NCT00179777

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.

Trial Health

98
On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment
5,156

participants targeted

Target at P75+ for not_applicable

Timeline
Completed

Started May 2002

Longer than P75 for not_applicable

Geographic Reach
14 countries

16 active sites

Status
completed

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

Study Start

First participant enrolled

May 6, 2002

Completed
3.4 years until next milestone

First Submitted

Initial submission to the registry

September 10, 2005

Completed
6 days until next milestone

First Posted

Study publicly available on registry

September 16, 2005

Completed
11.5 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

March 31, 2017

Completed
6 months until next milestone

Study Completion

Last participant's last visit for all outcomes

September 30, 2017

Completed
3.8 years until next milestone

Results Posted

Study results publicly available

July 30, 2021

Completed
Last Updated

July 30, 2021

Status Verified

July 1, 2021

Enrollment Period

14.9 years

First QC Date

September 10, 2005

Results QC Date

June 22, 2020

Last Update Submit

July 9, 2021

Conditions

Diabetes Mellitus, Type 1

Keywords

Diabetes Mellitus, Type 1Genetic Predisposition to DiseaseInfant NutritionPrimary Prevention

Outcome Measures

Primary Outcomes (1)

  • 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 Outcomes (1)

  • Number of Participants With Diabetes Associated Autoantibodies

    3, 6, 9, 12, 18 months and annually from 2 years up to 14 years

Study Arms (2)

Hydrolysed infant formula

EXPERIMENTAL

Hydrolysed infant formula

Dietary Supplement: Hydrolysed infant formula

Nonhydrolysed infant formula

PLACEBO COMPARATOR

Nonhydrolysed cow's milk based infant formula

Dietary Supplement: Nonhydrolysed infant formula

Interventions

Hydrolysed infant formulaDIETARY_SUPPLEMENT

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.

Hydrolysed infant formula
Nonhydrolysed infant formulaDIETARY_SUPPLEMENT

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.

Nonhydrolysed infant formula

Eligibility Criteria

AgeUp to 7 Days
Sexall
Healthy VolunteersNo
Age GroupsChild (0-17)

You may qualify if:

  • 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

You may not qualify if:

  • 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.

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (18)

The University of South Florida

Tampa, Florida, 33620, United States

Location

University of Pittsburgh

Pittsburgh, Pennsylvania, 15213-2583, United States

Location

Children's Hospital at Westmead

Westmead, New South Wales, 2145, Australia

Location

Robarts Research Institute

London, Ontario, N6A 5K8, Canada

Location

3rd Faculty of Medicine, Charles University, University Hospital Vinohrady

Prague, 10, Czechia

Location

Tartu University Children's Hospital

Tartu, 51014, Estonia

Location

University of Helsinki

Helsinki, 00029HUS, Finland

Location

Kinderkrankenhaus auf der Bult

Hanover, 30173, Germany

Location

Semmelweis Medical University

Budapest, 1083, Hungary

Location

St. Michele Hospital

Cagliari, Sardinia, 09134, Italy

Location

University Campus Bio-Medico of Rome

Rome, 00155, Italy

Location

Centre Hospitalier de Luxembourg

Luxembourg, 1210, Luxembourg

Location

Sophia Children's Hospital

Rotterdam, 3015 GJ, Netherlands

Location

Medical University of Wroclaw

Wroclaw, 50-376, Poland

Location

Hospital de Cruces

Barakaldo, Vizcaya, 48903, Spain

Location

Hospital Clinico San Carlos

Madrid, 28040, Spain

Location

University of Linkoping

Linköping, S-58185, Sweden

Location

University Children's Hospital

Zurich, CH-8032, Switzerland

Location

Related Publications (14)

  • 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.

    PMID: 15838685BACKGROUND

  • 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.

    PMID: 17550422BACKGROUND

  • 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.

    BACKGROUND

  • 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.

    PMID: 29297078RESULT

  • Biradar R, Kalim UU, Lonnberg T, Junttila S, Suomi T, Norman SZ, Starskaia I, Paulin N, Mikkola L, Vaarala O, Rasool O, Knip M, Elo LL, Lahesmaa R. Single-cell RNA-seq analysis of longitudinal CD4+ T cell samples reveals cell-type-specific changes during early stages of type 1 diabetes. Genome Med. 2025 Dec 29;17(1):154. doi: 10.1186/s13073-025-01574-x.

    PMID: 41462339DERIVED

  • 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.

    PMID: 38906178DERIVED

  • 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.

    PMID: 35693790DERIVED

  • 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.

    PMID: 33474583DERIVED

  • 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.

    PMID: 33026463DERIVED

  • 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.

    PMID: 32548702DERIVED

  • 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.

    PMID: 31912198DERIVED

  • 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.

    PMID: 24915259DERIVED

  • 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.

    PMID: 24216218DERIVED

  • 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.

    PMID: 21153533DERIVED

Related Links

MeSH Terms

Conditions

Diabetes Mellitus, Type 1Genetic Predisposition to Disease

Condition Hierarchy (Ancestors)

Diabetes MellitusGlucose Metabolism DisordersMetabolic DiseasesNutritional and Metabolic DiseasesEndocrine System DiseasesAutoimmune DiseasesImmune System DiseasesDisease SusceptibilityDisease AttributesPathologic ProcessesPathological Conditions, Signs and Symptoms

Results Point of Contact

Title
Professor Mikael Knip
Organization
University of Helsinki
mikael.knip@helsinki.fi
+3582941 25222

Study Officials

  • Mikael Knip, MD

    University of Helsinki

    PRINCIPAL INVESTIGATOR

Publication Agreements

PI is Sponsor Employee
No
Restrictive Agreement
No

Study Design

Study Type
interventional
Phase
not applicable
Allocation
RANDOMIZED
Masking
QUADRUPLE
Who Masked
PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
Purpose
PREVENTION
Intervention Model
PARALLEL
Sponsor Type
OTHER
Responsible Party
PRINCIPAL INVESTIGATOR
PI Title
Professor, Principal Investigator

Study Record Dates

First Submitted

September 10, 2005

First Posted

September 16, 2005

Study Start

May 6, 2002

Primary Completion

March 31, 2017

Study Completion

September 30, 2017

Last Updated

July 30, 2021

Results First Posted

July 30, 2021

Record last verified: 2021-07

Data Sharing

IPD Sharing
Will not share

Locations

FI(1)DE(1)ES(1)CA(1)HU(1)AU(1)NL(1)IT(2)LU(1)SE(1)CH(1)PL(1)US(2)CZ(1)