Mikael Knip1,2, Hans K Åkerblom1, Eva Al Taji3, Dorothy Becker4, Jan Bruining5, Luis Castano6, Thomas Danne7, Carine de Beaufort8, Hans-Michael Dosch9, John Dupre10, William D Fraser11, Neville Howard12, Jorma Ilonen13, Daniel Konrad14, Olga Kordonouri7, Jeffrey P Krischer15, Margaret L Lawson16, Johnny Ludvigsson17, Laszlo Madacsy18, Jeffrey L Mahon10, Anne Ormisson19, Jerry P Palmer20, Paolo Pozzilli21, Erkki Savilahti1, Manuel Serrano-Rios22, Marco Songini23, Shayne Taback24, Outi Vaarala1,25, Neil H White26, Suvi M Virtanen27, Renata Wasikowa28. 1. University of Helsinki, Helsinki, Finland. 2. Helsinki University Hospital, Helsinki, Finland. 3. Charles University, 3rd Faculty of Medicine, Prague, Czech Republic. 4. University of Pittsburgh, Pittsburgh, Pennsylvania. 5. Sophia Children's Hospital, Rotterdam, the Netherlands. 6. Cruces University Hospital-UPV/EHU-CIBERDEM/CIBERER, Barakaldo, Spain. 7. Kinder-und Jugendkrankenhaus Auf Der Bult, Hannover, Germany. 8. Centre Hospitalier de Luxembourg, Luxembourg City, Luxembourg. 9. University of Toronto, Toronto, Ontario, Canada. 10. University of Western Ontario, London, Ontario, Canada. 11. Université de Sherbrooke, Sherbrooke, Quebec, Canada. 12. Children's Hospital of Westmead, Sydney, Australia. 13. University of Turku and Turku University Hospital, Turku, Finland. 14. University Children's Hospital Zürich, Zürich, Switzerland. 15. University of South Florida, Tampa. 16. Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada. 17. Linköping University, Linköping, Sweden. 18. Semmelweis Medical University, Budapest, Hungary. 19. Tartu University, Tartu, Estonia. 20. University of Washington, Seattle. 21. University Campus Bio-Medico of Rome, Rome, Italy. 22. Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain. 23. St Michelle Hospital /Azienda Ospedaliera Brotzu-Diabetes Unit, Cagliari, Italy. 24. University of Manitoba, Winnipeg, Manitoba, Canada. 25. Respiratory, Inflammation and Autoimmunity, Innovative Medicine, AstraZeneca, Gothenburg, Sweden. 26. Washington University School of Medicine, St Louis, Missouri. 27. National Institute of Health and Welfare, Helsinki, Finland. 28. Medical University of Wroclaw, Wroclaw, Poland.
Abstract
Importance: Early exposure to complex dietary proteins may increase the risk of type 1 diabetes in children with genetic disease susceptibility. There are no intact proteins in extensively hydrolyzed formulas. Objective: To test the hypothesis that weaning to an extensively hydrolyzed formula decreases the cumulative incidence of type 1 diabetes in young children. Design, Setting, and Participants: An international double-blind randomized clinical trial of 2159 infants with human leukocyte antigen-conferred disease susceptibility and a first-degree relative with type 1 diabetes recruited from May 2002 to January 2007 in 78 study centers in 15 countries; 1081 were randomized to be weaned to the extensively hydrolyzed casein formula and 1078 to a conventional formula. The follow-up of the participants ended on February 28, 2017. Interventions: The participants received either a casein hydrolysate or a conventional adapted cow's milk formula supplemented with 20% of the casein hydrolysate. The minimum duration of study formula exposure was 60 days by 6 to 8 months of age. Main Outcomes and Measures: Primary outcome was type 1 diabetes diagnosed according to World Health Organization criteria. Secondary outcomes included age at diabetes diagnosis and safety (adverse events). Results: Among 2159 newborn infants (1021 female [47.3%]) who were randomized, 1744 (80.8%) completed the trial. The participants were observed for a median of 11.5 years (quartile [Q] 1-Q3, 10.2-12.8). The absolute risk of type 1 diabetes was 8.4% among those randomized to the casein hydrolysate (n = 91) vs 7.6% among those randomized to the conventional formula (n = 82) (difference, 0.8% [95% CI, -1.6% to 3.2%]). The hazard ratio for type 1 diabetes adjusted for human leukocyte antigen risk group, duration of breastfeeding, duration of study formula consumption, sex, and region while treating study center as a random effect was 1.1 (95% CI, 0.8 to 1.5; P = .46). The median age at diagnosis of type 1 diabetes was similar in the 2 groups (6.0 years [Q1-Q3, 3.1-8.9] vs 5.8 years [Q1-Q3, 2.6-9.1]; difference, 0.2 years [95% CI, -0.9 to 1.2]). Upper respiratory infections were the most common adverse event reported (frequency, 0.48 events/year in the hydrolysate group and 0.50 events/year in the control group). Conclusions and Relevance: Among infants at risk for type 1 diabetes, weaning to a hydrolyzed formula compared with a conventional formula did not reduce the cumulative incidence of type 1 diabetes after median follow-up for 11.5 years. These findings do not support a need to revise the dietary recommendations for infants at risk for type 1 diabetes. Trial Registration: clinicaltrials.gov Identifier: NCT00179777.
RCT Entities:
Importance: Early exposure to complex dietary proteins may increase the risk of type 1 diabetes in children with genetic disease susceptibility. There are no intact proteins in extensively hydrolyzed formulas. Objective: To test the hypothesis that weaning to an extensively hydrolyzed formula decreases the cumulative incidence of type 1 diabetes in young children. Design, Setting, and Participants: An international double-blind randomized clinical trial of 2159 infants with human leukocyte antigen-conferred disease susceptibility and a first-degree relative with type 1 diabetes recruited from May 2002 to January 2007 in 78 study centers in 15 countries; 1081 were randomized to be weaned to the extensively hydrolyzed casein formula and 1078 to a conventional formula. The follow-up of the participants ended on February 28, 2017. Interventions: The participants received either a casein hydrolysate or a conventional adapted cow's milk formula supplemented with 20% of the casein hydrolysate. The minimum duration of study formula exposure was 60 days by 6 to 8 months of age. Main Outcomes and Measures: Primary outcome was type 1 diabetes diagnosed according to World Health Organization criteria. Secondary outcomes included age at diabetes diagnosis and safety (adverse events). Results: Among 2159 newborn infants (1021 female [47.3%]) who were randomized, 1744 (80.8%) completed the trial. The participants were observed for a median of 11.5 years (quartile [Q] 1-Q3, 10.2-12.8). The absolute risk of type 1 diabetes was 8.4% among those randomized to the casein hydrolysate (n = 91) vs 7.6% among those randomized to the conventional formula (n = 82) (difference, 0.8% [95% CI, -1.6% to 3.2%]). The hazard ratio for type 1 diabetes adjusted for human leukocyte antigen risk group, duration of breastfeeding, duration of study formula consumption, sex, and region while treating study center as a random effect was 1.1 (95% CI, 0.8 to 1.5; P = .46). The median age at diagnosis of type 1 diabetes was similar in the 2 groups (6.0 years [Q1-Q3, 3.1-8.9] vs 5.8 years [Q1-Q3, 2.6-9.1]; difference, 0.2 years [95% CI, -0.9 to 1.2]). Upper respiratory infections were the most common adverse event reported (frequency, 0.48 events/year in the hydrolysate group and 0.50 events/year in the control group). Conclusions and Relevance: Among infants at risk for type 1 diabetes, weaning to a hydrolyzed formula compared with a conventional formula did not reduce the cumulative incidence of type 1 diabetes after median follow-up for 11.5 years. These findings do not support a need to revise the dietary recommendations for infants at risk for type 1 diabetes. Trial Registration: clinicaltrials.gov Identifier: NCT00179777.
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