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.

Centre Hospitalier de Luxembourg Luxembourg City Luxembourg

Charles University 3rd Faculty of Medicine Prague Czech Republic

Children's Hospital of Eastern Ontario Ottawa Ontario Canada

Children's Hospital of Westmead Sydney Australia

Cruces University Hospital UPV EHU CIBERDEM CIBERER Barakaldo Spain

Helsinki University Hospital Helsinki Finland

Kinder und Jugendkrankenhaus Auf Der Bult Hannover Germany

Linköping University Linköping Sweden

Medical University of Wroclaw Wroclaw Poland

National Institute of Health and Welfare Helsinki Finland

Respiratory Inflammation and Autoimmunity Innovative Medicine AstraZeneca Gothenburg Sweden

Semmelweis Medical University Budapest Hungary

Sophia Children's Hospital Rotterdam the Netherlands

Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders Madrid Spain

St Michelle Hospital Azienda Ospedaliera Brotzu Diabetes Unit Cagliari Italy

Tartu University Tartu Estonia

Université de Sherbrooke Sherbrooke Quebec Canada

University Campus Bio Medico of Rome Rome Italy

University Children's Hospital Zürich Zürich Switzerland

University of Helsinki Helsinki Finland

University of Manitoba Winnipeg Manitoba Canada

University of Pittsburgh Pittsburgh Pennsylvania

University of South Florida Tampa

University of Toronto Toronto Ontario Canada

University of Turku and Turku University Hospital Turku Finland

University of Washington Seattle

University of Western Ontario London Ontario Canada

Washington University School of Medicine St Louis Missouri

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Neglected Facts on Mycobacterium Avium Subspecies Paratuberculosis and Type 1 Diabetes

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ClinicalTrials.gov
NCT00179777, NCT00179777