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

• Sponsor: University of Helsinki (Other)
• Overall Status: Completed
• CT.gov ID: NCT00179777
• Collaborator: US Congress (Other), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (NIH), Canadian Institutes of Health Research (CIHR) (Other), Juvenile Diabetes Research Foundation (Other), European Community (EC) (Other), 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)
• Enrollment: 5,156
• Locations: 18
• Arms: 2
• Actual Duration (Months): 184.8
• Patients Per Site: 286.4
• Patients Per Site Per Month: 1.5

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus, Type 1	Dietary Supplement: Hydrolysed infant formula; Dietary Supplement: Nonhydrolysed infant formula	N/A

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 Design

• Study Type: Interventional
• Actual Enrollment: 5156 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: TRIGR - Trial to Reduce IDDM in the Genetically at Risk
• Actual Study Start Date: May 6, 2002
• Actual Primary Completion Date: Mar 31, 2017
• Actual Study Completion Date: Sep 30, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Hydrolysed infant formula Hydrolysed infant formula	Dietary Supplement: 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.
Placebo Comparator: Nonhydrolysed infant formula Nonhydrolysed cow's milk based infant formula	Dietary Supplement: 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.

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Type 1 Diabetes Mellitus [12 and 18 months and annually from 2 years up to 14 years]

   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.

Secondary Outcome Measures

1. Number of Participants With Diabetes Associated Autoantibodies [3, 6, 9, 12, 18 months and annually from 2 years up to 14 years]

   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

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 7 Days
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	The University of South Florida	Tampa	Florida	United States	33620
2	University of Pittsburgh	Pittsburgh	Pennsylvania	United States	15213-2583
3	Children's Hospital at Westmead	Westmead	New South Wales	Australia	2145
4	Robarts Research Institute	London	Ontario	Canada	N6A 5K8
5	3rd Faculty of Medicine, Charles University, University Hospital Vinohrady	Prague		Czechia	10
6	Tartu University Children's Hospital	Tartu		Estonia	51014
7	University of Helsinki	Helsinki		Finland	00029HUS
8	Kinderkrankenhaus auf der Bult	Hannover		Germany	30173
9	Semmelweis Medical University	Budapest		Hungary	1083
10	St. Michele Hospital	Cagliari	Sardinia	Italy	09134
11	University Campus Bio-Medico of Rome	Rome		Italy	00155
12	Centre Hospitalier de Luxembourg	Luxembourg		Luxembourg	1210
13	Sophia Children's Hospital	Rotterdam		Netherlands	3015 GJ
14	Medical University of Wroclaw	Wroclaw		Poland	50-376
15	Hospital de Cruces	Barakaldo	Vizcaya	Spain	48903
16	Hospital Clinico San Carlos	Madrid		Spain	28040
17	University of Linkoping	Linkoping		Sweden	S-58185
18	University Children's Hospital	Zurich		Switzerland	CH-8032

Sponsors and Collaborators

• University of Helsinki
• US Congress
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Canadian Institutes of Health Research (CIHR)
• Juvenile Diabetes Research Foundation
• European Community (EC)
• European Foundation for the Study of Diabetes
• Mead Johnson Nutrition
• Academy of Finland
• Diabetes Research Foundation, Finland
• Dutch Diabetes Research Foundation

Investigators

• Principal Investigator: Mikael Knip, MD, University of Helsinki

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Apr 15, 2015

More Information

Additional Information:

• 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

Publications

• 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.
• Akerblom HK, Virtanen SM, Ilonen J, Savilahti E, Vaarala O, Reunanen A, Teramo K, Hämäläinen AM, Paronen J, Riikjärv 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. Epub 2005 Apr 19. Erratum in: Diabetologia. 2005 Aug;48(8):1676. Riikjärv, 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.

• Responsible Party: Mikael Knip, Professor, Principal Investigator, University of Helsinki
• ClinicalTrials.gov Identifier: NCT00179777
• Other Study ID Numbers: MCT-49395; U01HD040364; U01HD042444
• First Posted: Sep 16, 2005
• Last Update Posted: Jul 30, 2021
• Last Verified: Jul 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Mikael Knip, Professor, Principal Investigator, University of Helsinki: Diabetes Mellitus, Type 1; Genetic Predisposition to Disease; Infant Nutrition; Primary Prevention
• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 1

Study Results

Participant Flow

Recruitment Details	2002-2007 Recruited through local clinics and obstetrics unit

Arm/Group Title	Hydrolysed Infant Formula	Nonhydrolysed Infant Formula
Arm/Group Description	Hydrolysed infant formula hydrolysed infant formula: hydrolysed infant formula	Nonhydrolysed infant formula nonhydrolysed infant formula: nonhydrolysed infant formula
Period Title: Overall Study
STARTED	2613	2543
COMPLETED	1081	1078
NOT COMPLETED	1532	1465

Baseline Characteristics

Arm/Group Title	Nonhydrolysed Infant Formula	Hydrolysed Infant Formula	Total
Arm/Group Description	A conventional adapted cow's milk formula supplemented with 20% of the casein hydrolysate.	Hydrolysed Infant Formula missing intact cows milk proteins	Total of all reporting groups
Overall Participants	1078	1081	2159
Age (Count of Participants)
<=18 years	1078 100%	1081 100%	2159 100%
Between 18 and 65 years	0 0%	0 0%	0 0%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Median (Full Range) ]
At at randomization	0	0	0
Age at Last Follow-up	11.96	11.93	11.95
Sex: Female, Male (Count of Participants)
Female	516 47.9%	505 46.7%	1021 47.3%
Male	562 52.1%	576 53.3%	1138 52.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	53 4.9%	53 4.9%	106 4.9%
Not Hispanic or Latino	987 91.6%	989 91.5%	1976 91.5%
Unknown or Not Reported	38 3.5%	39 3.6%	77 3.6%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	3 0.3%	3 0.3%	6 0.3%
Asian	10 0.9%	13 1.2%	23 1.1%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	10 0.9%	16 1.5%	26 1.2%
White	1040 96.5%	1034 95.7%	2074 96.1%
More than one race	9 0.8%	6 0.6%	15 0.7%
Unknown or Not Reported	6 0.6%	9 0.8%	15 0.7%
Region of Enrollment (participants) [Number]
Hungary	12 1.1%	11 1%	23 1.1%
United States	196 18.2%	199 18.4%	395 18.3%
Czechia	82 7.6%	82 7.6%	164 7.6%
Switzerland	6 0.6%	37 3.4%	43 2%
Spain	31 2.9%	29 2.7%	60 2.8%
Canada	262 24.3%	265 24.5%	527 24.4%
Netherlands	29 2.7%	24 2.2%	53 2.5%
Sweden	47 4.4%	49 4.5%	96 4.4%
Luxembourg	3 0.3%	4 0.4%	7 0.3%
Finland	212 19.7%	212 19.6%	424 19.6%
Poland	46 4.3%	48 4.4%	94 4.4%
Italy	26 2.4%	28 2.6%	54 2.5%
Australia	51 4.7%	51 4.7%	102 4.7%
Germany	57 5.3%	55 5.1%	112 5.2%
Estonia	18 1.7%	17 1.6%	35 1.6%
family history of type 1 diabetes (Count of Participants)
Only mother with type 1 diabetes	522 48.4%	530 49%	1052 48.7%
Only father with type 1 diabetes	367 34%	355 32.8%	722 33.4%
Only one sibling with type 1 diabetes	157 14.6%	151 14%	308 14.3%
More than one family member with type 1 diabetes	32 3%	45 4.2%	77 3.6%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Type 1 Diabetes Mellitus
Description	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.
Time Frame	12 and 18 months and annually from 2 years up to 14 years

Outcome Measure Data

Analysis Population Description

Analysis population consisted of participants with increased genetic risk (defined HLA genotypes) for type 1 diabetes

Arm/Group Title	Nonhydrolysed Infant Formula	Hydrolysed Infant Formula
Arm/Group Description	Number of participants diagnosed with type 1 diabetes	Number of participants diagnosed with type 1 diabetes
Measure Participants	1078	1081
Number [participants]	82 7.6%	91 8.4%

2. Secondary Outcome

Title	Number of Participants With Diabetes Associated Autoantibodies
Description	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
Time Frame	3, 6, 9, 12, 18 months and annually from 2 years up to 14 years

Outcome Measure Data

Analysis Population Description

Analysis population consisted of participants with increased genetic risk (defined HLA genotypes) for type 1 diabetes

Arm/Group Title	Nonhydrolysed Infant Formula	Hydrolysed Infant Formula
Arm/Group Description	Diabetes associated autoantibodies (ICA, IAA, GADA, IA-2A) in the nonhydrolysed infant formula	Diabetes associated autoantibodies (ICA, IAA, GADA, IA-2A) in the hydrolysed infant formula
Measure Participants	1078	1081
ICA+	373 34.6%	394 36.4%
IAA+	162 15%	183 16.9%
GADA+	186 17.3%	207 19.1%
IA-2A+	102 9.5%	115 10.6%

Adverse Events

Time Frame	11.5 years
Arm/Group Title	Nonhydrolysed Infant Formula		Hydrolysed Infant Formula
Arm/Group Description	Reported Adverse Events during the Follow-up in the Nonhydrolysed Infant Formula Group		Reported Adverse Events during the Follow-up in the Hydrolysed Infant Formula Group
All Cause Mortality
	Nonhydrolysed Infant Formula		Hydrolysed Infant Formula
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/1078 (0.5%)		5/1081 (0.5%)
Serious Adverse Events
	Nonhydrolysed Infant Formula		Hydrolysed Infant Formula
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	379/1078 (35.2%)		377/1081 (34.9%)
Ear and labyrinth disorders
Middle Ear Infection	23/1078 (2.1%)	24	27/1081 (2.5%)	35
Gastrointestinal disorders
Gastroenteritis	35/1078 (3.2%)	46	29/1081 (2.7%)	36
Suspected Study Formula Intolerence	5/1078 (0.5%)	5	3/1081 (0.3%)	3
General disorders
Malignancy	1/1078 (0.1%)	1	2/1081 (0.2%)	2
Accident (Not Requiring Hospitalization)	9/1078 (0.8%)	11	11/1081 (1%)	13
Accident (Requiring Hospitalization)	27/1078 (2.5%)	29	23/1081 (2.1%)	25
Hospitalization	47/1078 (4.4%)	58	52/1081 (4.8%)	75
Life-threatening event	4/1078 (0.4%)	4	2/1081 (0.2%)	2
Other Unspecified Adverse Event	190/1078 (17.6%)	268	215/1081 (19.9%)	320
Infections and infestations
Other Unspecified Infection	62/1078 (5.8%)	64	61/1081 (5.6%)	65
Injury, poisoning and procedural complications
Disability/incapacity	3/1078 (0.3%)	3	1/1081 (0.1%)	2
Renal and urinary disorders
Urinary Tract Infection	12/1078 (1.1%)	12	11/1081 (1%)	13
Respiratory, thoracic and mediastinal disorders
Upper Respiratory Infection	51/1078 (4.7%)	64	46/1081 (4.3%)	56
Pneumonia	12/1078 (1.1%)	15	9/1081 (0.8%)	9
Asthma, Other Forms of Allergy	10/1078 (0.9%)	14	15/1081 (1.4%)	15
Other (Not Including Serious) Adverse Events
	Nonhydrolysed Infant Formula		Hydrolysed Infant Formula
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1010/1078 (93.7%)		1012/1081 (93.6%)
Ear and labyrinth disorders
Middle Ear Infection	534/1078 (49.5%)	1951	525/1081 (48.6%)	1796
Endocrine disorders
Hypoglycemia requiring IV glucose	20/1078 (1.9%)	20	10/1081 (0.9%)	10
Gastrointestinal disorders
Gastroenteritis	515/1078 (47.8%)	1519	494/1081 (45.7%)	1598
Suspected Study Formula Intolerance	56/1078 (5.2%)	73	49/1081 (4.5%)	61
General disorders
Other, unspecified adverse event	804/1078 (74.6%)	4452	814/1081 (75.3%)	4380
Infections and infestations
Other, unspecified infection	765/1078 (71%)	3285	740/1081 (68.5%)	3226
Injury, poisoning and procedural complications
Accident, not requiring hospitalization	151/1078 (14%)	194	140/1081 (13%)	189
Renal and urinary disorders
Urinary Tract Infection	91/1078 (8.4%)	123	80/1081 (7.4%)	130
Respiratory, thoracic and mediastinal disorders
Upper Respiratory Infection	772/1078 (71.6%)	6206	754/1081 (69.8%)	5952
Pneumonia	93/1078 (8.6%)	119	91/1081 (8.4%)	110
Asthma, other forms of allergy	359/1078 (33.3%)	783	332/1081 (30.7%)	696

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.