Clinical trial NCT00570102: Nutritional Prevention Pilot Trial for Type 1 Diabetes
Official title: Trial to Reduce IDDM in the Genetically at Risk (TRIGR): the Pilot Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Type 1 Diabetes Mellitus
Keywords: dietary manipulation
infants
feasibility
Type 1 Diabetes Mellitus, Beta-cell Autoimmunity
Lead sponsor: University of Helsinki
Sponsor class: OTHER
Collaborators: name: Academy of Finland
name: European Union
name: Juvenile Diabetes Research Foundation
name: Diabetes Research Foundation, Finland
name: Novo Nordisk A/S
First posted: 2007-12-10
Enrollment: 230
Sex: ALL
Minimum age (years): 1
Maximum age (years): 7
Standard ages: CHILD
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: The overall objective of the study is to assess whether complete avoidance of cow's milk (CM) proteins, for at least the first 6 months of life, prevents type 1 diabetes (insulin-dependent diabetes mellitus, IDDM) in genetically susceptible children who have a mother, biological father or sibling affected by type 1 diabetes.

Detailed description: Among the environmental factors leading to type 1 diabetes in childhood, the most important are certain viral infections and possibly some dietary factors. Among the latter cow's milk proteins are of special interest. They have been shown to be involved in the pancreatic beta-cell lesion in animal experiments. In humans there are some indications of a role of early exposure to cow's milk proteins as a risk factor for later type 1 diabetes. The hypothesis has not been confirmed, but a randomized, controlled double-blinded intervention trial should provide a definite answer.

This study aims at assessing whether one can decrease the future incidence of beta-cell autoimmunity and/or type 1 diabetes in children who have an increased genetic risk for the disease, by administering in infancy after breast feeding until the age of 6-8 months such a formula, in which the cow's milk proteins have been hydrolyzed to smaller peptides. The children in the control group, carrying a similar increased genetic risk, will receive a conventional cow's milk based formula .

This project is a pilot multicenter trial comprising 15 hospitals in Finland.

Eligibility criteria: Inclusion Criteria:

* the participant must have a mother, biological father or sibling with type 1 diabetes
* the participant must carry a susceptible HLA genotype(HLA-DQB1\*02 and/or DQB1\*0302 without protective alleles (DQB1\*0301, \*0602 and \*0603)

Exclusion Criteria:

* no telephone
* no accessibility to any of the research centers
* inability of parents to understand the study and instructions
* unwillingness/inability to feed the infant CM-containing food for any reason (e.g. religious, cultural reasons)
* gestational age less than 36 weeks
* Any severe illness such as chromosomal abnormalities, congenital malformations, respiratory failure, enzyme deficiencies of the newborn.
* the newborn infant has received any cow's milk-based product prior to randomization

Primary outcomes:
measure: Positivity for two or more diabetes-associated autoantibodies and/or clinical type 1 diabetes
timeFrame: 10 years
Secondary outcomes:
Other outcomes:
Locations:
city: Espoo
country: Finland
facility: Jorvi Hospital
city: Helsinki
country: Finland
facility: University of Helsinki, Department of Obstetrics and Gynecology
city: Helsinki
country: Finland
facility: National Public Health Institute
city: Helsinki
country: Finland
facility: Helsinki University Hospital, Maternity Hospital
city: Helsinki
country: Finland
facility: University of Helsinki, Hospital for Children and Adolescents
city: Hämeenlinna
country: Finland
facility: Kanta-Häme Central Hospital, Department of Pediatrics
city: Joensuu
country: Finland
facility: North Karelia Central Hospital
city: Jyväskylä
country: Finland
facility: Central Finland Central Hospital
city: Kotka
country: Finland
facility: Kymenlaakso Central Hospital, Department of Pediatrics
city: Kuopio
country: Finland
facility: University of Kuopio, Department of Pediatrics
city: Lahti
country: Finland
facility: Päijät-Häme Central Hospital
city: Lappeenranta
country: Finland
facility: South Karelia Central Hospital
city: Oulu
country: Finland
facility: University of Oulu, Department of Pediatrics
city: Pori
country: Finland
facility: Satakunta Central Hospital
city: Seinäjoki
country: Finland
facility: South Ostrobothnia Central Hospital
city: Tampere
country: Finland
facility: Tampere University Hospital, Department of Pediatrics
city: Turku
country: Finland
facility: University of Turku, Department of Virology
city: Vaasa
country: Finland
facility: Vaasa Central Hospital
Study officials:
affiliation: University of Helsinki, Helsinki, Finland
name: Hans K Åkerlom, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Akerblom HK, Savilahti E, Saukkonen TT, Paganus A, Virtanen SM, Teramo K, Knip M, Ilonen J, Reijonen H, Karjalainen J, et al. The case for elimination of cow's milk in early infancy in the prevention of type 1 diabetes: the Finnish experience. Diabetes Metab Rev. 1993 Dec;9(4):269-78. doi: 10.1002/dmr.5610090407. No abstract available.
citation: Akerblom HK, Knip M. Putative environmental factors in Type 1 diabetes. Diabetes Metab Rev. 1998 Mar;14(1):31-67. doi: 10.1002/(sici)1099-0895(199803)14:13.0.co;2-a.
citation: Knip M, Akerblom HK. IDDM prevention trials in progress--a critical assessment. J Pediatr Endocrinol Metab. 1998 Apr;11 Suppl 2:371-7. No abstract available.
citation: Knip M, Akerblom HK. Environmental factors in the pathogenesis of type 1 diabetes mellitus. Exp Clin Endocrinol Diabetes. 1999;107 Suppl 3:S93-100. doi: 10.1055/s-0029-1212160.
citation: Vaarala O, Hyoty H, Akerblom HK. Environmental factors in the aetiology of childhood diabetes. Diabetes Nutr Metab. 1999 Apr;12(2):75-85. No abstract available.
citation: Akerblom HK, Vaarala O, Hyoty H, Ilonen J, Knip M. Environmental factors in the etiology of type 1 diabetes. Am J Med Genet. 2002 May 30;115(1):18-29. doi: 10.1002/ajmg.10340.
citation: Knip M, Akerblom HK. Early nutrition and later diabetes risk. Adv Exp Med Biol. 2005;569:142-50. doi: 10.1007/1-4020-3535-7_21.
citation: Knip M, Veijola R, Virtanen SM, Hyoty H, Vaarala O, Akerblom HK. Environmental triggers and determinants of type 1 diabetes. Diabetes. 2005 Dec;54 Suppl 2:S125-36. doi: 10.2337/diabetes.54.suppl_2.s125.
citation: Paronen J, Knip M, Savilahti E, Virtanen SM, Ilonen J, Akerblom HK, Vaarala O. Effect of cow's milk exposure and maternal type 1 diabetes on cellular and humoral immunization to dietary insulin in infants at genetic risk for type 1 diabetes. Finnish Trial to Reduce IDDM in the Genetically at Risk Study Group. Diabetes. 2000 Oct;49(10):1657-65. doi: 10.2337/diabetes.49.10.1657.
citation: Hamalainen AM, Ronkainen MS, Akerblom HK, Knip M. Postnatal elimination of transplacentally acquired disease-associated antibodies in infants born to families with type 1 diabetes. The Finnish TRIGR Study Group. Trial to Reduce IDDM in the Genetically at Risk. J Clin Endocrinol Metab. 2000 Nov;85(11):4249-53. doi: 10.1210/jcem.85.11.6987.
citation: Ronkainen MS, Hamalainen AM, Koskela P, Akerblom HK, Knip M; Finnish Trigr Study Group. Pregnancy induces nonimmunoglobulin insulin-binding activity in both maternal and cord blood serum. Clin Exp Immunol. 2001 May;124(2):190-6. doi: 10.1046/j.1365-2249.2001.01506.x.
citation: Hamalainen AM, Savola K, Kulmala PK, Koskela P, Akerblom HK, Knip M; Finnish TRIGR Study Group. Disease-associated autoantibodies during pregnancy and at birth in families affected by type 1 diabetes. Clin Exp Immunol. 2001 Nov;126(2):230-5. doi: 10.1046/j.1365-2249.2001.01676.x.
citation: Sadeharju K, Hamalainen AM, Knip M, Lonnrot M, Koskela P, Virtanen SM, Ilonen J, Akerblom HK, Hyoty H; Finnish TRIGR Study Group. Enterovirus infections as a risk factor for type I diabetes: virus analyses in a dietary intervention trial. Clin Exp Immunol. 2003 May;132(2):271-7. doi: 10.1046/j.1365-2249.2003.02147.x.
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: Tiittanen M, Paronen J, Savilahti E, Virtanen SM, Ilonen J, Knip M, Akerblom HK, Vaarala O; Finnish TRIGR Study Group. Dietary insulin as an immunogen and tolerogen. Pediatr Allergy Immunol. 2006 Nov;17(7):538-43. doi: 10.1111/j.1399-3038.2006.00447.x.
citation: Sadeharju K, Knip M, Virtanen SM, Savilahti E, Tauriainen S, Koskela P, Akerblom HK, Hyoty H; Finnish TRIGR Study Group. Maternal antibodies in breast milk protect the child from enterovirus infections. Pediatrics. 2007 May;119(5):941-6. doi: 10.1542/peds.2006-0780.
citation: Knip M, Virtanen SM, Seppa K, Ilonen J, Savilahti E, Vaarala O, Reunanen A, Teramo K, Hamalainen AM, Paronen J, Dosch HM, Hakulinen T, Akerblom HK; Finnish TRIGR Study Group. Dietary intervention in infancy and later signs of beta-cell autoimmunity. N Engl J Med. 2010 Nov 11;363(20):1900-8. doi: 10.1056/NEJMoa1004809.
citation: Hyytinen M, Savilahti E, Virtanen SM, Harkonen T, Ilonen J, Luopajarvi K, Uibo R, Vaarala O, Akerblom HK, Knip M; Finnish TRIGR Pilot Study Group. Avoidance of Cow's Milk-Based Formula for At-Risk Infants Does Not Reduce Development of Celiac Disease: A Randomized Controlled Trial. Gastroenterology. 2017 Oct;153(4):961-970.e3. doi: 10.1053/j.gastro.2017.06.049. Epub 2017 Jul 5.
citation: de Goffau MC, Luopajarvi K, Knip M, Ilonen J, Ruohtula T, Harkonen T, Orivuori L, Hakala S, Welling GW, Harmsen HJ, Vaarala O. Fecal microbiota composition differs between children with beta-cell autoimmunity and those without. Diabetes. 2013 Apr;62(4):1238-44. doi: 10.2337/db12-0526. Epub 2012 Dec 28.