publications
- 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. Erratum In: Diabetologia. 2005 Aug;48(8):1676. Riikjarv, MA [added]; Ormisson, A [added]; Ludvigsson, J [added]; Dosch, HM [added]; Hakulinen, T [added]; Knip, M [added].
- 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, 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. Erratum In: Diabetologia. 2011 Aug;54(8):2210.
Study record dates
Study Major Dates
Study Start (ACTUAL)
Primary Completion (ACTUAL)
Study Completion (ACTUAL)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (ESTIMATE)
Study Record Updates
Last Update Posted (ACTUAL)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- MCT-49395
- U01HD040364 (NIH)
- U01HD042444 (NIH)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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