| Outcome Measures: |
Primary: The activation of an immune response (antibody or CD4+ T cell) against insulin., The responses are as previously defined in the Pre-POINT study (JAMA 313:1541-9). An antibody response is defined as serum IAA positivity in the competitive immuno-precipitation assay, an increase from baseline (\>10 cpm) in serum IgG binding to insulin, or a positive salivary IgA binding to insulin. A CD4+ T cell response is defined as a stimulation index \>3 and a \>2-fold increase from stimulation index at baseline. A positive response (responder) will be defined as a child with an antibody or T cell response to insulin at any time point during treatment. The number of responders in the insulin treated group will be compared with the number of responders in the placebo treated group., change from baseline (visit 1) in CD4+ T cell response measured as a stimulation index at 3 months (visit 2) and 6 months (visit 3) of treatment | Other: Hypoglycemia, Metabolic changes within two hours after receiving study drug. This will be performed at the first administration of intranasal insulin or placebo at baseline, 3 months and 6 months of treatment (visit 1, visit 2, and visit 3). At these visits, blood glucose concentrations will be measured at 0 minutes, 30 minutes, 60 minutes, and 120 minutes after receiving study drug to determine whether the treatment induces hypoglycaemia which is defined as \<50 mg/dl., Measured at baseline (visit 1) and at each subsequent visit at 3 months (visit 2) and 6 months (visit 3) of treatment.|GAD, IA-2 and ZnT8 autoantibodies, The purpose is to detect seroconversion to islet autoantibody positive. Measurements are performed using a radiobinding immunoprecipitation assay. Frequency of confirmed positive autoantibody results (i.e. autoantibody positive in two consecutive serum samples) will be compared between placebo vs. insulin treated children, Measured at baseline and at 3 months, 6 months.|Gene expression analysis of single cells., The gene expression of the insulin responsive cells will be compared between the placebo and study drug treated children using different multivariable gene expression analysis methods (for instance Stochastic Neighbor Embedding (tSNE) analysis)., baseline, 3 months and 6 months|FOXP3/IFNG signature ratio, The FOXP3 signature/IFNG signature ratio of the insulin responsive cells will be compared between the placebo and study drug treated children., baseline, 3 months and 6 months|Change in IgG-IAA, The change from baseline in IgG-IAA measured by radio-binding assay will be compared between placebo and study drug treated children., baseline, 3 months and 6 months|Antibody responses, Antibody responses will be compared between placebo and study drug treated children using time to event analyses., baseline,3 months and 6 months|CD4+ T cells responses to insulin, CD4+ T cells responses to insulin will be compared between placebo and study drug treated children using time to event analyses., baseline, 3 months and 6 months|CD4+ T cells responses to pre-proinsulin peptides, CD4+ T cells responses to pre-proinsulin peptides will be compared between placebo and study drug treated children using time to event analyses., change from baseline to 3 months and 6 months|CD8+ T cell responses to insulin, CD8+ T cell responses to insulin using the definition for CD4+ T cells as defined above will be compared between placebo and study drug treated children using time to event analyses., baseline, 3 months and 6 months|CD8+ T cells responses to pre-proinsulin peptides, CD8+ T cells responses to pre-proinsulin peptides will be compared between placebo and study drug treated children using time to event analyses., baseline, 3 months and 6 months|T cell and monocyte populations, Peripheral blood T cell and monocyte populations will be compared between placebo and study drug treated children., baseline, 3 months and 6 months|Plasma inflammatory markers, Plasma inflammatory markers will be compared between placebo and study drug treated children.Therefore, the Olink Target 96 Inflammation protein biomarker panel is used. An overview of all 92 biomarkers can be seen on the following homepage: https://www.olink.com/products/inflammation/, baseline, 3 months and 6 months|Transcriptome of peripheral blood cell populations, If available, transcriptome of peripheral blood cell populations will be compared between placebo and study drug treated children., baseline, 3 months and 6 months
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| Locations: |
Klinik und Poliklinik für Kinder und Jugendmedizin, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, Fetscherstraße 74, 01307 Dresden, Germany, Dresden, 01307, Germany|Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Lehrstuhl für Diabetes und Gestationsdiabetes der Technischen Universität München, München, 80804, Germany
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