Nasal insulin to prevent type 1 diabetes in children with HLA genotypes and autoantibodies conferring increased risk of disease: a double-blind, randomised controlled trial

Autor: Tuula Simell, Olli Simell, Jukka Sipilä, Lotta Haavisto, Satu Simell, Kirsti Näntö-Salonen, A. Kupila, Heikki Hyöty, Mikael Knip, Marja Siltala, Jari Hakalax, Juhani Tuominen, Jorma Ilonen, Sari Korhonen, Anne Hekkala, Risto Erkkola, Heli Siljander, Tiina Salonsaari, Riitta Veijola
Rok vydání: 2008
Předmět:
Zdroj: The Lancet. 372:1746-1755
ISSN: 0140-6736
DOI: 10.1016/s0140-6736(08)61309-4
Popis: Summary Background In mouse models of diabetes, prophylactic administration of insulin reduced incidence of the disease. We investigated whether administration of nasal insulin decreased the incidence of type 1 diabetes, in children with HLA genotypes and autoantibodies increasing the risk of the disease. Methods At three university hospitals in Turku, Oulu, and Tampere (Finland), we analysed cord blood samples of 116 720 consecutively born infants, and 3430 of their siblings, for the HLA-DQB1 susceptibility alleles for type 1 diabetes. 17 397 infants and 1613 siblings had increased genetic risk, of whom 11 225 and 1574, respectively, consented to screening of diabetes-associated autoantibodies at every 3–12 months. In a double-blind trial, we randomly assigned 224 infants and 40 siblings positive for two or more autoantibodies, in consecutive samples, to receive short-acting human insulin (1 unit/kg; n=115 and n=22) or placebo (n=109 and n=18) once a day intranasally. We used a restricted randomisation, stratified by site, with permuted blocks of size two. Primary endpoint was diagnosis of diabetes. Analysis was by intention to treat. The study was terminated early because insulin had no beneficial effect. This study is registered with ClinicalTrials.gov, number NCT00223613. Findings Median duration of the intervention was 1·8 years (range 0–9·7). Diabetes was diagnosed in 49 index children randomised to receive insulin, and in 47 randomised to placebo (hazard ratio [HR] 1·14; 95% CI 0·73–1·77). 42 and 38 of these children, respectively, continued treatment until diagnosis, with yearly rates of diabetes onset of 16·8% (95% CI 11·7–21·9) and 15·3% (10·5–20·2). Seven siblings were diagnosed with diabetes in the insulin group, versus six in the placebo group (HR 1·93; 0·56–6·77). In all randomised children, diabetes was diagnosed in 56 in the insulin group, and 53 in the placebo group (HR 0·98; 0·67–1·43, p=0·91). Interpretation In children with HLA-conferred susceptibility to diabetes, administration of nasal insulin, started soon after detection of autoantibodies, could not be shown to prevent or delay type 1 diabetes. Funding International: Juvenile Diabetes Research Foundation International; European Union; Novo Nordisk Foundation. Finland: Academy of Finland; TEKES National Technology Agency of Finland; Special Research Funds for University Hospitals in Finland; Finnish Office for Health Technology Assessment; Diabetes Research Foundation, Finland; Sigrid Juselius Foundation; Emil Aaltonen Foundation; Jalmari and Rauha Ahokas Foundation; Signe and Ane Gyllenberg Foundation; the Research Foundation of Orion Corporation; Foundation for Pediatric Research; Paivikki and Sakari Sohlberg Foundation.
Databáze: OpenAIRE
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